Conditions: Pulmonary Arterial Hypertension Hypertension, Pulmonary
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 168
Healthy volunteers: no

Brief summary:
This is a two-part (Phase 2/Phase 3) study of frespaciguat, an inhaled soluble guanylate cyclase stimulator, in participants with pulmonary arterial hypertension (PAH).

The first part (Phase 2) will assess three different doses of frespaciguat compared to placebo in a base period of 12 weeks, followed by comparison of three different doses of frespaciguat during an optional 40 month extension period. The treatment dose with the best efficacy and safety profile in the phase 2 cohort base period will be selected for use in the second part (Phase 3) of the study. The primary hypothesis of Phase 2 is that at least one frespaciguat dose is superior to placebo in reducing pulmonary vascular resistance (PVR) from baseline at week 12.

The purpose of the second part (Phase 3) of the study is to confirm the efficacy, safety, and tolerability of frespaciguat at the selected dose compared to placebo during a 12 week base period followed by an extension period of up to 5 years. The primary hypothesis of Phase 3 is that frespaciguat is superior to placebo in increasing 6-minute walk distance (6MWD) from baseline at week 12. Due to sponsor's decision this phase/part was not conducted.

Detailed description:

Arms:
arm 1: Participants receive frespaciguat 380 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period. arm 2: Participants receive frespaciguat 100 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period. arm 3: Participants receive frespaciguat 32 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period. arm 4: Participants receive placebo via oral inhalation once daily for 12 week base period, and one of the MK-5475 doses (380, 100, or 32 µg) for the optional 40 month extension period. arm 5: Participants receive one of 3 frespaciguat doses (380, 100 or 32 µg) to be selected at end of the Phase 2 Cohort, administered via oral inhalation once daily for 12-week base period and up to 40 months in the extension period arm 6: Participants receive placebo via oral inhalation once daily for 12 week base period and up to 40 months in the extension period.

Interventions: intervention 1: Frespaciguat intervention 2: Placebo to Frespaciguat
Intervention descriptions: intervention 1: Frespaciguat (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation intervention 2: Placebo administered as dry powder inhalation

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
NCT04732221
Document Date:
07-NOV-2023
A Phase 2/3, Multicenter, Randomized, Double-
blind, Placebo-Controlled, Adaptive Design 
Study to Evaluate the Efficacy and Safety of 
MK-5475 in Adults with Pulmonary Arterial 
Hypertension


PRODUCT: MK-5475
1
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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 2/3, Multicenter, Randomized, Double-blind, Placebo-Controlled, 
Adaptive Design Study to Evaluate the Efficacy and Safety of MK-5475 in Adults with 
Pulmonary Arterial Hypertension
Protocol Number: 007-03
Compound Number: MK-5475
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
04732221
EU CT
2022-500877-15
EudraCT
2020-001108-40
JRCT
Not applicable
WHO
Not applicable
UTN
U1111-1278-4977
IND
149503
Approval Date: 07 November 2023
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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 3
07-NOV-2023
Amended to 1) extend the duration of the Phase 2 
Cohort Extension Period to allow participants 
continued access to study intervention; and 2) add 
a provision to collapse all treatment groups in the 
Phase 2 Cohort Extension Period to a single dose 
group after selection of the Phase 3 dose.
Amendment 2
18-OCT-2022
Amended to add an interim analysis for the 
Phase 2 Cohort Base Period.
Amendment 1
17-MAR-2022
Amended to add a blinded Extension Period to 
the Phase 2 Cohort, to evaluate the longer-term 
safety and tolerability of MK-5475.
Original Protocol
13-NOV-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendment:
This protocol was amended to 1) extend the duration of the Phase 2 Cohort Extension Period
to allow participants continued access to study intervention; and 2) add a provision to 
collapse all treatment groups in the Phase 2 Cohort Extension Period to a single dose group 
after selection of the Phase 3 dose.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reasons for Amendment
Section 1.1, Synopsis
Duration of the Phase 2 Cohort 
Extension Period extended by 
16 months.
To allow participants continued access to study 
intervention.
Section 1.2, Schema
Section 1.3.1, Phase 2 Cohort 
Schedule of Activities
Section 4.1, Overall Design
Section 6.1, Study 
Intervention(s) Administered
Section 1.1, Synopsis
Provision added to collapse all 
treatment groups into a single 
group for the remainder of the 
Phase 2 Cohort Extension Period 
after the Phase 3 dose is selected.
To permit Phase 2 participants to receive the 
selected Phase 3 dose.
Section 1.2, Schema
Section 2.1, Study Rationale
Section 4.1, Overall Design
Section 6.1, Study 
Intervention(s) Administered
Section 6.3.1, Intervention 
Assignment
Section 6.6, Dose 
Modification
Section 9.1, Statistical 
Analysis Plan Summary
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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 relevant changes and their primary 
reasons are included for completeness.
Title Page
Regulatory Agency identifying 
numbers updated.
To comply with current industry regulations and 
guidelines.
Section 1.2, Schema
Phase 2 Cohort Extension Period 
scheduled visit frequency updated.
To align with updated information about the 
stability of MK-5475.
Section 1.3, Schedule of 
Activities
Clinic in-person visit guidance 
updated.
To clarify that clinic in-person visits may be 
replaced by telephone, video, or home visits 
using site staff or a nursing service after 
consultation with the Sponsor.
Option for home delivery of study 
intervention added.
To prevent study intervention interruption during 
exceptional situations.
Reference to Appendix 7 for 
country-specific requirements 
added.
To align with country-specific pregnancy testing 
requirements.
Section 1.3.1 Phase 2 Cohort 
Schedule of Activities
Phase 2 Cohort Extension Period 
scheduled visit frequency updated.
Refer to Section 1.2 rationale regarding 
scheduled visit frequency.
Section 4.4.1, Clinical Criteria 
for Early Study Termination
Criteria for early study termination 
updated.
To clarify that early study termination of both 
the Phase 2 and/or Phase 3 cohorts may be the 
result of the Sponsor’s plan to modify or 
discontinue the development of MK-5475 in 
PAH.
Section 5.1, Inclusion Criteria
Contraception requirements 
updated.
New data available.
Section 6.2.2, Handling, 
Storage, and Accountability
Option for home delivery of study 
intervention added.
Refer to Section 1.3 rationale regarding optional 
home delivery.
Section 8, STUDY 
ASSESSMENTS AND 
PROCEDURES
Clinic in-person visit guidance 
updated.
Refer to Section 1.3 rationale regarding
replacement of clinic in-person visits.
Section 8.1.8.4, Dispense 
Double-blind Study 
Intervention
Phase 2 Cohort Extension Period 
scheduled visit frequency updated.
Refer to Section 1.2 rationale regarding 
scheduled visit frequency.
Section 8.3.7, Pregnancy 
Testing
Reference to Appendix 7 for 
country-specific requirements
added.
Refer to Section 1.3 rationale regarding country-
specific pregnancy testing requirements.
Section 8.4.4, Regulatory 
Requirements for SAEs
Reference to Appendix 7 for 
country-specific requirements 
added.
To clarify that notification to the Sponsor of 
SAEs and AESIs must occur immediately 
without exceeding 24 hours.
Section 8.11.4, Treatment 
Period
Phase 2 Cohort Extension Period 
scheduled visit frequency updated.
Refer to Section 1.2 rationale regarding stability 
of MK-5475.
Clinic in-person visit guidance 
updated.
Refer to Section 1.3 rationale regarding
replacement of clinic in-person visits.
Section 9.7, Interim Analyses
Futility analysis plan corrected.
To correct typographical errors.
Section 10.5.2, Contraceptive 
Requirements
Contraception requirements 
updated.
New data available.
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Section Number and Name
Description of Change
Brief Rationale
Section 10.7, Appendix 7: 
Country-specific 
Requirements
Country-specific requirements 
added.
Refer to Section 1.3 rationale regarding country-
specific pregnancy testing requirements and 
Section 8.4.4 rationale regarding regulatory 
requirements for SAEs and AESIs.
Section 10.8, Appendix 8: 
Approximate Blood Volume 
Tables, Table 11
Phase 2 Cohort Extension Period 
scheduled visit frequency updated.
Refer to Section 1.2 rationale regarding 
scheduled visit frequency.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical 
changes were made.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................20
2
INTRODUCTION..........................................................................................................35
2.1
Study Rationale....................................................................................................35
2.2
Background ..........................................................................................................35
2.2.1
Pharmaceutical and Therapeutic Background .............................................36
2.2.2
Preclinical and Clinical Studies ...................................................................37
2.2.3
Information on Other Study-related Therapy ..............................................39
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................41
4
STUDY DESIGN............................................................................................................44
4.1
Overall Design......................................................................................................44
4.2
Scientific Rationale for Study Design.................................................................47
4.2.1
Rationale for Endpoints ...............................................................................47
4.2.1.1
Efficacy Endpoints.............................................................................47
4.2.1.2
Patient-Reported Outcomes ...............................................................49
4.2.1.3
Safety Endpoints................................................................................50
4.2.1.4
Pharmacokinetic Endpoints ...............................................................50
4.2.1.5
Pharmacodynamic Endpoints.............................................................51
4.2.1.6
Planned Exploratory Biomarker Research.........................................51
4.2.1.6.1
Planned Genetic Analysis ........................................................51
4.2.1.7
Future Biomedical Research..............................................................51
4.2.2
Rationale for the Use of Placebo .................................................................51
4.3
Justification for Dose...........................................................................................52
4.4
Beginning and End-of-Study Definition ............................................................54
4.4.1
Clinical Criteria for Early Study Termination .............................................54
5
STUDY POPULATION ................................................................................................55
5.1
Inclusion Criteria.................................................................................................55
5.2
Exclusion Criteria................................................................................................58
5.3
Lifestyle Considerations......................................................................................61
5.3.1
Caffeine, Alcohol, and Tobacco Restrictions ..............................................61
CCI
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5.3.2
Activity Restrictions ....................................................................................61
5.4
Screen Failures.....................................................................................................61
5.5
Participant Replacement Strategy......................................................................61
6
STUDY INTERVENTION............................................................................................62
6.1
Study Intervention(s) Administered...................................................................62
6.2
Preparation/Handling/Storage/Accountability .................................................65
6.2.1
Dose Preparation..........................................................................................65
6.2.2
Handling, Storage, and Accountability........................................................65
6.3
Measures to Minimize Bias: Randomization and Blinding..............................66
6.3.1
Intervention Assignment..............................................................................66
6.3.2
Stratification.................................................................................................66
6.3.3
Blinding........................................................................................................66
6.4
Study Intervention Compliance..........................................................................67
6.5
Concomitant Therapy..........................................................................................67
6.5.1
Rescue Medications and Supportive Care ...................................................68
6.6
Dose Modification ................................................................................................68
6.7
Intervention After the End of the Study............................................................69
6.8
Clinical Supplies Disclosure................................................................................69
6.9
Standard Policies..................................................................................................69
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................70
7.1
Discontinuation of Study Intervention...............................................................70
7.2
Participant Withdrawal From the Study...........................................................71
7.3
Lost to Follow-up .................................................................................................71
8
STUDY ASSESSMENTS AND PROCEDURES........................................................72
8.1
Administrative and General Procedures ...........................................................72
8.1.1
Informed Consent.........................................................................................72
8.1.1.1
General Informed Consent.................................................................73
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................73
8.1.2
Inclusion/Exclusion Criteria ........................................................................73
8.1.3
Participant Identification Card.....................................................................73
8.1.4
Medical History ...........................................................................................74
8.1.5
Prior and Concomitant Medications Review...............................................74
8.1.5.1
Prior Medications...............................................................................74
8.1.5.2
Concomitant Medications..................................................................74
8.1.6
Assignment of Screening Number...............................................................74
8.1.7
Assignment of Treatment/Randomization Number.....................................74
8.1.8
Study Intervention Administration ..............................................................75
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8.1.8.1
Timing of Dose Administration.........................................................75
8.1.8.2
Dry Powder Inhaler Use Training......................................................75
8.1.8.3
Witnessed Dosing ..............................................................................76
8.1.8.4
Dispense Double-blind Study Intervention........................................76
8.1.8.5
Dispense/Review Participant Dosing Diary.......................................76
8.1.8.6
Investigational Product Compliance and Accountability ..................76
8.1.8.7
Telephone Contact Between Study Visits..........................................77
8.1.9
Discontinuation and Withdrawal .................................................................77
8.1.9.1
Withdrawal From Future Biomedical Research ................................77
8.1.10
Participant Blinding/Unblinding..................................................................77
8.1.11
Calibration of Equipment.............................................................................78
8.2
Efficacy Assessments ...........................................................................................79
8.2.1
Right Heart Catheterization .........................................................................79
8.2.2
6-Minute Walk Test .....................................................................................79
8.2.3
WHO Functional Class ................................................................................80
8.2.4
NT-proBNP..................................................................................................80
8.2.5
Patient-reported Outcomes...........................................................................80
.........................................................................81
8.3
Safety Assessments...............................................................................................81
8.3.1
Physical Examinations.................................................................................82
8.3.2
Body Weight................................................................................................82
8.3.3
Vital Signs....................................................................................................82
8.3.4
Pulmonary Function Testing and DLCO.....................................................82
8.3.5
Electrocardiograms ......................................................................................83
8.3.6
Clinical Safety Laboratory Assessments .....................................................83
8.3.7
Pregnancy Testing........................................................................................84
8.3.8
Vital Status Assessment...............................................................................84
8.3.9
AE Monitoring.............................................................................................84
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................85
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................85
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......87
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...87
8.4.4
Regulatory Reporting Requirements for SAE .............................................87
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................87
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................88
8.4.7
Events of Clinical Interest............................................................................88
CCI
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8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions......................................................................................88
8.5
Treatment of Overdose........................................................................................89
8.6
Pharmacokinetics.................................................................................................89
8.6.1
Blood Collection for Plasma MK-5475 .......................................................89
8.7
Pharmacodynamics..............................................................................................90
8.8
Biomarkers ...........................................................................................................91
8.8.1
Planned Genetic Analysis Sample Collection..............................................91
8.9
Future Biomedical Research Sample Collection...............................................91
8.10
Health Economics Medical Resource Utilization and Health Economics.......91
8.11
Visit Requirements...............................................................................................91
8.11.1
Scheduling the Visits ...................................................................................92
8.11.2
Screening......................................................................................................92
8.11.3
Randomization.............................................................................................94
8.11.4
Treatment Period..........................................................................................95
8.11.5
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................96
8.11.6
Final Visit.....................................................................................................97
8.11.7
Follow-up Visit............................................................................................97
9
STATISTICAL ANALYSIS PLAN .............................................................................98
9.1
Statistical Analysis Plan Summary.....................................................................98
9.2
Responsibility for Analyses/In-house Blinding ...............................................100
9.3
Hypotheses/Estimation ......................................................................................101
9.4
Analysis Endpoints.............................................................................................101
9.4.1
Phase 2 Cohort Efficacy Endpoints ...........................................................101
9.4.2
Phase 3 Cohort Efficacy Endpoints ...........................................................102
9.4.3
Safety Endpoints........................................................................................102
9.4.4
Derivations of Efficacy Endpoints.............................................................103
9.5
Analysis Populations..........................................................................................103
9.5.1
Efficacy Analysis Population.....................................................................103
9.5.2
Safety Analysis Population........................................................................103
9.6
Statistical Methods.............................................................................................104
9.6.1
Statistical Methods for Efficacy Analyses.................................................104
9.6.1.1
Phase 2 Cohort.................................................................................104
9.6.1.2
Phase 3 Cohort.................................................................................107
9.6.2
Analysis Methods for Safety Analyses......................................................109
9.6.2.1
Overall Safety Assessment ..............................................................110
9.6.3
Summaries of Demographic and Baseline Characteristics ........................111
9.7
Interim Analyses ................................................................................................112
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9.8
Multiplicity .........................................................................................................114
9.9
Sample Size and Power Calculations ...............................................................114
9.9.1
Efficacy......................................................................................................114
9.10
Subgroup Analyses.............................................................................................115
9.11
Compliance (Medication Adherence)...............................................................116
9.12
Extent of Exposure.............................................................................................116
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................117
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......117
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................117
10.1.2
Financial Disclosure...................................................................................120
10.1.3
Data Protection...........................................................................................121
10.1.3.1
Confidentiality of Data ....................................................................121
10.1.3.2
Confidentiality of Participant Records.............................................121
10.1.3.3
Confidentiality of IRB/IEC Information..........................................122
10.1.4
Committees Structure.................................................................................122
10.1.4.1
Executive Oversight Committee......................................................122
10.1.4.2
Steering Committee .........................................................................122
10.1.4.3
External Data Monitoring Committee .............................................122
10.1.4.4
Clinical Adjudication Committee (CAC) ........................................123
10.1.5
Publication Policy......................................................................................123
10.1.6
Compliance with Study Registration and Results Posting Requirements .124
10.1.7
Compliance with Law, Audit, and Debarment ..........................................124
10.1.8
Data Quality Assurance .............................................................................125
10.1.9
Source Documents .....................................................................................126
10.1.10
Study and Site Closure...............................................................................126
10.2
Appendix 2: Clinical Laboratory Tests............................................................127
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................129
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................129
10.3.2
Definition of AE ........................................................................................129
10.3.3
Definition of SAE ......................................................................................130
10.3.4
Additional Events Reported.......................................................................131
10.3.5
Recording AE and SAE .............................................................................131
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................134
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................136
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10.4.1
Definitions..................................................................................................136
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ..137
10.5
Appendix 5: Contraceptive Guidance..............................................................138
10.5.1
Definitions..................................................................................................138
10.5.2
Contraceptive Requirements......................................................................139
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................140
10.7
Appendix 7: Country-specific Requirements..................................................144
10.7.1
Argentina-specific Requirements...............................................................144
10.7.2
France-specific Requirements....................................................................144
10.8
Appendix 8: Approximate Blood Volume Tables ...........................................145
10.9
Appendix 9: Abbreviations ...............................................................................147
11
REFERENCES.............................................................................................................152
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LIST OF TABLES
 
52
Table 2
Study Interventions..........................................................................................63
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................86
Table 4
Participant Re-randomization Probability in the Phase 2 Cohort Extension 
Period...............................................................................................................94
Table 5
Analysis Strategy for Primary and Secondary Efficacy Endpoints in the 
Phase 2 Cohort...............................................................................................107
Table 6
Analysis Strategy for Primary and Secondary Efficacy Endpoints in the 
Phase 3 Cohort...............................................................................................109
Table 7
Analysis Strategy for Safety Parameters........................................................111
Table 8
Power to Demonstrate Superiority of MK-5475 vs placebo on the Primary 
Endpoint of % Change in PVR in Phase 2 Cohort Base Period at the 
Interim Analysis.............................................................................................112
.....................113
Table 10
Protocol-required Laboratory Assessments...................................................127
Table 11
Phase 2 Cohort Approximate Blood Volumes Drawn/Collected by Trial 
Visit and by Sample Types ............................................................................145
Table 12
Phase 3 Cohort Approximate Blood Volumes Drawn/Collected by Trial 
Visit and by Sample Types ............................................................................146
CCI
CCI
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LIST OF FIGURES
Figure 1
Study Design – Phase 2 Cohort .......................................................................20
Figure 2
Study Design – Phase 3 Cohort .......................................................................21
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-Controlled, 
Adaptive Design Study to Evaluate the Efficacy and Safety of MK-5475 in Adults with 
Pulmonary Arterial Hypertension
Short Title: Phase 2/3 Study of MK-5475 in Adults with Pulmonary Arterial Hypertension
Acronym: INSIGNIA-PAH
Hypotheses, Objectives, and Endpoints:
This study will be carried out in 2 parts, a Phase 2 dose selection cohort and a Phase 3 
confirmatory cohort. Each cohort includes a Base Period and an Extension Period.
In men and women aged 18 to 75 years (inclusive) with pulmonary arterial hypertension 
(PAH):
Primary Objectives
Primary Endpoints
Phase 2 Cohort – to evaluate the effect of 
MK-5475 versus placebo on the pulmonary 
vascular resistance (PVR) at Week 12.
Hypothesis: at least one MK-5475 dose is 
superior to placebo in reducing PVR from 
baseline at Week 12.
PVR (centrally assessed)
Phase 3 Cohort – to evaluate the effect of 
MK-5475 versus placebo on 6-minute walk 
distance (6MWD) at Week 12.
Hypothesis: MK-5475 is superior to placebo 
in increasing 6MWD from baseline at 
Week 12.
6MWD
Secondary Objectives
Secondary Endpoints
Phase 2 Cohort - to evaluate the effect of 
MK-5475 versus placebo on 6MWD at 
Week 12.
6MWD
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Phase 2 Cohort - to evaluate the effect of 
MK-5475 versus placebo on hemodynamic 
parameters other than PVR at Week 12.
-Mean right arterial pressure (mRAP)
-Cardiac index
-Stroke volume index (SVI)
Phase 3 Cohort – to evaluate the effect of 
MK-5475 versus placebo on 6MWD at 
Week 24.
6MWD
Phase 3 Cohort - to evaluate the effect of 
MK-5475 versus placebo on the WHO 
functional PAH class at Week 12.
WHO functional class
Phase 2 and Phase 3 Cohorts 
(independently) – to evaluate the safety 
and tolerability of MK-5475.
-Adverse Events (AEs)
-Discontinuation of study intervention due 
to AEs
Overall Design:
Study Phase
Phase 2/3
Primary Purpose
Treatment
Indication
Pulmonary arterial hypertension
Population
Men and women aged 18 to 75 years 
(inclusive) with PAH.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 6 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.
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Number of Participants:
Approximately 450 participants will be randomized in this operationally seamless adaptive 
Phase 2/3 study. Approximately 164 participants will be randomized in the Phase 2 dose 
selection cohort and approximately 286 participants will be randomized in the Phase 3 
confirmatory cohort.
Intervention Groups and Duration:
In the Phase 2 Cohort Base Period, participants will be randomized in a 1:1:1:1 ratio to once-
daily dosing with 1 of 3 doses of MK-5475 (380 μg, 100 μg, or 32 μg) or placebo. In the 
Phase 2 Cohort Extension Period, the participants who received placebo during the Base 
Period will initially be assigned randomly in a 1:1:1 ratio to 1 of the 3 doses of MK-5475 
(380 μg, 100 μg, or 32 μg) and will be given new randomization numbers. Participants who 
received MK-5475 during the Base Period will initially receive the same MK-5475 doses in 
the Extension Period and will be assigned new randomization numbers, to maintain the study 
blinding. 
After selection of the MK-5475 dose for Phase 3, the 3 MK-5475 dose groups in the Phase 2 
Cohort Extension Period will be collapsed into a single dose group for the remainder of the 
Phase 2 Cohort Extension Period.
In the Phase 3 Cohort, participants will be randomized in a 1:1 ratio to once-daily dosing
with either placebo or one of the 3 doses of MK-5475 selected in the Phase 2 Cohort Base 
Period.
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
Phase 2 Cohort 
Group 1
MK-5475
380 µg
380 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and for ~40 months 
Extension Period
Test 
Product
Phase 2 Cohort 
Group 2
MK-5475
100 µg
100 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and for ~40 months 
Extension Period
Test 
Product
Phase 2 Cohort 
Group 3
MK-5475
32 µg
32 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and for ~40 months 
Extension Period
Test 
Product
Phase 2 Cohort 
Group 4
Placebo
0 µg
0 µg
Inhalation
Oral inhalation once 
daily for 12 weeks
Base Period
Placebo
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Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
Phase 2 Cohort 
Group 4a 
(before Phase 3 
dose selection)
MK-5475
380 µg
380 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
Phase 2 Cohort 
Group 4b 
(before Phase 3 
dose selection)
MK-5475
100 µg
100 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
Phase 2 Cohort 
Group 4c 
(before Phase 3 
dose selection)
MK-5475
32 µg
32 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
Phase 2 Cohort 
Group 4a, 4b, & 
4c (after 
Phase 3 dose 
selection)
MK-5475
380 µg OR 
100 µg OR 
32 µg
380 µg 
OR 
100 µg 
OR 
32 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
Phase 3 Cohort 
Group 1
MK-5475
380 µg OR 
100 µg OR 
32 µg
380 µg 
OR 
100 µg 
OR 
32 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and up to 60-month 
Extension Period
Test 
Product
Phase 3 Cohort 
Group 2
Placebo
0 µg
0 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and up to 60-month 
Extension Period
Placebo
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Total Number of 
Intervention Groups/Arms
Phase 2 Cohort Base Period - 4 treatment groups
Phase 2 Cohort Extension Period - 3 treatment groups
Phase 3 Cohort Base and Extension Periods - 2 treatment 
groups
Duration of Participation
Each participant will take part in the trial from the time the 
participant provides documented informed consent through 
the final contact. Participants eligible for enrollment in the 
Phase 2 Cohort Extension Period will be required to provide 
documented informed consent for that study period.
Phase 2 Cohort: After a screening period of up to 28 days, 
each eligible participant will be randomized to receive
assigned double-blind study intervention for 12 weeks in 
the Base Period. The participants who complete the Base 
Period and provide documented informed consent will be 
re-randomized to continue treatment in an ~40-month 
Extension Period. The participants who discontinue study 
intervention or complete the Base Period before 
Amendment 01 is approved and the Extension Period 
becomes available are not eligible to enroll in the Extension 
Period.
Phase 3 Cohort: After a screening period of up to 28 days, 
each eligible participant will be randomized to receive 
assigned double-blind study intervention for 12 weeks in 
the Base Period and then will continue treatment in an 
Extension Period of up to 5 years.
A telephone follow-up visit will occur 14 days after the last 
study visit, for adverse event monitoring.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1. The Data Monitoring 
Committee for this study is external to the Sponsor.
Study Accepts Healthy Participants: No
A list of abbreviations used in this document can be found in Appendix 9.
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1.2
Schema
The study design for Phase 2 Cohort is depicted in Figure 1. The study design for Phase 3 Cohort is depicted in Figure 2.
Figure 1
Study Design – Phase 2 Cohort
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Figure 2
Study Design – Phase 3 Cohort
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2
INTRODUCTION
MK-5475 is a small-molecule stimulator of sGC, formulated as a dry powder for inhaled 
delivery, which is being developed for the treatment of PAH.
2.1
Study Rationale
PAH defines a group of rare, progressive conditions characterized by increased vascular 
resistance in the pulmonary arterial circulation, related to pre-capillary disease. Despite 
substantial progress in PAH management, increased awareness, and multiple PAH-specific 
therapies, the long-term prognosis for PAH patients remains poor and the disease can 
progress to right-sided heart failure and death.
Localized/inhaled delivery of the sGC stimulator MK-5475 is anticipated to provide benefit 
in PAH patients by selectively reducing PVR and pulmonary arterial pressure via 
sGC/cGMP-mediated pulmonary vasodilation, without lowering systemic vascular resistance 
or BP. Inhalation results in MK-5475 delivery to the deepest segments of the lung airways 
(respiratory bronchioles and alveoli). MK-5475 has properties suitable for dry powder 
formulation and delivery and demonstrates pulmonary-selective blood pressure reduction 
following inhalation dosing in an animal model of PAH and participants with PAH. Inhaled 
delivery of MK-5475 is thus expected to have sGC-based effects on endpoints associated 
with PAH, while minimizing systemic sGC pharmacology. 
The purpose of this multicenter, randomized, placebo-controlled, double-blind Phase 2/3 
operationally seamless adaptive study is to evaluate the efficacy, safety, and tolerability of 
MK-5475 in participants with PAH. This study will be carried out in 2 parts. The first part is 
a Phase 2 dose selection cohort which includes a 12-week Base Period followed by a blinded
treatment Extension Period, to further inform on the safety and tolerability of MK-5475.
Initially, responses to the 3 different doses of MK-5475, compared to placebo, will be 
assessed in the Phase 2 Cohort Base Period. After selection of the MK-5475 dose for 
Phase 3, the 3 MK-5475 dose groups in the Phase 2 Cohort Extension Period will be 
collapsed into a single dose group for the remainder of the Phase 2 Cohort Extension Period.
The treatment dose with the best efficacy and safety profile in the Phase 2 Cohort Base 
Period will be evaluated in the subsequent Phase 3 confirmatory cohort.
The design is operationally seamless adaptive; of the 3 doses studied in the Phase 2 Cohort, a 
single dose of interest will be evaluated in the Phase 3 Cohort. In the Phase 3 Cohort of this 
operationally seamless adaptive Phase 2/3 study, the 12-week Base Period will be followed 
by a blinded treatment Extension Period, to further inform on the safety and efficacy of
MK-5475 in this population.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-5475.
Pulmonary hypertension is a chronic disorder of the pulmonary circulation characterized by 
increased PVR, ultimately leading to right ventricular failure and death. The Updated 
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Clinical Classification of Pulmonary Hypertension (Nice, 2018) [Simonneau, G., et al 2019]
classifies the numerous conditions that are known to lead to, or to be associated with, the 
development of PH into 5 groups, based on their similar clinical presentation, pathology, 
pathophysiology, prognosis, and therapeutic approach. PAH, or Group 1 PH, may occur in 
the absence of a demonstrable cause or known triggering factor (idiopathic PAH, Group 1.1),
in the context of familial history of PAH or a gene mutation known to be associated with 
PAH (heritable PAH, Group 1.2), as the result of the use of drugs and toxins (Group 1.3), or
associated with various conditions including connective tissue diseases, HIV infection, portal 
hypertension, and congenital heart disease (Group 1.4). PAH in long-term responders to 
calcium channel blockers (Group 1.5), PAH with venous/capillary involvement (Group 1.6), 
and persistent PH of the newborn (Group 1.7) are less frequent pre-capillary PH forms, also 
included in Group 1, but with a distinct clinical presentation, prognosis, and treatment.
The epidemiology of PAH displays some variation, probably related to selection biases. The
incidence of adult PAH is estimated to be 2.3 cases per million in the United States [Frost, A. 
E., et al 2011]. European registry data revealed an estimated incidence of PAH ranging from
2.4 to 7.6 cases per million [Swinnen, K., et al 2019] [Frost, A. E., et al 2011]. Estimated
PAH prevalence rate ranges from 6.6 to 291 per million in the US [Kirson, N. Y., et al 2011] 
[Dubroff, J., et al 2020] [Fenstad, E. R., et al 2019] [Frost, A. E., et al 2011] and from 6.6 to 
52 per million in 4 European countries (France, Scotland, United Kingdom, and Germany)
[Humbert, M., et al 2006] [Peacock, A. J., et al 2007] [Ling, Y., et al 2012] [Hoeper, M. M., 
et al 2016]. Both old and contemporary registries have shown that PAH predominantly 
affects females. The NIH cohort noted that females were 1.8 times more likely to be affected 
by PAH relative to their male counterparts. Both the REVEAL and the French registry found 
the female: male ratio to be 3.6:1 and 1.9:1, respectively [Frost, A. E., et al 2011] [Humbert, 
M., et al 2006].
2.2.1
Pharmaceutical and Therapeutic Background
PAH is caused by pulmonary arterial constriction and obstruction associated with 
proliferative vascular remodeling, formation of plexiform lesions and in situ thrombosis. The 
pathophysiology of PAH involves multiple pathways, which are influenced by many 
overlapping secondary messenger systems. Expression of the vasoconstrictor endothelin is 
increased while production of vasodilators, such as prostacyclin and NO, is decreased. 
Therapies for PAH have sought to achieve vasodilation in the pulmonary arterial circulation
by targeting these 3 specific pathways (the endothelin pathway, the prostacyclin pathway and 
the NO pathway), thus decreasing elevated PVR and lessening right ventricular afterload. 
There are 2 currently approved PAH treatment options which focus on the NO pathway: 
PDE5 inhibitors and the oral sGC stimulator, riociguat. In healthy individuals, endothelial 
cell-derived NO acts on smooth muscle cells to induce vasodilation by increasing production 
of the second messenger cGMP via stimulation of sGC. In PAH, the NO-sGC-cGMP 
pathway is downregulated because of endothelial dysfunction leading to reduced NO 
bioavailability and subsequent relative sGC and cGMP deficiency. PDE5 inhibitors act to 
decrease the degradation of cGMP, whereas the sGC stimulator riociguat acts to increase the 
formation of cGMP; both lead to pulmonary vasodilation. However, in addition to pulmonary 
artery vasodilation, the sGC stimulator riociguat also induces systemic vasodilation, which 
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can result in systemic hypotension and hypotension-related events, poorly tolerated by PAH
patients. Due to activity within the same pathway and increased risk of hypotension, the 
concomitant use of riociguat and PDE5 inhibitors is contraindicated. 
The limitations of nonselective vasodilation in the pulmonary and systemic arteries extends 
to most other commonly prescribed therapies for PAH, such as ERAs and prostacyclin-based 
therapies, which have vasodilatory properties and are administered either orally or 
parenterally. Due to mechanism-based systemic side effects and concerns of hypotension, 
these medications require careful monitoring and dose titration, and their potential to reduce 
PVR in PAH patients may not be fully realized. Based on the current high morbidity and 
mortality rates for PAH patients and based on the side effect and titration profiles of current 
available PAH-specific medication, there is a high unmet medical need for new PAH 
therapies.
Inhaled administration of pulmonary vasodilators represents an attractive alternative to oral 
or parenteral drug therapy, due to direct delivery to the desired site of action, potentially 
increasing pulmonary circulation selectivity and diminishing systemic side effects, such as 
hypotension. MK-5475 is a small-molecule stimulator of sGC, which has been formulated as 
a dry powder for inhaled delivery. An inhaled dry-powder sGC stimulator is hypothesized to 
avoid most of the side effects associated with systemically administered vasodilators and to 
allow coadministration of MK-5475 with other PAH medications, including PDE5 inhibitors. 
Compared with nebulization, inhalation of dry powder microparticles is faster and more 
efficient because of the much higher respirable fraction and minimal extrapulmonary drug 
loss. Dry powder inhalers are also convenient and easy to use.
2.2.2
Preclinical and Clinical Studies
 
 
 
 
 
 
 
 
 
 
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2.2.3
Information on Other Study-related Therapy
Not applicable.
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 product.
Potential participants will be informed of the risks and benefits of, as well as alternatives to, 
study participation. At a minimum, participant management and PAH-specific background 
therapy will take into account the local standard of care. 
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By delivering this compound via inhalation, decreased systemic exposure will enable 
therapeutic effect at the site of action while minimizing the potential for adverse effects, such 
as hypotension due to excessive systemic arterial vasodilation.
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
This study will be carried out in 2 parts, a Phase 2 dose selection cohort and a Phase 3 
confirmatory cohort. Each cohort includes a Base Period and an Extension Period.
In men and women aged 18 to 75 years (inclusive) with pulmonary arterial hypertension 
(PAH):
Primary Objectives
Primary Endpoints
Phase 2 Cohort – to evaluate the effect of 
MK-5475 versus placebo on the pulmonary 
vascular resistance (PVR) at Week 12.
Hypothesis: at least one MK-5475 dose is 
superior to placebo in reducing PVR from 
baseline at Week 12.
PVR (centrally assessed)
Phase 3 Cohort – to evaluate the effect of 
MK-5475 versus placebo on 6-minute walk 
distance (6MWD) at Week 12.
Hypothesis: MK-5475 is superior to placebo 
in increasing 6MWD from baseline at 
Week 12.
6MWD
Secondary Objectives
Secondary Endpoints
Phase 2 Cohort - to evaluate the effect of 
MK-5475 versus placebo on 6MWD at 
Week 12.
6MWD
Phase 2 Cohort - to evaluate the effect of 
MK-5475 versus placebo on hemodynamic 
parameters other than PVR at Week 12.
-Mean right arterial pressure (mRAP)
-Cardiac index
-Stroke volume index (SVI)
Phase 3 Cohort – to evaluate the effect of 
MK-5475 versus placebo on 6MWD at 
Week 24.
6MWD
Phase 3 Cohort - to evaluate the effect of 
MK-5475 versus placebo on the WHO 
functional PAH class at Week 12.
WHO functional class
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Phase 2 and Phase 3 Cohorts 
(independently) – to evaluate the safety 
and tolerability of MK-5475.
-Adverse Events (AEs)
-Discontinuation of study intervention due 
to AEs
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4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, randomized, placebo-controlled, parallel-group, double-blind Phase 2/3 
operationally seamless adaptive study to evaluate the efficacy, safety, and tolerability of 
inhaled MK-5475 in participants with PAH. This study will be conducted in conformance 
with GCP principles and will be carried out in 2 parts: a Phase 2 dose selection cohort and a 
Phase 3 confirmatory cohort, each including a 12-week Base Period and an Extension Period.
Participants in both cohorts of this Phase 2/3 study will be adults with PAH (Groups 1.1 to 
1.4), as defined in the Updated Clinical Classification of Pulmonary Hypertension (Nice, 
2018) [Simonneau, G., et al 2019]. The PAH diagnosis must have been established using the 
updated scientific guidelines [Frost, A., et al 2019] and confirmed by a diagnostic RHC 
performed at any time prior to Screening. Participants will not be eligible for the study if they 
have been diagnosed with PH associated with left heart disease (Group 2 PH), lung disease 
(Group 3 PH), pulmonary artery obstructions (Group 4 PH) or PH with unclear and/or 
multifactorial mechanisms (Group 5 PH). All participants will continue to receive their PAH-
specific background therapy during the course of the study.
For both cohorts, during the 28-day screening period (Visit 1), participant study eligibility 
will be assessed based on the demographic, disease diagnostic, hemodynamic, functional, 
echocardiographic, pulmonary function, and prior/concomitant therapy I/E criteria outlined 
in Sections 5.1 and 5.2. Consented participants will complete all Visit 1 procedures, as 
detailed in the SoAs.
Participants meeting all study entry eligibility criteria at Screening may be considered for 
randomization after Sponsor concurrence on key I/E criteria (See Section 8.11.2). Eligibility 
for study participation will be reassessed by the investigator at Randomization (Visit 2) to 
determine if participants continue to meet the I/E criteria and if, between Screening and 
Randomization, they experienced events that would exclude them for participating in the 
study, eg, acutely decompensated right heart failure or changes in PAH-specific therapy.
Participants who have completed or prematurely discontinued the Phase 2 Cohort are not 
eligible to participate in the Phase 3 Cohort.
At Visit 2, participants who meet study eligibility criteria will enter the double-blind 
treatment period, as described below for each cohort.
 
 
Phase 2 Cohort 
In the Phase 2 Cohort Base Period, 3 doses of MK-5475 (380 µg, 100 µg, and 32 µg) will be
compared to placebo. The efficacy, safety, and tolerability of each MK-5475 dose will be 
assessed when all participants in the Phase 2 Cohort Base Period have completed or 
discontinued the 12-week treatment period. An IA for efficacy and futility (nonbinding) is 
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planned when approximately 120 participants have completed or discontinued the Phase 2 
Cohort Base Period. The Phase 2 Cohort Base Period may stop at the IA and a dose for the 
Phase 3 Cohort may be selected at that time OR the study may be stopped early for futility 
(Section 9.7).
The primary objective of the Phase 2 Cohort Base Period is to evaluate the effect of 
MK-5475 versus placebo on PVR in participants with PAH at Week 12. Of the 3 MK-5475 
doses studied, the dose (380 µg, 100 µg, or 32 µg) with the best efficacy and safety profile in 
the Base Period of this cohort will be selected for evaluation in the subsequent Phase 3 
confirmatory cohort, alongside a placebo control group.
Participants who remain on study intervention and complete the Visit 6/Week 12 assessments
(including RHC) may enroll in the ~40-month blinded Extension Period if they satisfy the
SpO2 and seated BP study eligibility criteria (Section 5.2) at Week 12 and provide 
documented informed consent. Participants who discontinue study intervention or complete 
the Phase 2 Cohort Base Period before Amendment 01 is approved and the Extension Period 
becomes available will not be eligible to enroll in the Extension Period.
The objective of the Phase 2 Cohort Extension Period is to evaluate the longer-term safety
and tolerability of the 3 doses of MK-5475 (380 µg, 100 µg, or 32 µg) in this participant 
population.
To supplement the routine blinded trial monitoring outlined in this study, an external DMC 
will monitor the interim data (Section 9.7).
This Phase 2/3 study may be stopped if analysis of the data collected either at the time of the
IA or at the end of the Phase 2 Cohort Base Period shows that none of the MK-5475 doses 
has a desirable efficacy and safety profile.
Participants will take part in the Phase 2 Cohort Base Period for approximately 16 weeks, 
including a screening period of up to 4 weeks and a 12-week double-blind treatment period.
Approximately 164 eligible participants will be randomized in a 1:1:1:1 ratio to MK-5475 
380 µg, MK-5475 100 µg, MK-5475 32 µg, and placebo. Participants will be instructed to 
inhale 1 dose per day, in the morning, for 84 consecutive days. At the end of the 12-week 
treatment period, pulmonary vascular hemodynamics will be assessed via RHC, following 
the same procedures as for the baseline measurements. In the Extension Period, the 
participants who received placebo during the Base Period will initially be assigned randomly 
in a 1:1:1 ratio to once-daily dosing with 1 of the 3 doses of MK-5475 (380 µg, 100 µg, or 
32 µg) and will be given new randomization numbers. The participants who received 
MK-5475 during the Base Period will initially receive the same MK-5475 doses in the 
Extension Period and will be assigned new randomization numbers, to maintain study 
blinding.
After selection of the MK-5475 dose for Phase 3, the 3 MK-5475 dose groups in the Phase 2 
Cohort Extension Period will be collapsed into a single dose group for the remainder of the 
Phase 2 Cohort Extension Period.
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Phase 3 Cohort
In both the Base and the Extension Period of the Phase 3 Cohort, the MK-5475 dose (either 
380 µg, 100 µg, or 32 µg) selected in the Phase 2 Cohort Base Period will be compared to 
placebo. The primary objective for the Base Period of Phase 3 Cohort is to evaluate the effect 
of MK-5475 versus placebo on 6MWD in participants with PAH at Week 12. The Base 
Period will be followed by a double-blind Extension Period, to further inform on the efficacy, 
safety, and tolerability of MK-5475 in this participant population.
In the Phase 3 Cohort Base Period, participants will take part in the study for approximately 
16 weeks, including a screening period of up to 4 weeks and a 12-week double-blind 
treatment period. Approximately 286 eligible participants will be randomized in a 1:1 ratio to 
MK-5475 and placebo. Participants will be instructed to inhale 1 dose per day, in the 
morning, for 84 consecutive days. 6MWD will be measured, using the same procedure as for 
the baseline measurement, every 4 weeks and at the end of Phase 3 Cohort Base Period. All 
participants will continue treatment in an Extension Period until a requisite number of 
clinical worsening events are observed in the Phase 3 Cohort and a second Phase 3 study. 
The second Phase 3 study will be described in a separate protocol. A separate integrated 
analysis plan will be written, providing more details. A CAC, whose members are blinded to 
the study group assignments, will review all reported clinical events and adjudicate the 
clinical events related to clinical worsening (See Appendix 1). 
In both Phase 2 and Phase 3 Cohorts, additional hemodynamic parameters, changes in 
symptoms, biomarkers, and participant self-rated quality-of-life questionnaire scores will be 
used to evaluate response to treatment throughout the study.
Selected members of the Sponsor study team and management will be unblinded to results 
from Phase 2 Cohort Base Period and Phase 3 Cohort Base Period, to evaluate the efficacy 
and safety profile of MK-5475 (Section 9.7). For the Phase 2 Cohort Extension Period and 
Phase 3 Cohort Extension Period, separate blinded Sponsor study teams will monitor the 
ongoing study.
For each cohort, the double-blind treatment period concludes with a final visit. All 
participants will complete a telephone follow-up visit 14 days (+ 2 days) after the final visit, 
for AE monitoring.
AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined in Section 10.3.4. Regular safety assessments will be performed during 
the study (Section 8.3.9).
To supplement the routine trial monitoring outlined in this study, an external DMC will 
monitor interim data (Section 9.7).
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.
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4.2
Scientific Rationale for Study Design
This operationally seamless adaptive Phase 2/3 study is being conducted to evaluate the 
efficacy, safety, and tolerability of MK-5475 for the treatment of PAH, when added to 
PAH-specific background therapy. The conduct of this study is supported by evidence from 
preclinical and clinical studies, in which MK-5475 appeared to be safe and well tolerated, 
and in which proof of concept has been established - single doses of MK-5475 can 
effectively reduce PVR, without inducing systemic hypotension in this patient population. 
The operationally seamless adaptive design, by combining into a single study objectives 
which otherwise would have been evaluated in 2 separate studies, will reduce the 
development timelines while using the same operational infrastructure. The study team will 
select a dose for the Phase 3 Cohort after reviewing all safety and efficacy information 
collected in the Phase 2 Cohort Base Period. Given the severity of the disease and the unmet 
medical need, this study design allows expedited clinical drug development and accelerated 
timeline for potential registration and patient access, while ensuring study integrity [Food 
and Drug Administration 2019].
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Pulmonary Vascular Hemodynamics
PAH is characterized by increased vascular resistance in the pulmonary arterial circulation. 
Hemodynamic measures, such as pulmonary arterial pressure, pulmonary vascular resistance, 
right atrial pressure, and cardiac index, are the cornerstones of diagnosis and risk 
stratification in PAH and play an important role during early drug development, to elucidate 
the mechanism of action and to define the dose-response relationship. Several studies have 
evaluated the prognostic utility of hemodynamic variables after PAH-specific treatment 
initiation [Weatherald, J., et al 2018] [Tiede, H., et al 2013]. Invasive assessment of
pulmonary vascular hemodynamics is a reliable indicator of treatment efficacy and reduction 
in PVR induced by PAH-specific therapies was shown to correlate with improved exercise 
capacity and improved clinical outcomes, supporting the use of PVR as the primary or 
secondary endpoint in Phase 2 studies of investigational PAH therapies as a signal for 
efficacy [Savarese, G., et al 2013]. The variables used for the calculation of PVR, as well as 
other hemodynamic variables, are obtained during RHC. The percent change from baseline in 
PVR at Week 12 will be used as the primary efficacy analysis for the Phase 2 Cohort Base 
Period.
6-Minute Walk Distance
Whereas hemodynamic measures play an important role during the early development of the 
drug, to elucidate the mechanism of action and to define the dose-response relationship in 
Phase 2 studies, Phase 3 efficacy study objectives focus on improving exercise capacity, 
ameliorating symptoms, reducing PAH-related morbidity, and improving QoL. Furthermore, 
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the use of an invasive hemodynamic measurement endpoint, acceptable in a smaller Phase 2 
study, would be challenging in a larger sample Phase 3 study.
The 6MWT is a submaximal exercise test during which the distance walked (6MWD),
oxygen saturation, systemic BP, heart rate, and the degree of dyspnea and fatigue (Borg 
CR10 Scale) are evaluated. The 6MWT provides an indirect estimate of aerobic capacity and 
correlates with pulmonary vascular hemodynamics. In particular, 6MWD is directly 
correlated with cardiac index increase and inversely correlated with PVR decrease [Savarese, 
G., et al 2013]. The use of the change in 6MWD as a primary endpoint in clinical trials is 
based on findings from studies which demonstrated that increases in 6MWD are associated 
with improved clinical outcomes among patients with PAH. A clinically meaningful 6MWD 
increase of 30 to 50 meters is considered predictive of better long-term prognosis and reflects 
positively in patient-important outcomes, such as HRQoL [Mathai, S. C., et al 2012] [Divers, 
C., et al 2017]. Change in 6MWD at Week 12 will be the primary efficacy endpoint of the 
Base Period of the Phase 3 Cohort. The change in 6MWD will be a secondary efficacy 
endpoint for the Phase 2 Cohort Base Period at Week 12 and for the Extension Period of 
Phase 3 Cohort at Week 24, and an exploratory endpoint for the Phase 2 Cohort Extension 
Period at Week 24.
Time to Clinical Worsening 
TTCW is a composite endpoint of morbidity and mortality in a time-to-event analysis
[Sitbon, O., et al 2015] [Pulido, T., et al 2013] [Galie, N., et al 2015]. The components of this 
composite endpoint include death, PAH-related hospitalization, and disease progression.
WHO Functional Class
The WHO classification of functional status is a measure of disease severity, based on a 
patient’s description of their level of functioning and symptoms of disease in relation to their 
everyday activity. Patients are assigned 1 of 4 WHO-FC, dependent on limits of physical 
activity. As WHO-FC increases from I to IV, limits of physical activity increase. WHO-FC is 
a predictor of survival, both before and during treatment [Waxman, A. B. 2015], and remains 
an important part of the ongoing assessment of patients with PAH. Improvement in WHO-FC 
predicts survival independently of PAH cause or time of diagnosis. Furthermore, changes in 
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6MWD correlate with WHO-FC; increases in 6MWD are observed for those who show 
improvement in WHO-FC and decreases in 6MWD are observed for those who show
worsening of WHO-FC [Divers, C., et al 2017]. As such, the effect of MK-5475 on WHO-
FC will be assessed throughout both Phase 2 and Phase 3 Cohorts.
NT-proBNP
The most widely studied biomarker in PAH is brain (B-type) natriuretic peptide, secreted by 
ventricular cardiomyocytes in response to stretching. Serum levels of its N-terminal fragment 
(NT-proBNP) have been correlated with right ventricular function in PAH and high plasma 
levels of NT-proBNP with additional serial increases have a strong independent association 
with mortality [Lewis, R. A., et al 2020]. As such, the effect of MK-5475 on NT-proBNP 
serum level will be assessed during the Phase 2 Cohort up to Week 24 and throughout the 
Phase 3 Cohort.
4.2.1.2
Patient-Reported Outcomes
Physical/functional, emotional and social aspects of HRQoL are negatively impacted by 
PAH. The clinical definition of disease severity, including invasive and noninvasive 
measurements, does not capture the extensive realm of physical, emotional and psychosocial 
issues which affect PAH patients. PAH-targeted therapies produce a variable benefit in 
HRQoL, and some measures of HRQoL may also correlate with survival prognosis. The 
effect of treatment on PROs will be evaluated using a disease-specific QoL questionnaire, the 
LPH questionnaire. Interpretation of the magnitude of change in the LPH questionnaire (total 
and physical dimension) scores will be based on clinically meaningful thresholds estimated 
using the PGI-S and PGI-C questions. The PROs will be assessed during the Phase 2 Cohort
Base Period and throughout the Phase 3 Cohort.
Living With Pulmonary Hypertension (LPH) Questionnaire
A 21-item, disease-specific tool, the LPH questionnaire will assess the impact of PAH on 
HRQoL. Adapted from the Minnesota Living with Heart Failure Questionnaire for use in 
patients with PAH, the LPH questionnaire has demonstrated strong content and psychometric 
validity [Bonner, N., et al 2013]. Participants are asked to recall how their PAH impacted 
their life during the past week. It takes approximately 5 minutes to complete. Response 
options are on a 6-point Likert-type scale ranging from 0 ‘No’ to 5 ’Very much’. A total 
(overall) score is calculated by summing the responses to all questions. A physical dimension 
score and an emotional dimension score can also be calculated [Bonner, N., et al 2013]. A 
higher score indicates that the participants are more affected by their medical condition (ie, 
have worse QoL). The total (overall) and physical dimension scores will be the key PRO 
endpoints in the study, as they have shown to be more responsive to change over time 
compared to the emotional score [Bonner, N., et al 2013].
Patient Global Impression of Change (PGI-C) and Severity (PGI-S)
Considering that minimally important difference thresholds indicating clinically significant 
changes or differences using anchor-based approaches for the LPH questionnaire have not 
yet been established, PGI-C and PGI-S questionnaires will be used to validate clinically 
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meaningful thresholds for the total and physical dimension scores from the LPH 
questionnaire in the study population.
The PGI-C will include 2 single-item questionnaires for assessing overall change in the 
disease and disease-related physical limitations, respectively, compared with the start of 
treatment. Each PGI-C questionnaire contains one question (1a) asking the participant to 
assess the degree of change compared to the start of the treatment using the following 
response options: “much better”, “a little better”, “no change”, “a little worse”, or “much 
worse”. A subsequent question (1b) then asks the participant to indicate whether he/she feels 
the degree of change (improvement or worsening) reported is important or not (yes/no). 
The PGI-S will include 2 single-item questionnaires for assessing the current severity of 
disease and disease-related physical limitations, respectively, using the following response 
options: “None”, “Mild”, “Moderate”, “Severe”, or “Very severe.” 
It is anticipated to take approximately 4 minutes to answer all PGI-C and PGI-S questions. 
Data from these questions will be used to provide anchors for estimating minimally 
important differences in the total and physical dimension scores from the LPH questionnaire.
4.2.1.3
Safety Endpoints
The safety data for MK-5475 to date is described in the IB. General safety and tolerability 
will be evaluated by clinical review of relevant parameters, including AEs, physical
examinations, vital signs (ie, pulse rate, BP, temperature, arterial oxygen saturation, 
respiratory rate), PFTs, 12-lead ECG, laboratory safety tests (blood chemistry, hematology, 
anticoagulation tests, urinalysis, and urine pregnancy testing for all WOCBPs) at prespecified 
time points.
AEs associated with symptomatic hypotension, pulmonary hemorrhage, and hemoptysis are 
prespecified safety topics of interest (See Section 9.6.2.1).
All procedures will be conducted at the time points specified in the SoA. AEs will be 
recorded according to Section 8.4 and assessed as defined in Section 10.3.4.
4.2.1.4
Pharmacokinetic Endpoints
MK-5475 is an inhaled drug being developed for the management of PAH. As with any 
inhaled compound, PK exposures are primarily determined by lung burden, which cannot be 
directly measured. Therefore, the exploratory PK endpoints for this study will consist of 
assessments of systemic AUC0-24 and Cmax. Acknowledging the limitations of these data, they 
will be used for PK modeling to determine systemic exposures and to explore their 
relationship with pharmacodynamic endpoints and systemic hemodynamic measurements. 
PK samples will be collected from all participants as described in the SoA (Section 1.3) and 
Section 8.6.1.
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4.2.1.5
Pharmacodynamic Endpoints
Reduction in PVR is being employed as the primary pharmacodynamic endpoint in the 
Phase 2 Cohort Base Period. This measurement directly reflects disease severity and 
response to therapy, as it incorporates measurements of pulmonary vasoconstriction 
(pulmonary artery pressure) and cardiac performance (cardiac output), in the context of a 
well-established relationship between PVR and the clinical endpoint of 6MWD.
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in 
Appendix 6.
4.2.2
Rationale for the Use of Placebo
The placebo control group is an essential arm in this study, as it supports the evaluation of 
the safety and efficacy of MK-5475 in adult participants with PAH. The efficacy profile of a 
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new agent is best characterized by comparison to placebo. Similarly, the safety profile of any 
drug is best characterized versus placebo, to facilitate an unbiased assessment of safety and 
tolerability. Participants receiving placebo during the study will continue to receive their 
background PAH-specific therapy.
4.3
Justification for Dose
Inhaled administration of pulmonary vasodilators represents an attractive alternative to oral 
or parenteral therapy, due to direct delivery to the desired site of action, potentially 
increasing pulmonary circulation selectivity and diminishing systemic side effects, such as 
hypotension. Inhaled MK-5475 has been evaluated in 5 completed and 3 ongoing Phase 1 
clinical studies. Based on data from these studies, inhaled MK-5475 is generally well
tolerated when administered as single or multiple inhaled doses of up to 380 µg in healthy 
adult participants, and when administered as a single inhaled dose of up to 480 µg in adult 
participants with PAH.
The 3 dose levels are selected to provide data to characterize the exposure-response 
relationship that will inform dose selection for the Phase 3 Cohort of this study and future 
studies. 
 
 
 
 
 
 
 
 
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The proposed doses will be administered once per day; the regimens were selected based on 
the following considerations:

Data from Study PN002 at single nominal doses of 120, 240, and 360 µg in 23 PAH 
participants with RHC, showing mean peak reduction in PVR from baseline of 
approximately 26%, with no clear relationship between the magnitude of PVR reduction 
and the evaluated doses.

Data from Study PN002 at single nominal doses of 120, 240, and 360 µg in 23 PAH 
participants with functional respiratory imaging, showing maximal pulmonary blood 
volume increase from baseline at 8 hours postdose of approximately 5%, with generally 
no clear relationship between pulmonary blood volume change and the evaluated doses, 
except that significant pulmonary blood volume increase was observed at 24 hours 
postdose only with the 360 µg dose. 

Based on in vitro data, MK-5475 dissociates slowly in the MK-5475-sGC complex, with 
an estimated
 for the complex. In addition, a 
 
 
 

Based on data from Study PN002 across dose levels evaluated with RHC (up to 360 µg), 
there was no evidence of decreasing systolic BP or increasing heart rate with increasing 
plasma MK-5475 concentration, supporting that a minimal systemic hemodynamic effect 
is expected following inhaled MK-5475 administration at doses up to 360 µg.

Data from Study PN008 showed that MK-5475 plasma exposure following 
administration using the single-actuation inhaler at 380 µg and 100 µg was generally 
within the predefined PK comparability bounds of the multiple-actuation Phase 1 inhaler 
at the 360 (6 x 60) µg dose and the 120 (2 x 60) µg dose, respectively.
Based on all the considerations, the top dose selected for the Phase 2 Cohort of this study is 
380 µg. A low dose of 32 µg is selected for evaluation in the Phase 2 Cohort, to expand the 
exposure-response dataset that can be used to inform dose selection for the Phase 3 Cohort 
and for future studies and to define a minimally efficacious dose. The 32 µg inhaler 
formulated for the Phase 2/3 study is the lowest feasible strength that can be developed using 
a conventional formulation. The mid dose of 100 µg is selected for evaluation in the Phase 2 
Cohort based on minimal overlap of plasma exposures from that at the high dose at 380 µg
and the low dose at 32 µg. 
Participant response to the 3 different doses of MK-5475 (32 µg, 100 µg, and 380 µg) will be 
assessed in the Phase 2 Cohort Base Period. Of these, the treatment dose that shows the best 
efficacy, as assessed by pulmonary vascular hemodynamics, no evidence of clinically 
meaningful systemic hypotension, and overall favorable safety profile will be selected for the 
subsequent Phase 3 Cohort.
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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.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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.
Early study termination of both the Phase 2 and/or Phase 3 cohorts may be the result of the 
Sponsor’s plan to modify or discontinue the development of MK-5475 in PAH.
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5
STUDY POPULATION
Adult participants with PAH will be enrolled in this study. All I/E criteria apply to both 
Phase 2 and Phase 3 Cohorts, except where specified.
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. Has the following PAH groups, as defined by the Updated Clinical Classification of 
Pulmonary Hypertension (Nice, 2018) [Simonneau, G., et al 2019]:
a.
Group 1.1
Idiopathic PAH
b. Group 1.2
Heritable PAH
c.
Group 1.3
Drug and toxin-induced PAH
d. Group 1.4
PAH associated with:

Connective tissue disease

HIV infection

Simple repaired congenital systemic-to-pulmonary shunt (atrial septal defect, 
ventricular septal defect, patent ductus arteriosus) with persistent PH ≥1 year after 
surgical repair and with no clinically significant residual shunt.
2. Has a diagnosis of PAH performed as standard of care, per scientific guidelines, and 
documented by historical RHC at any time prior to Screening; if participant is 
postsurgical repair of systemic-to-pulmonary shunt, diagnostic RHC must have been 
performed at least 1 year after surgery.
3. Has an eligibility RHC, meeting all the following criteria: 

mean pulmonary artery pressure (mPAP) ≥25 mmHg

PVR of ≥3 Wood units

PCWP or LVEDP ≤15 mmHg.
For the Phase 2 Cohort, the eligibility RHC should be performed during Screening and 
will be centrally reviewed. A participant with RHC performed 
prior to 
Visit 1/Screening may have the RHC results submitted for central review and, if deemed 
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adequate, the RHC may count as baseline. In each case, the RHC should be performed 
after at 
.
For the Phase 3 Cohort, an RHC performed 
 prior to Visit 1/Screening 
may count for eligibility assessment. An RHC will be performed during Screening if an 
RHC performed 
 prior to Visit 1/Screening is not available.
4. Has WHO-FC symptoms Class II to IV.
5. Has two 6MWD measurements between 150 and 500 meters, 1 at Screening and 1 at 
Randomization. The relative difference between the 2 measurements (ie, absolute 
difference/mean) must be ≤15%. If the relative difference between the two 6MWD 
measurements is >15%, the Randomization 6MWT may be repeated after at least 4 hours.
If the relative difference between the 2 Randomization 6MWD measurements is ≤15%, 
the participant can be randomized and the last 6MWD will be considered the baseline 
value.
6. Has stable concomitant background PAH-specific therapy
 
 
 with any of the following agents:

an ERA and/or

a PDE5i and/or

an oral prostacyclin analogue or oral prostacyclin receptor agonist (eg, oral 
beraprost, oral treprostinil, oral selexipag), an intravenous prostacyclin analogue
(eg, IV treprostinil, IV epoprostenol, IV iloprost) or a subcutaneous prostacyclin 
analogue (eg, SC treprostinil).
7. If on vasodilators other than PAH-specific therapy (including calcium channel blockers 
or L-arginine supplementation), has stable concomitant use (no change in dose for at least 
 to and over the duration of Screening).
8. If on calcium channel blockers, a participant from Groups 1.1, 1.2, and 1.3 must have a 
history of being a nonresponder to acute pulmonary vasoreactivity testing.
9. If on anticoagulants, has stable concomitant use (the same dosage of direct oral 
anticoagulants and in the same therapeutic range for vitamin K antagonists) for at 
 
to and over the duration of Screening.
Demographics
10. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent.
11. Has a BMI between 18.5 kg/m2 and 40 kg/m2.
12. Is willing to comply with scheduled visits, treatment plan, laboratory tests, and/or other 
study procedures and study restrictions (see Section 5.3 for a complete summary of study 
restrictions).
13. Agrees to allowing site contact via phone or email for follow-up purposes.
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Male Participants
14. There are no contraception requirements for male participants.
Female Participants
15. A female participant is eligible to participate if not pregnant or breastfeeding, and at least 
one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and:
-
Uses an acceptable contraceptive method, 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 14 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 
WOCBPs 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.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) 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 8.3.7.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a WOCBP with an early 
undetected pregnancy.
Informed Consent
16. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. A supplemental documented informed consent/assent is 
required for participation in the Phase 2 Cohort Extension Period. The participant may 
also provide consent/assent for future biomedical research. However, the participant may 
participate in the main study without participating in future biomedical research.
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Additional Categories
17. Sponsor concurrence on key criteria must be obtained before the participant is 
randomized into the study.
Notes:

Procedures performed as standard of care for PAH (clinical assessments, diagnostic 
investigations) prior to and during Screening may be used to determine eligibility. 

The investigator must provide the required supporting documentation (eg, specific 
information about a participant’s medical history and prior hemodynamic diagnosis of 
PAH) to the Sponsor, to support participant’s eligibility for participation in the study.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Has Group 2 PH, Group 3 PH (including PH associated with idiopathic interstitial 
pneumonia), Group 4 PH, or Group 5 PH according to the Updated Clinical 
Classification of Pulmonary Hypertension (Nice, 2018) [Simonneau, G., et al 2019].
2. Has Group 1.5 PAH, long-term responders to calcium channel blockers, defined by 
sustained clinical improvement to WHO-FC I or II and sustained hemodynamic 
improvement after at least 1 year on CCBs only.
3. Has Group 1.6 PAH, with overt features of venous/capillary (PVOD/PCH) involvement. 
4. For participants with Group 1.4 HIV-associated PAH, has any of the following within 
90 days prior to and for the duration of Screening: 

concomitant active opportunistic infections; 

plasma HIV-1 RNA ≥50 copies/mL or CD4+ T-cell count <200/mm3; 

changes in antiretroviral regimen.
5. Has evidence of more-than-mild obstructive lung disease on PFT at Screening with
FEV1/FVC <70% and FEV1 <60% of predicted value after bronchodilator 
administration.
6. Has evidence of more-than-mild parenchymal lung disease based on medical history and 
chest imaging (eg, high-resolution CT), and/or restrictive lung disease with Total Lung 
Capacity (TLC) <60% of predicted on PFT at Screening. 
7. Has evidence of more-than-mild OSA that is untreated. Participants with well-controlled, 
treated OSA are eligible.
8. Has evidence or history of left heart disease, including any of the following:

left ventricular ejection fraction (LVEF) ≤45%; 
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
moderate or severe left-sided valvular disease (aortic or mitral valve stenosis or 
regurgitation); 

Grade 3 and 4 left ventricular diastolic function on echocardiographic evaluation.
A historical transthoracic Doppler echocardiogram performed 
 prior to 
Screening is acceptable to demonstrate echocardiographic eligibility criteria. If a 
historical echocardiogram is not available, a transthoracic Doppler echocardiogram will 
be performed during Screening.
9. Has 3 or more of the following risk factors for heart failure with preserved ejection 
fraction: 

BMI >30 kg/m2; 

history of essential systemic hypertension; 

diabetes mellitus of any type; 

history of coronary artery disease established by any of the following: history of 
stable angina, history of myocardial infarction, previous or planned percutaneous 
coronary intervention or coronary artery bypass graft, angiographic evidence of 
significant coronary artery disease (>70% stenosis in more than 1 vessel), positive 
stress test.
10. Has oxygen saturation measured by pulse oximetry (SpO2) <90%, despite supplemental 
oxygen therapy. In case the accuracy of oxygen saturation measurement by pulse 
oximetry is unreliable, arterial blood gas sampling (SaO2) should be performed.
11. Had clinically unstable or acutely decompensated right heart failure within 30 days prior 
to and over the duration of Screening including, but not limited to, hospitalization or 
emergency room visit for acute decompensated heart failure.
12. Has seated systolic BP >160 mmHg or <90 mmHg or seated diastolic BP >100 mmHg.
13. Has significant chronic renal insufficiency, as defined by eGFR <30 mL/min/1.73 m2
(calculated using the MDRD equation) or by ongoing dialytic support.
14. Has evidence of chronic liver disease (ie, Child-Pugh B or C), portal hypertension, 
cirrhosis, or hepatic laboratory abnormalities (ALT or AST ≥3 times the ULN or total 
bilirubin ≥2 x ULN).
15. Is included in a cardiopulmonary rehabilitation program initiated within 90 days prior to 
Screening or is planning to initiate cardiopulmonary rehabilitation during the study.
16. Has acute or chronic impairment(s) (other than dyspnea), limiting the ability to perform 
6MWT.
17. Is a current smoker or currently uses electronic cigarettes (vapes). 
18. Is unable to correctly use the DPI prior to randomization due to, but not limited to, 
cognitive impairment or physical limitations.
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19. Has other severe acute or chronic medical or laboratory abnormality that may increase 
the risk associated with study participation or that would confound study analysis or 
impair study participation or cooperation.
20. Has a history of cancer (malignancy). Exceptions: (1) Adequately treated 
nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or; (2) Other 
malignancies which have been successfully treated, with appropriate follow-up, and 
therefore unlikely to recur for the duration of the study, in the opinion of the investigator 
(eg, malignancies which have been successfully treated ≥5 years prior to Screening).
21. Has a known hypersensitivity to any of the ingredients or excipients of the IMP.
22. At the time of signing the informed consent, is a user of illicit drugs or has had a recent 
history (within the last year) of drug or alcohol abuse or dependence.
23. Has a known psychiatric or any other cognitive disorder that would, in the opinion of the 
investigator, interfere with the participant’s ability to cooperate with the requirements of 
the study.
24. Is a WOCBP who has a positive urine pregnancy test within 24 hours before the first dose 
of study intervention (see Appendix 5). If the urine test cannot be confirmed as negative, 
a serum pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
Prior/Concomitant Therapy
25. Has used intravenous inotropes including, but not limited to levosimendan, dopamine, 
dobutamine, epinephrine, norepinephrine, noradrenaline or milrinone within 30 days 
prior to and over the duration of Screening.
26. Has concomitant use of inhaled prostacyclin analogues (eg, inhaled iloprost, inhaled 
epoprostenol or inhaled treprostinil), inhaled NO, or oral sGC modulators (eg, riociguat, 
vericiguat), or has used these medications within 90 days prior to and over the duration of 
Screening.
Prior/Concurrent Clinical Study Experience
27. Has participated in another investigational study 
 
 prior to Screening. This window will be derived from the date of 
the last dose of study medication taken in the previous study. Participants enrolled in 
observational studies may be included and will be reviewed on a case-by-case basis for 
approval by the Sponsor.
28. For Phase 2 Cohort Extension Period: has not completed Visit 6/Week 12 study 
assessments, as listed in the SoA.
29. For Phase 2 Cohort Extension Period: has discontinued study intervention or completed 
the Phase 2 Cohort Base Period before Amendment 01 was approved and the Extension 
Period became available.
30. For Phase 3 Cohort enrollment: is currently participating in, has prematurely
discontinued, or has completed the Phase 2 Cohort.
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Other Exclusions
31. 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.
5.3
Lifestyle Considerations
No restrictions are required.
5.3.1
Caffeine, Alcohol, and Tobacco Restrictions
No caffeine or alcohol restrictions are required. Use of tobacco products will not be allowed 
for the duration of the study. Tobacco use will be assessed as indicated in the SoA 
(Section 1.3).
5.3.2
Activity Restrictions
Participants will be advised to abstain from strenuous exercise before each study visit 
requiring blood collection for clinical laboratory tests, as NT-proBNP may be affected by 
recent exercise. Similarly, NT-proBNP plasma samples must be collected prior to the 
6MWT.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized 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 as required. 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 are outlined in Table 2.
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Table 2
Study Interventions
Arm Name
Arm Type
Interven-
tion 
Name
Interven-
tion 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/ Treatment 
Period/ Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Phase 2 Cohort 
Group 1
Experimental
MK-5475 Drug
Powder
380 µg
380 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and for ~40 months 
Extension Period
Test 
Product
IMP
Sponsor
Phase 2 Cohort 
Group 2
Experimental
MK-5475 Drug
Powder
100 µg
100 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and for ~40 months 
Extension Period
Test 
Product
IMP
Sponsor
Phase 2 Cohort 
Group 3
Experimental
MK-5475 Drug
Powder
32 µg
32 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and for ~40 months 
Extension Period
Test 
Product
IMP
Sponsor
Phase 2 Cohort 
Group 4
Placebo 
Comparator
Placebo
Drug
Powder
0 µg
0 µg
Inhalation
Oral inhalation once 
daily for 12 weeks
Base Period
Placebo IMP
Sponsor
Phase 2 Cohort 
Group 4a (before 
Phase 3 dose 
selection)
Experimental
MK-5475 Drug
Powder
380 µg
380 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
IMP
Sponsor
Phase 2 Cohort 
Group 4b (before 
Phase 3 dose 
selection)
Experimental
MK-5475 Drug
Powder
100 µg
100 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
IMP
Sponsor
Phase 2 Cohort 
Group 4c (before 
Phase 3 dose 
selection)
Experimental
MK-5475 Drug
Powder
32 µg
32 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
IMP
Sponsor
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Arm Name
Arm Type
Interven-
tion 
Name
Interven-
tion 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/ Treatment 
Period/ Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Phase 2 Cohort 
Group 4a, 4b, & 
4c (after Phase 3 
dose selection)
Experimental
MK-5475 Drug
Powder
380 µg OR
100 µg OR
32 µg
380 µg 
OR 
100 µg 
OR 
32 µg
Inhalation
Oral inhalation once 
daily for ~40 months 
Extension Period
Test 
Product
IMP
Sponsor
Phase 3 Cohort 
Group 1
Experimental
MK-5475 Drug
Powder
380 µg OR 
100 µg OR 
32 µg
380 µg 
OR 
100 µg 
OR 
32 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and up to 60-month 
Extension Period
Test 
Product
IMP
Sponsor
Phase 3 Cohort 
Group 2
Placebo 
Comparator
Placebo
Drug
Powder
0 µg
0 µg
Inhalation
Oral inhalation once 
daily for 12 weeks 
Base Period
and up to 60-month 
Extension Period
Placebo IMP
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
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.
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All supplies indicated in Table 2 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.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. 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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Study intervention may be dispensed via home delivery to the participant if allowed per local 
guidelines. Home delivery should only be used in exceptional circumstances (eg, DPI 
malfunction) and after consultation with the Sponsor. Only authorized site staff are permitted 
to organize the shipment of the study intervention from the site to the participant. Refer to the 
Study Operations Manual for procedures to ensure participant data privacy, ensure 
temperature control, manage temperature excursions, maintain full traceability, return of used 
and unused study intervention, and preserve the study blind.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. This study has 2 parts, 
a Phase 2 dose selection cohort and a Phase 3 confirmatory cohort. There are 4 study 
intervention arms in the Phase 2 Cohort Base Period, 3 study intervention arms in the Phase 2 
Cohort Extension Period, and 2 study intervention arms in the Phase 3 Cohort. Participants in 
the Phase 2 Cohort Base Period will be assigned randomly in a 1:1:1:1 ratio to 1 of 3 doses of 
MK-5475 (380 µg, 100 µg, or 32 µg) or a matching placebo study intervention, respectively.
In the Phase 2 Cohort Extension Period, the participants who received placebo during the 
Base Period will initially be assigned randomly in a 1:1:1 ratio to 1 of the 3 doses of 
MK-5475 (380 µg, 100 µg, or 32 µg) and will be given new randomization numbers. The 
participants who received MK-5475 during the Base Period will initially receive the same 
MK-5475 doses in the Extension Period and will be assigned new randomization numbers, to 
maintain study blinding.
After selection of the MK-5475 dose for Phase 3, the 3 MK-5475 dose groups in the Phase 2 
Cohort Extension Period will be collapsed into a single dose group for the remainder of the 
Phase 2 Cohort Extension Period.
Participants in the Phase 3 Cohort will be assigned randomly in a 1:1 ratio to the MK-5475 
dose selected in the Phase 2 Cohort Base Period or matching placebo study intervention.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. WHO-FC at the time of randomization (Class II or Class III/IV).
6.3.3
Blinding
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Selected members of the Sponsor study team and management will be unblinded to data 
analysis results from the Phase 2 Cohort Base Period and the Phase 3 Cohort Base Period, to 
evaluate the efficacy and safety profile of MK-5475. For the Phase 2 Cohort Extension 
Period and the Phase 3 Cohort Extension Period, separate blinded Sponsor study teams will 
monitor the ongoing study (Section 9.7). Individuals directly involved with study conduct 
will not be unblinded. 
Blinding to intervention assignment will be maintained at all investigational sites. For both 
Phase 2 Cohort Base Period and Phase 3 Cohort Base Period, the data analysis results will 
not be shared with the investigators before the completion of each respective cohort of the 
study, inclusive of each cohort’s Extension Period.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment for 3 consecutive days OR compliance 
≤90% require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
Records of study intervention compliance for each participant will be kept during the study. 
The investigator or qualified designees will review study intervention compliance during
each site visit and at the completion of the study. 
Participants are expected to self-administer an inhaled dose every morning and record each 
administration (ie, date and time) in their medication diary. Compliance assessments will be 
based on participant reporting (medication diary), corroborated with inspection of the 
returned DPIs during the site visits. Data in the medication diary will be documented in the 
source documents and the eCRF. Compliance calculations will be defined in the sSAP. Issues 
with compliance should be discussed with the participant and addressed as deemed 
appropriate by the investigator.
A record of the number of MK-5475 or placebo DPIs dispensed to and used by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
Intervention start and stop dates, including dates for intervention delays will also be recorded 
in the eCRF.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. 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 
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supportive therapy 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 OTC 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
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Listed below are specific examples of prohibited concomitant therapy:
•
Any inhaled prostacyclin or prostacyclin analogue (eg, inhaled iloprost, inhaled 
epoprostenol, or inhaled treprostinil)
•
Any sGC stimulators (eg, riociguat, vericiguat)
•
Inhaled NO
•
Inhaled nitrates (eg, amyl nitrite)
Note: A medication should not be stopped for the purpose of meeting study inclusion criteria. 
The decision to stop/interrupt medication is based on investigator’s judgment.
Long-term chronic oxygen therapy use is allowed. Oxygen should be given at the standard 
flow rate used at home at each assessment throughout the study, including the administration 
of 6MWT. Note: the 6MWT should be performed with the same oxygen equipment used at 
home.
6.5.1
Rescue Medications and Supportive Care
CRUs will be staffed with medically trained personnel with appropriate access to full-service 
acute care hospitals to facilitate rapid institution of medical intervention.
6.6
Dose Modification
Participants will be randomized to a fixed-dose regimen of MK-5475 or matching placebo 
for the duration of Phase 2 Cohort Base Period (380 µg, 100 µg, 32 µg, or placebo) and 
Phase 3 Cohort (the MK-5475 dose selected in the Phase 2 Cohort Base Period or placebo).
In the Phase 2 Cohort Extension Period, the participants who received placebo during the 
Base Period will initially be assigned randomly in a 1:1:1 ratio to 1 of the 3 doses of 
MK-5475 (380 µg, 100 µg, or 32 µg) and will be given new randomization numbers. 
Participants who received MK-5475 during the Base Period will initially receive the same 
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MK-5475 doses in the Extension Period and will be assigned new randomization numbers, to 
maintain the study blinding.
After selection of the MK-5475 dose for Phase 3, the 3 MK-5475 dose groups in the Phase 2 
Cohort Extension Period will be collapsed into a single dose group for the remainder of the 
Phase 2 Cohort Extension Period.
No other dose modifications are permitted.
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
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
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 8.11.5 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’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a change in medical condition, change in medical treatment 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 pregnancy.
•
The participant fails to comply with the dosing, evaluations, or other requirements of the 
study, despite investigator’s repeated efforts to reinforce compliance.
•
An individual participant reports an SAE considered related to the study intervention by 
the investigator.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
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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 specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
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 providing documented informed consent 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.
•
Clinic in-person visit may be replaced by telephone, video, or home visit using site staff 
or a nursing service, if circumstances do not support an in-person site visit and after 
consultation with the Sponsor .
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed approximately 500 mL (Table 11, Table 12).
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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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.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all his/her questions, 
and obtain documented informed consent. before performing any procedure related to FBR. 
A copy of the informed consent. will be given to the participant before performing any 
procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All I/E criteria will be reviewed by the investigator, who is a qualified physician, to ensure 
that the participant qualifies for the study. The Sponsor will review participant’s key I/E 
criteria prior to randomization into the study. The investigator will make the final decision to 
include a participant in 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
randomization, site personnel will add the treatment/randomization number to the participant 
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identification card. For the Phase 2 Cohort Extension Period, each participant who completes 
the Base Period, satisfies the eligibility criteria, and provides documented informed consent 
will be given a new participant identification card with their new Extension Period
treatment/randomization number.
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
Participants’ medical history, including medical conditions, diagnostic results, allergies, and 
relevant physical examination findings, will be obtained by the investigator or qualified 
designee. The site must provide the required supporting documentation (specific information 
about a participant’s medical history and prior hemodynamic diagnosis of PAH) to support 
participant’s eligibility for participation in the study.
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 90 days before starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication taken by the participant during 
the study on the appropriate eCRF (See Sections 1.3 and 6.5).
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number for the cohort for which 
they are screened, that will be used to identify the participant for all procedures that occur 
prior to randomization in that cohort. Each participant will be assigned only 1 screening 
number. Screening numbers must not be reused for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.2.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number, in a numerical 
sequence specific for each cohort (Section 8.11.3), identifies the participant for all 
procedures occurring within the cohort after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
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In the Phase 2 Cohort, each participant who completes the Base Period and provides 
documented informed consent for the Extension Period will be assigned a new 
treatment/randomization number for the Extension Period. 
In the Phase 3 Cohort, a single participant cannot be assigned more than 1 
treatment/randomization number.
8.1.8
Study Intervention Administration
The first dose of study intervention will be administered at the study site at Visit 2 . 
Subsequent dosing will be performed once daily by the participant (ie, unsupervised at 
his/her home) at approximately the same time each day.
8.1.8.1
Timing of Dose Administration
Study intervention will be administered once daily, in the morning, at approximately the 
same time throughout the duration of the study.
8.1.8.2
Dry Powder Inhaler Use Training 
Participants will be trained by site staff on the proper use of the DPI.
At Visit 1/Screening
1. Participants will receive training from the site staff and will review instructions for DPI
use.
2. Participants will be expected to administer a placebo dose under the guidance of the site 
staff.
3. Participants unable to correctly use the DPI (after instruction by the site staff) at this visit 
due to, but not limited to, physical limitations or cognitive impairment, are not eligible 
for study enrollment.
At Visit 2/Randomization
1. Site staff will review the process for DPI use with the participant.
2. The site will document that retraining occurred.
3. Participants will administer the double-blind study intervention (MK-5475 or matching 
placebo) in the presence of the site staff.
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At Visit 3/Day 7 (+ 2days) – Telephone visit
The site staff will contact the participant to assess whether the participant is experiencing 
DPI performance issues. If the participant is experiencing DPI performance issues, site staff 
will re-review the process for DPI use with the participant and/or caregiver. An unscheduled 
visit will occur if the issues cannot be addressed via telephone.
8.1.8.3
Witnessed Dosing
Administration of study intervention will be witnessed by the investigator and/or qualified 
study staff at the randomization visit.
8.1.8.4
Dispense Double-blind Study Intervention
For both cohorts, the double-blind study intervention for the Base Period (MK-5475 or 
matching placebo) will be dispensed to participants at Visit 2/Day 1, Visit 4/Week 4, and 
Visit 5/Week 8. Study intervention for the Extension Period of Phase 2 Cohort (MK-5475 
380 µg, 100 µg, or 32 µg) will be dispensed starting at Visit 6 and every 6 weeks thereafter, 
until the end of the Extension Period. For participants already enrolled in the Phase 2 Cohort 
Extension Period, the transition to an every 6-week visit frequency will occur at Week 24 or 
at the next visit that falls on a 12-week interval (eg, Week 36, 48, 60. and every 12 weeks 
thereafter through study completion). Study intervention for the Extension Period of Phase 3 
Cohort (MK-5475 or matching placebo) will be dispensed starting at Visit 6 and every 
12 weeks thereafter, until the end of the Extension Period.
Defective DPIs will be replaced by the site as needed. Refer to the Study Operations Manual
for further details.
8.1.8.5
Dispense/Review Participant Dosing Diary
Participants will receive paper-based dosing diaries as specified in the SoA (Section 1.3) to 
document administering the study intervention and to include any comments related to the 
DPI use. Participants should bring their completed diary to all study visits. Site personnel 
should review the diaries at each study visit to monitor compliance and review for any 
potential AEs from the comments entered. 
8.1.8.6
Investigational Product Compliance and Accountability
Adherence to study intervention will be assessed by participant report during the double-
blind treatment period as described in the SoA (Section 1.3). Every effort will be made to 
maintain adherence as close to 100% as possible. Interruptions from the protocol-specified 
treatment plan for 3 consecutive days or compliance ≤90% (defined as 3 or more missed 
doses of study intervention within 30 days, between scheduled study visits) requires 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
Refer to Section 6.4 for further details on study intervention compliance.
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8.1.8.7
Telephone Contact Between Study Visits
Unscheduled telephone contact between study visits may occur as needed. Unscheduled 
visit(s) may be performed as needed, or if the participant requires retraining on study 
intervention administration.
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 (including 
vital status assessment at the end of the study) as outlined in the SoA and Section 8.11.5, to 
minimize missing outcome data.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final visit for that study period 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 and additional Visit Requirements (refer to SoA, 
Section 1.3).
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
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qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc, in the 
medical record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
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.
All measuring instruments used for hemodynamic measurements must be calibrated 
according to the hospital standards and/or manufacturer’s instructions. Additional details are 
provided in the RHC Guidance Document.
The spirometer is to be calibrated according to ATS/ERS technical standards [Graham, B. L., 
et al 2019] and the device manual, on the days when spirometry is performed. It is preferred 
that the calibration equipment used to calibrate the spirometer be subjected to a validated 
calibration, according to manufacturer’s specifications.
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8.2
Efficacy Assessments
Refer to the SoAs for the planned time points of these assessments.
8.2.1
Right Heart Catheterization
Pulmonary vascular hemodynamic measurements are necessary to confirm study 
participants’ eligibility in the Phase 2 and Phase 3 Cohorts and for primary and secondary 
endpoint analyses in Phase 2 Cohort (Section 1.3). RHC using a pulmonary artery floating 
catheter (eg, Swan-Ganz catheter) will be performed for pulmonary vascular hemodynamic 
assessment, if not available within the required time frame for both cohorts (Section 5.1).
For Phase 2 Cohort, the Week 12 RHC will be performed within 4 to 8 hours after the last 
morning dose of study intervention. Participants who withdraw early from the study will be 
encouraged to complete the RHC at the Week 12 visit.
Both RHC procedures will include complete hemodynamic profile, cardiac output, arterial 
oxygen saturation (SaO2, %), mixed venous oxygen saturation (SvO2, %), hemoglobin, 
systemic BP (noninvasive), heart rate, and body weight. If, despite all efforts, PCWP is 
deemed unreliable, left heart catheterization must be performed to measure LVEDP. 
Standards for RHC performance and invasive pressure measurement are described in the 
RHC Guidance Document. To guarantee standardized conditions for RHC and hemodynamic 
measurements across participating study centers, investigators must follow the principles 
defined in the RHC Guidance Document.
All RHC measurements should be recorded on source documents and entered into the 
respective eCRF. RHC pressure tracings will be labeled in accordance with the blinding 
process described in the RHC Guidance Document and submitted for central review.
8.2.2
6-Minute Walk Test
The 6MWT (including Borg CR10 Scale rating) will be performed at Screening, 
Randomization, Week 12, and Week 24 in the Phase 2 Cohort, and at all site visits in the 
Phase 3 Cohort.
For study enrollment, the Screening and the Randomization 6MWD must be between 
150 and 500 meters, with the 2 values within ± 15% of each other. If the relative difference 
between the two 6MWD measurements is >15%, the Randomization 6MWT may be repeated 
after at least 4 hours. If the relative difference between the 2 Randomization 6MWD 
measurements is ≤15%, the participant can be randomized and the last 6MWT (including 
Borg Scale assessment) will be considered the baseline test.
The 6MWT will be performed in accordance with the official European Respiratory 
Society/American Thoracic Society technical standard for field walking tests in chronic 
respiratory disease[Holland, A. E., et al 2014]. Technicians performing the test will be 
trained according to these published procedures [Holland, A. E., et al 2014]. Participants will 
refrain from physical exercise for a minimum of 2 hours prior to testing. The 6MWT will be 
performed preferably at approximately the same time of day at each visit, to minimize 
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intraday variability, and after the NT-proBNP blood sample is obtained. Long-term chronic 
oxygen therapy use is allowed during 6MWT. Oxygen should be kept at the standard flow 
rate and with the same equipment used at home. Sites will be provided with detailed 
instructions in the Study Operations Manual.
8.2.3
WHO Functional Class
The WHO-FC will be assessed at every site visit in the Phase 2 Cohort Base Period, every 
12 weeks in the Phase 2 Cohort Extension Period, and throughout the Phase 3 Cohort. 
Participants will be assigned 1 of 4 functional classes, according to the modified WHO 
classification of functional status of patients with pulmonary hypertension [Stuart, R. 1998]:
Class I – Patients with pulmonary hypertension in whom there is no limitation of usual 
physical activity; ordinary physical activity does not cause increased dyspnea, fatigue, chest 
pain, or near syncope.
Class II – Patients with pulmonary hypertension who have mild limitation of physical 
activity. There is no discomfort at rest, but normal physical activity causes increased 
dyspnea, fatigue, chest pain, or near syncope.
Class III – Patients with pulmonary hypertension who have a marked limitation of physical 
activity. There is no discomfort at rest but less than ordinary activity causes increased 
dyspnea, fatigue, chest pain, or near syncope.
Class IV – Patients with pulmonary hypertension who are unable to perform any physical 
activity and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be 
present at rest and symptoms are increased by any physical activity. 
PAH participants who have experienced a syncopal episode should be assigned to 
WHO-FC IV.
8.2.4
NT-proBNP
Blood samples for assessment of NT-proBNP will be collected as specified in the SoA for 
Phase 2 Cohort (at baseline [Visit 2], Week 12, and Week 24) and in the SoA for Phase 3 
Cohort (at baseline [Visit 2], Visit 6 [Week 12], and every other visit thereafter [every 
24 weeks]). As NT-proBNP may be affected by recent exercise, participants will be advised 
to abstain from exercise before each study visit requiring blood collection for clinical 
laboratory tests. Similarly, NT-proBNP plasma samples must be taken prior to the 6MWT. 
This sample should be collected with the participant in the same position at each visit 
(eg, sitting or semi-recumbent).
8.2.5
Patient-reported Outcomes
All PRO questionnaires will be administered by trained site personnel and completed
electronically by participants in the following order: LPH, PGI-S (physical limitations), 
PGI-S (overall), PGI-C (physical limitations) and PGI-C (overall). The questionnaires should 
be administered according to the SoAs (Section 1.3). It is best practice and strongly 
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recommended that ePROs are administered to randomized participants prior to drug 
administration, AE evaluation, and disease status notification. To that extent, the PRO 
administration should be the first procedure performed during each site visit. If the visit is 
expected to extend over multiple days (Visit 2/Randomization and/or Visit 6), the PROs will 
be administered as the first procedure on the first day of that visit. 
If a participant discontinues the study intervention or withdraws consent during the Base 
Period of either cohort, Visit 6/Week 12 PROs will be administered. If a Phase 3 Cohort 
participant prematurely discontinues study intervention and agrees to be followed for the 
remaining study duration, he/she will be asked to complete the PROs up to the final visit, 
according to the SoA (Section 1.3.2). If the participant does not complete the ePROs at a 
scheduled time point, the MISS_MODE form must be completed to capture the reason the 
assessment was not performed. In the eventuality that electronic administration of the PROs 
is not available, study teams can use the paper back-up process, if allowed per the Site 
Monitoring Plan (see Study Operations Manual). 
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, 
CCI
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including approximate blood volumes drawn/collected by visit and by sample type per 
participant, can be found in Appendix 8 (Table 11, Table 12).
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Complete and directed physical examinations will be conducted by an investigator or 
medically qualified designee (consistent with local requirements) per institutional standard 
and as outlined in the SoAs (Section 1.3). Height and weight will be measured and recorded. 
The complete physical examinations will, at a minimum, include assessments of general 
appearance, skin, lymphatic system, eyes, ears, nose, throat, CV system, respiratory system, 
abdomen/gastrointestinal system, musculoskeletal system, and neurological system. The 
directed physical examinations will, at a minimum, include assessment of the cardiovascular 
and respiratory systems. Other body systems may be evaluated with either type of 
examination. Abnormalities considered clinically significant should be reported as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. A physical examination (complete or directed) may be performed at any 
unscheduled visit if deemed necessary by the investigator or medically qualified designee.
8.3.2
Body Weight
Body weight (kg) will be measured using a standardized scale at each of the predefined time 
points outlined in SoAs (Section 1.3). Participant will be weighed wearing light clothing and 
no shoes. Body weight should be reported with precision to 1 decimal place (eg, 0.1 kg).
8.3.3
Vital Signs
Oral, axillar, tympanic, or temporal artery temperature, pulse rate, pulse oximetry, respiratory 
rate, and systolic and diastolic BP will be assessed. The same method should be used for all 
measurements across visits.
BP and pulse measurements will be assessed in seated position with an automated device. 
Manual techniques will be used only if an automated device is not available.
Vital signs will be measured in a sitting position after 5 minutes of rest.
Detailed information regarding BP and heart rate monitoring is contained in the Study 
Operations Manual. After the first dose of study intervention, new clinically significant 
abnormal findings should be recorded as AEs or ECIs.
8.3.4
Pulmonary Function Testing and DLCO
Pulmonary function testing and single-breath carbon monoxide uptake should be performed 
in accordance with the technical standards established by the ATS/ERS [Miller, M. R., et al 
2005] [Graham, B. L., et al 2019] [Graham, B. L., et al 2017]. PFT includes spirometry and 
body plethysmography. Spirometry will only be reassessed after bronchodilation 
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responsiveness testing in participants who do not meet the PFT inclusion criteria of either 
FEV1/FVC <70% or FEV1 <60% of predicted value.
FVC, FEV1, FEV1/FVC ratio, FEF25-75, PEF, TLC and DLCO will be recorded at 
Visit 1/Screening and Visit 6, in both Phase 2 and Phase 3 Cohorts, as outlined in the SoA 
(Section 1.3). The largest FEV1 and the largest FVC, as well as their ratio (FEV1/FVC), 
should be reported, even if they were not recorded during the same measurement.
The spirometer is to be calibrated according to the ATS/ERS technical standards and the 
device manual. Spirometry procedural details not covered by the ATS/ERS technical 
standards will follow site SOPs and manufacturer’s specifications. Spirometry procedural 
details not covered by the ATS/ERS technical standards document will follow site SOPs and 
manufacturer’s specifications. Every effort should be made to use the same spirometer for 
each participant and throughout the study. 
Report data from each PFT must be available in the source documents.
8.3.5
Electrocardiograms
A standard supine 12-lead ECG will be obtained and reviewed by an investigator or 
medically qualified designee (consistent with local requirements) as outlined in the SoA 
(Section 1.3) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. 
ECGs should be performed after the participant has rested quietly for at least 5 minutes in a 
supine position and before the assessment of BP and heart rate as well as before blood 
collection.
All ECGs performed should be reviewed at the investigative site for participant safety 
monitoring. The investigator is responsible for retaining all copies of the ECG reports.
8.3.6
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 SoAs (Section 1.3).
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•
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 14 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.
•
Serum hCG testing will be performed in female participants where a pregnancy is 
suspected.
8.3.7
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at all site visits, as specified in the SoA (Section 1.3).
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure.
-
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.
Refer to Appendix 7 for country-specific requirements.
8.3.8
Vital Status Assessment
Vital status is collected for all participants at the time points specified in the SoA and at the 
Final Phone Contact. This assessment can also be performed at any point in the trial when 
vital status is in question, unless the participant has specifically withdrawn consent for 
further follow-up. The investigator should explore all possible options to contact the 
participant, per local regulations. The site must document all attempts to contact the 
participant in source documents.
8.3.9
AE Monitoring
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs, as specified in the SoAs (Section 1.3), and more frequently if 
clinically indicated. AEs will be graded and recorded throughout the study and during the 
follow-up period (Section 10.3.4).
The criteria for discontinuation of study intervention for individual participants are in 
Section 7.1.
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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).
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 randomization, must be reported by 
the investigator, 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 randomization through 14 days 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 Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
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
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
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
Exception: A 
positive 
pregnancy test at 
the time of initial 
screening is not a 
reportable event.
Report all
Report if participant 
has been exposed to 
any protocol-specified 
intervention. 
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
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Not required
Within 5 
calendar days of 
learning of event
(unless serious)
Overdose
Not applicable 
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
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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 randomized 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.
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.
Refer to Appendix 7 for country-specific 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.
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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
Disease-related events and or disease-related outcomes not qualifying as AEs or SAEs are 
not applicable to this study.
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. Symptomatic hypotension, defined as a physical finding of systolic BP <90 mmHg or 
systolic BP decrease of more than 40 mmHg below the participant’s baseline which is 
accompanied by at least 1 symptom, such as presyncope, dizziness, mental status 
changes, etc. (reported by participant or otherwise witnessed).
2. Pulmonary hemorrhage
3. Hemoptysis
4. Potential DILI events defined as an elevated AST or ALT lab value that is greater than or 
equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is 
greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon 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).
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions
The method of documenting and reporting of such events (ie, complaints associated with 
medical devices including PQCs/malfunctions) will occur as below and in Appendix 4.
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To fulfill regulatory reporting obligations worldwide, medical device information associated 
with AEs will be collected and reported to the Sponsor in the same time frame as AEs per 
Section 8.4.1 via CRF (paper or electronic) and as per data entry guidelines.
PQCs/malfunctions, including those that involve a participant or any user/associated person, 
must be reported to the Sponsor. Sponsor shall review reported events by the investigator to 
fulfill the legal responsibility of notifying appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices and drug-device combination 
products being used in clinical studies.
During the course of the study, a participant may provide feedback related to the device or 
devicelike features of a drug delivery system. This “customer feedback” is defined as a report 
that does not allege a PQC or defect and has no relevant safety information/untoward event 
associated with it (eg, goodwill or courtesy replacement, consumer preference or suggestion, 
remark that may suggest an improvement in the functionality or quality of a medical device 
or devicelike features of a drug delivery system). All reports of customer feedback must be 
reported to the Sponsor within 14 calendar days of awareness. Sponsor contact information 
can be found in the Investigator Trial File Binder (or equivalent).
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
8.5
Treatment of Overdose
In this study, an overdose will be defined as any dose of study intervention administered as 
part of the study exceeding the dose prescribed by the protocol (ie, >1 inhalation/day). It is 
up to the investigator to decide on the treatment of an overdose, based on the clinical 
evaluation of the participant, in consultation with the Sponsor.
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of PK will 
be collaboratively determined by the appropriate departments (Department of Quantitative 
Pharmacology and Pharmacometrics and the appropriate department within Clinical 
Research) in the Sponsor’s organization. If indicated, these samples may also be assayed
and/or pooled for assay in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-5475
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations/Laboratory Manual.
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PK samples will be collected from all randomized participants according to the PK sampling 
timelines outlined in the SoA (Section 1.3). At all study visits during the double-blind 
treatment period where a PK sample will be collected, the participant must ensure that their 
MK-5475/matching placebo dose aligns with the clinic visit time and PK sample collection. 
The date and time of the last MK-5475/matching placebo dose taken before PK sample 
collection will be recorded. The date and time of each PK sample will also be recorded. The 
PK sampling will occur after the administration of study intervention, as follows: 
For participants who prematurely discontinue study intervention, a PK sample should be 
collected during the discontinuation visit. For the PK samples collected during the 
discontinuation visit, the date and time of the last MK-5475/matching placebo dose taken 
before sample collection, as well as the date and time of PK sample collection will be 
recorded.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
provided in the Operations/Laboratory Manual.
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8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research will be collected from all participants as specified in the 
SoA:
•
Blood for genetic analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be collected for planned analysis of the 
association between genetic variants in DNA and drug response. This sample will not be 
collected at the site if there is either a local law or regulation prohibiting collection, or if the 
IRB/IEC does not approve the collection of the sample for these purposes. If the sample is 
collected, leftover extracted DNA will be stored for FBR if the participant provides 
documented informed consent for FBR. If the planned genetic analysis is not approved, but 
FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
The planned genetic analysis sample should be obtained predose on Day 1 but may be 
collected at the next scheduled visit, if needed. Sample collection, storage, and shipment 
instructions for planned genetic analysis samples will be in the Operations/Laboratory 
Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:

Leftover DNA for future research

Serum for future research

Plasma for future research
8.10
Health Economics Medical Resource Utilization and Health Economics
Not applicable.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
If a participant misses a scheduled visit and the study site staff are unable to reach the 
participant, the site will contact the ‘external contact person’ identified by the participant 
during Screening (see Section 1.3), to collect participant’s vital status (Section 8.3.8).
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8.11.1
Scheduling the Visits
For both Phase 2 and Phase 3 Cohorts, the screening RHC (if applicable) will be scheduled in 
advance at the initial screening visit. For the Phase 2 Cohort, the Visit 6 RHC will be 
scheduled in advance at Visit 2/Randomization.
During the double-blind treatment period, at the end of each study visit, the next study visit 
should be scheduled. Every effort should be made to adhere to the visit schedule 
(Section 1.3). For both Phase 2 and Phase 3 Cohorts, Visit 3/ Day 7 should be scheduled 
within + 2 days, Visit 4/Week 4 and Visit 5/Week 8 within ± 5 days, and Visit 6/Week 12 
within + 7 days. During the Phase 2 Cohort Extension Period, all visits (except Final Visit)
should be scheduled within ± 5 days; during the Phase 3 Cohort Extension Period, all visits 
(except Final Visit) should be scheduled within ± 7 days. If unavoidable, and after 
consultation with the Sponsor, a visit may be scheduled at a time outside of this 
recommended range, but the schedule for subsequent visits must be adjusted so that the total 
duration of the double-blind treatment period is as close as possible to 12 weeks for the Base 
Period in both cohorts. 
Visits should be scheduled relative to the date of Visit 2/ Day 1. If a visit is scheduled at a 
time other than the protocol designated time, careful consideration must be given to the 
amount of investigational product the participant has available.
Study sites should update IRT at each scheduled study visit (except screening visits) for 
purposes of enrollment tracking.
8.11.2
Screening
Over a period of approximately 28 days (Visit 1/Screening), consented potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5. The screening period may be extended, under special circumstances (eg, 
scheduling issues), with the explicit approval of the Sponsor Clinical Director. If a 
participant fails to meet the study entry criteria during Visit 1/Screening, procedures 
(except RHC) may be repeated once, based on investigator judgment and after consultation 
with the Sponsor. Participants may only be rescreened once. Unless otherwise indicated, all 
screening procedures apply for both Phase 2 and Phase 3 Cohort participants.
Participants will be assigned unique screening numbers, specific for each cohort. The 
Screening procedures will be performed such that the RHC (if required) is performed last, 
whenever possible. Determination of eligibility will be assessed based on the demographic, 
disease diagnostic, hemodynamic, functional, echocardiographic, pulmonary function, and 
prior/concomitant therapy criteria outlined in Sections 5.1 and 5.2. Potential participants will 
also be assessed for the availability of adequate historical PAH diagnostic data (RHC and 
echocardiography).
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RHC

For Phase 2 Cohort, participants
 
will have the 
RHC results reviewed by a blinded independent central reviewer. 

For Phase 3 Cohort, participants who have had an RHC performed 
 prior 
to Visit 1/Screening will have the RHC results reviewed by the investigator.
If an adequate historical RHC is not available, an eligibility RHC will be performed during 
Screening, preferably after the participant has satisfied all other criteria specified in 
Sections 5.1 and 5.2. 
If the results of an adequate RHC do not meet study eligibility criteria, the participant will be 
screen failed.
If the RHC results meet study eligibility criteria AND all the other entry criteria are met, the 
participant will progress to Visit 2/Randomization (both cohorts) and the RHC results will 
count as baseline (Phase 2 Cohort).
Echocardiography

Participants who had a transthoracic Doppler echocardiogram performed 
prior to Visit 1/Screening will have the test results reviewed by the investigator to 
demonstrate that related study eligibility criteria are met. If performed outside the 
180-day window or not available for review, the procedure will be performed during 
Screening. 
Considering the documented overlapping and multifactorial PH etiologies, accurate PAH 
differential diagnosis remains a challenge and requires various invasive and noninvasive
investigations. Simultaneously, pitfalls in interpretation of pulmonary vascular 
hemodynamics can also complicate the differentiation of PAH from other PH disorders and 
contribute to PAH misdiagnosis. The precise identification of PAH clinical and 
hemodynamic phenotype in the overall PH population is fundamental to safe study conduct, 
given that pharmacological strategies being developed for treatment of PAH may be 
deleterious to non-PAH PH patients. As such, a Sponsor Concurrence process is warranted to 
ensure that key I/E criteria for the study are met and that the selected population accurately 
reflects the PAH clinical and hemodynamic profile to be studied (see “Sponsor Concurrence 
Process” section in the Study Operations Manual).
The sites are responsible for entering participant data in the central database. This data will 
be reviewed by the Sponsor on an ongoing basis. Eligible participants will proceed to 
Visit 2/Randomization following completion of all screening procedures and Sponsor review 
and concurrence of key I/E criteria.
After completion of all screening procedures as specified in the SoA (Section 1.3), eligible 
participants will be provided instruction and be witnessed in the administration of the 
investigational product using the placebo DPI. Participants will be re-instructed on 
CCI
CCI
CCI
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appropriate inhalation administration technique as needed. See Section 8.1.8.2 for details. 
Participants who have completed or prematurely discontinued the Phase 2 Cohort are not 
eligible to participate in the Phase 3 Cohort.
8.11.3
Randomization
At Visit 2/Randomization (Day 1), eligibility for study participation will be reassessed to 
determine if participants continue to meet the I/E criteria and if, between Screening and 
Randomization, they experienced events that would exclude them for participating in the 
study, eg, acutely decompensated right heart failure or changes in PAH-specific therapy.
Participants who meet all study entry criteria will be randomized as follows:
1. Phase 2 Cohort
Participants in the Phase 2 Cohort Base Period will be assigned randomly in a 1:1:1:1 ratio to 
1 of 3 doses of MK-5475 (380 µg, 100 µg, or 32 µg) or a matching placebo, respectively, and 
will each be assigned a unique, cohort-specific randomization number.
At Visit 6 (Week 12), the participants who complete the Phase 2 Cohort Base Period, Visit 6 
assessments (including RHC), and provide documented informed consent for the Extension 
Period will be re-randomized in the Extension Period according to their Base Period 
treatment assignment and will receive another unique, cohort-specific randomization number. 
The re-randomization probability is shown in Table 4. 
Table 4
Participant Re-randomization Probability in the Phase 2 Cohort Extension 
Period 
Phase 2 Base Period 
Treatment Group
Phase 2 Extension Period 
Assigned Treatment Group
Re-randomization
Probability 
Placebo 
MK-5475   32 µg
1/3
Placebo 
MK-5475   100 µg
1/3
Placebo
MK-5475   380 µg
1/3
MK-5475 32 µg
MK-5475   32 µg
1
MK-5475 100 µg
MK-5475   100 µg
1
MK-5475 380 µg
MK-5475   380 µg
1
2. Phase 3 Cohort 
Participants in Phase 3 Cohort will be assigned randomly in a 1:1 ratio to MK-5475 or 
matching placebo and will each be assigned a unique, cohort-specific randomization number. 
For both cohorts, at Visit 2/Randomization, blood samples for PK analysis should be 
collected before study intervention administration and after dosing (Section 8.6.1). Study 
intervention will be administered by participants as a witnessed dose at the study site.
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Visit 2 procedures should preferably be completed in 1 day. In special circumstances (eg, 
scheduling issues, repeat 6MWT), Visit 2 may be extended to 2 days.
8.11.4
Treatment Period
Visit requirements are outlined in the SoAs (Section 1.3). Specific procedure-related details 
are provided in Sections 8.1 through 8.9. 
At all scheduled site visits from Visit 2/Day 1 onward, the site will dispense (supported by 
IRT) the appropriate number of DPIs for study intervention administration until the next 
scheduled site visit.
For both cohorts, Visit 6 (Week 12) is the last visit for the Base Period and the baseline visit 
for the Extension Period. If necessary, Visit 6 procedures may be performed over multiple 
days. If the visit is extended over multiple days, the PRO questionnaires will be administered 
as the first procedure on the first day of the visit.
1. Phase 2 Cohort 
Visit 6 is the last visit for the Base Period and the Baseline Visit for the Extension Period. At 
Visit 6, which may occur over multiple days, the participants will complete the Base Period 
study procedures (including RHC), as scheduled and specified in the SoA, and a 
reevaluation of SpO2 and seated systolic BP. If the SpO2 and seated BP measurements satisfy 
the study eligibility criteria (Section 5.2), the consented participants will be re-randomized in 
the Extension Period (Section 8.11.3) on the last day of Visit 6 and will be given new 
participant ID cards, medication diaries, and study intervention (MK-5475 380 µg, 100 µg, 
or 32 µg). The first study intervention administration of the Extension Period will be 
unsupervised, on the day following the last day of Visit 6. Site staff will contact the 
participants by telephone on that day (+2 days), to assess whether the participants are
experiencing any potential AEs. Participants in the Phase 2 Cohort Extension Period will 
receive study intervention every 6 weeks until Final Visit (Section 8.1.8.4). For participants 
already enrolled in the Phase 2 Cohort Extension Period, the transition to an every 6-week 
visit frequency will occur at Week 24 or at the next visit that falls on a 12-week interval 
(eg, Week 36, 48, 60, and every 12 weeks thereafter through study completion).
2. Phase 3 Cohort
Visit 6 is the last visit for the Base Period and the Baseline Visit for the Extension Period. At 
Visit 6, the participants will complete the Base Period study procedures as scheduled and 
specified in the SoA and will be given medication diaries and study intervention (MK-5475 
or placebo) for the next 12 weeks. Participants in the Phase 3 Cohort Extension Period will 
receive study intervention every 12 weeks until Final Visit (Section 8.1.8.4).
Participants in both cohorts will record in their medication diary the date and time of 
investigational product administration as well as any comments related to the administration 
experience (eg, device issues). Participants will return their diary and used and unused DPIs 
at every scheduled site visit.
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If, at any time during the study, a participant requires a reassessment of study-related clinical, 
functional, and/or analytical parameters (eg, 6MWD, WHO-FC), an unscheduled visit may 
occur. In the event of an unscheduled visit, vital signs, AEs, clinical events, and concomitant 
medication may be assessed, in addition to the procedure(s) that required reassessment.
Clinic in-person visit may be replaced by telephone, video or home visit using a site staff or a 
nursing service if circumstances do not support an in-person site visit and after consultation 
with the Sponsor.
8.11.5
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
All randomized participants should be followed through completion of the study, regardless 
of premature discontinuation of study intervention, unless the participant withdraws consent 
from any study follow-up. Participants who discontinue study intervention during the Phase 2 
Cohort Base Period should be followed through completion of that study period (Visit 6). 
In both Phase 2 and Phase 3 Cohorts, if a participant is discontinued from the study 
intervention at any time before the completion of the study (or study period, for participants 
who discontinue during the Phase 2 Cohort Base Period), the participant will complete the 
Discontinuation Visit procedures at the time of discontinuation and a follow-up visit 14 days 
(+ 2 days) after the last dose of study intervention, as specified in the SoA (Section 1.3).
After the discontinuation of study intervention, the site visits should continue to be 
performed at time points that correspond to each remaining study visit through the end of the 
study (or study period, for participants who discontinue during the Phase 2 Cohort Base
Period).

If a participant is discontinued from the study intervention at any time during the Base 
Period of either cohort, the participant will return to the clinic at Week 12 and will 
complete all Visit 6 procedures, as scheduled and specified in the SoA (Section 1.3).

At each post-discontinuation visit (other than Week 12 visit), Phase 2 Cohort participants 
will have their vital signs (pulse rate, BP, temperature, pulse oximetry, and respiratory 
rate) recorded and a review of AEs/SAEs. Participants who discontinue study 
intervention during the Extension Period on or before Week 24 will complete the 
WHO-FC assessment, the 6MWT, and NT-proBNP measurement, as specified in the SoA 
(Section 1.3), in addition to the review of AEs/SAEs and recording of their vital signs 
(pulse rate, BP, temperature, pulse oximetry, and respiratory rate).

At each post-discontinuation visit (other than Week 12 visit), Phase 3 Cohort participants
will complete the WHO-FC assessment and 6MWT, as specified in the SoA 
(Section 1.3), in addition to the review of AEs/SAEs and recording of their vital signs 
(pulse rate, BP, temperature, pulse oximetry, and respiratory rate).

Concomitant therapies specifically prohibited (Section 5.2) while the participant was 
receiving study intervention are no longer prohibited starting 14 days after 
discontinuation of study intervention. 
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For those participants who have discontinued study intervention early and who miss the 
remaining study visits, sites will be instructed to make efforts to contact them. To enable 
sites to reach the participants, the participants should provide primary and secondary contact 
information (eg, home telephone, work telephone, mobile telephone). Sites must document 
the outcome of the telephone contact(s) to demonstrate diligent efforts have been made.
Additionally, the ICF will explain the importance of continued data collection from 
participants, including the use of continued contact by telephone.
8.11.6
Final Visit
If applicable, participants will continue study intervention until Week 12 (participants in 
Phase 2 Cohort Base Period) or until the Final Visit (participants in Phase 2 Cohort 
Extension Period and in Phase 3 Cohort). For Phase 3 Cohort, the Final Visit will be 
conducted for all participants when the planned number of clinical worsening events is 
reached and is announced by the Sponsor. Participants in the Phase 2 Cohort Extension 
Period and in the Phase 3 Cohort who prematurely discontinue study intervention are 
required to attend the Final Visit for collection of clinical events and all assessments and 
procedures outlined in the SoA.
8.11.7
Follow-up Visit
Participants will receive a follow-up telephone call approximately 14 days after the last dose 
of study intervention (Visit 6/Week 12, for the participants in Phase 2 Cohort Base Period 
who do not enroll in the Extension Period, or Final Visit, for the participants in Phase 2 
Cohort Extension Period and the participants in Phase 3 Cohort) to determine if any AEs 
have occurred since the last clinic visit.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, the protocol will 
be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to final database
lock, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical Study 
Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in the 
CSR.
Other planned analyses (ie, those specific to the analysis of PK data and future biomedical 
research) are beyond the scope of this document.
In this operationally seamless adaptive Phase 2/3 study, all statistical analyses will be 
separated to address the primary/secondary/exploratory objectives in the Phase 2 Cohort and 
the Phase 3 Cohort independently. The dose of MK-5475 used in the Phase 3 Cohort will be 
determined based on the analysis of data collected in the Phase 2 Cohort Base Period. 
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.  
Phase 2 Cohort
Study Design Overview
Treatment Assignment
Base Period: Participants (approximately 41/group) will be 
randomized in a 1:1:1:1 ratio among 4 treatment groups: 
1)
MK-5475 380 µg
2)
MK-5475 100 µg
3)
MK-5475 32 µg
4)
placebo matching MK-5475
Extension Period: Participants in the 3 active treatment groups
in the Base Period will initially maintain the same treatment 
assignment in the Extension Period; participants who received 
placebo during the Base Period will initially be randomized in a 
1:1:1 ratio among the 3 treatment groups: 
1)
MK-5475 380 µg
2)
MK-5475 100 µg
3)
MK-5475 32 µg
After the Phase 3 dose is selected, all participants in the Phase 2 
Cohort Extension will receive the selected Phase 3 dose 
regardless of their randomized treatment group.
Analysis Populations
Efficacy: FAS
Safety: APaT
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Primary Endpoint
Percent Change from baseline in PVR at Week 12 
Key Secondary Endpoints
N/A
Statistical Methods for Key Efficacy 
Analyses
The differences (each MK-5475 dose minus placebo) in percent 
change from baseline and the associated 95% CIs and p-values 
will be provided based on a robust regression model. Missing 
PVR observations at Week 12 from participants in all treatment 
groups will be imputed based on the observed PVR observations
at Week 12 from the placebo group.
Statistical Methods for Key Safety 
Analyses
For analyses in which 95% CIs will be provided for between-
treatment differences (each MK-5475 dose minus placebo) in 
the percentage of participants with events, these analyses will be 
performed using the M&N method.
Interim Analyses
One interim analysis is planned when 
 
 have completed or discontinued the Phase 2 
Cohort Base Period. The purpose of the IA is to allow an early 
stop for Phase 2 Cohort Base Period for efficacy (including 
selection of the Phase 3 dose) or to stop the study for futility.
Results will be reviewed by an eDMC.
The primary analysis of efficacy data from the Phase 2 Cohort 
will occur when all participants in this cohort have completed 
(or discontinued prior to the end of) the Base Period. Although 
the Phase 2 Cohort can continue in the study (in the Extension 
Period), the Base Period analysis is not considered an interim 
analysis.
Multiplicity
There are 3 treatment group comparisons that may be tested to 
address the primary hypothesis. Testing will be done in a 
sequential manner in descending order of MK-5475 randomized 
dose group, stopping at the point statistical significance is not 
achieved.
Sample Size and Power 
The planned sample size is approximately 164 participants. For 
the percent change from baseline in PVR at Week 12, the study 
has 85% power to demonstrate that MK-5475 380 µg is superior 
to placebo group at an overall one-sided 2.5% alpha level.
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Phase 3 Cohort
Study Design Overview
Treatment Assignment
Participants (approximately 143/group) will be randomized in a 
1:1 ratio between 2 treatment groups: 
1)
MK-5475
2)
placebo matching MK-5475
Analysis Populations
Efficacy: FAS
Safety: APaT
Primary Endpoint
Change from baseline in 6MWD at Week 12 
Key Secondary Endpoints
N/A
Statistical Methods for Key Efficacy 
Analyses
The difference (MK-5475 minus placebo) in change from 
baseline and the associated 95% CI and p-value will be 
provided based on a robust regression model. Missing 6MWD
observations at Week 12 from participants in both treatment 
groups will be imputed based on the observed 6MWD
observations at Week 12 from the placebo group.
Statistical Methods for Key Safety 
Analyses
For analyses in which 95% CIs will be provided for between-
treatment differences (MK-5475 minus placebo) in the 
percentage of participants with events, these analyses will be 
performed using the M&N method.
Interim Analyses
No interim analyses are planned. (The primary analysis of 
efficacy data from the Phase 3 Cohort will occur when all 
participants in this cohort have completed [or discontinued prior 
to the end of] the Base Period. Although the Phase 3 Cohort will 
continue in the study [in the Extension Period], the Base Period 
analysis is not considered an interim analysis.)
Multiplicity
As there is a single hypothesis test involving a single endpoint 
and a single between-treatment comparison, no multiplicity 
adjustment is required.
Sample Size and Power 
The planned sample size is approximately 286 participants. For 
the change from baseline in 6MWD at Week 12, the study has 
90% power to demonstrate that MK-5475 is superior to placebo 
group at a one-sided 2.5% alpha level.
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 (both cohorts, Base and Extension Periods) will be conducted as a double-blind 
study under in-house blinding procedures. At the end of each Base Period of the study, a 
copy of the database will be frozen after medical/scientific review has been completed and 
data from the Base Period have been declared final and complete. The study team will be 
unblinded to perform and review the full analysis of data from the Base Period as well as 
author a CSR. A separate, blinded Sponsor team (ie, blinded to participant-level treatment 
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assignment) will then be assigned to continue the conduct of each Extension Period. All 
personnel who are unblinded for each Base Period data analysis will be excluded from any 
future data review at the individual participant level. For the purpose of the final analysis, the 
official clinical database will not be unblinded until medical/scientific review has been 
completed and data have been declared final and complete.  
Results of this study will be presented in 4 separate reports based on DBLs: 
1. At the end of the Phase 2 Base Period for Phase 2 Cohort primary analysis
2. At the end of the Phase 2 Extension Period for the Phase 2 Cohort final analysis
3. At the end of the Phase 3 Base Period for the Phase 3 Cohort primary analysis 
4. At the end of the Phase 3 Extension Period for the Phase 3 Cohort final analysis
The Sponsor will generate the randomized allocation schedules for study intervention 
assignment for this protocol, and the randomization will be implemented in the interactive 
voice response system.
Blinding issues related to the analyses to be conducted while the study is still ongoing are 
described in Section 9.7.  
9.3
Hypotheses/Estimation
Objectives and hypothesis of the Phase 2 Cohort and Phase 3 Cohort are stated in Section 3
separately.
9.4
Analysis Endpoints
9.4.1
Phase 2 Cohort Efficacy Endpoints
Primary Efficacy Endpoint

Mean percent change from baseline in PVR at Week 12
Secondary Efficacy Endpoints

Mean change from baseline in 6MWD at Week 12

Mean change from baseline in selected hemodynamic parameters at Week 12
o
mRAP
o
Cardiac index
o
SVI
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9.4.2
Phase 3 Cohort Efficacy Endpoints
Primary Efficacy Endpoint

Mean change from baseline in 6MWD at Week 12
Secondary Efficacy Endpoint

Mean change from baseline in 6MWD at Week 24

Proportion of participants whose WHO-FC is not worse at Week 12 relative to baseline
9.4.3
Safety Endpoints 
Safety parameters are described in Section 4.2.1.3
CCI
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Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, vital signs, laboratory safety tests and pulmonary function tests.
9.4.4
Derivations of Efficacy Endpoints 
Computational details for selected efficacy endpoints in Sections 9.4.1 and 9.4.2 are provided 
below:




PAH-related mortality TTCW is defined as the time from randomization to the first 
occurrence of PAH-related death, PAH-related hospitalization, or disease progression.

All-cause mortality TTCW is defined as the time from randomization to the first 
occurrence of all-cause death, PAH-related hospitalization, or disease progression.

LPH physical dimension score = sum of scores from the questions 2, 3, 4, 5, 6, 7, 12, 13
in the LPH questionnaire (each scored 0 to 5 allowing a score in the range of 0 to 40) 
[Bonner, N., et al 2013].

LPH total score = sum of all scores from the 21 questions in the LPH questionnaire (each 
scored 0 to 5 allowing a total score in the range of 0 to 105) [Bonner, N., et al 2013].
9.5
Analysis Populations
Although the analyses of the Phase 2 Cohort and Phase 3 Cohort will be performed 
separately, the definitions of analysis populations are the same for both cohorts.
9.5.1
Efficacy Analysis Population
The FAS population will serve as the primary population for all efficacy analyses. All 
randomized participants in the respective cohort who receive at least 1 dose of study 
treatment will serve as the basis for this population. For PVR and 6MWD, inclusion in the 
FAS population also requires having a baseline observation. For other efficacy endpoints 
except TTCW, inclusion in the FAS population requires having at least 1 observation 
(baseline or post-baseline). Participants will be included in the treatment group to which they 
are randomized.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study treatment. The analysis population will 
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be the same for analyses of both the Base and Extension Periods. Participants will be 
included in the treatment group corresponding to the study treatment they actually received 
for the analysis of safety data using the APaT population. This will be the treatment group to 
which they are randomized except for participants who take incorrect study treatment for the 
entire treatment period; such participants will be included in the treatment group 
corresponding to the study treatment actually received.
At least 1 laboratory, vital sign, or ECG measurement obtained subsequent to at least 1 dose 
of study treatment is required for inclusion in the analysis of the respective safety parameter. 
To assess change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values for secondary endpoints 
may be provided as an assessment of strength of evidence without intent to make inferential 
claims. All statistical tests will be conducted at the α=0.025 (one-sided) level.
For analysis purposes, the baseline assessment is considered the one closest to but before or 
on the day of randomization (Day 1).
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the exploratory objectives will be described in the sSAP.
Efficacy analyses of the Phase 2 Cohort and the Phase 3 Cohort will be performed separately.
The analyses at the end of the Extension Period will include data collected in both the Base 
and Extension Period of each study cohort. No statistical comparisons will be made for either 
Extension Period.
9.6.1.1
Phase 2 Cohort
In the Phase 2 Cohort, efficacy endpoints will be collected during the Base and Extension 
Periods. For the Base Period, the analysis timepoint of interest is Week 12. For the Extension 
Period, the analysis timepoint of interest is Week 24. Summary statistics will be provided for 
every planned data collection timepoint described in the SoA (Section 1.3). 
Primary Endpoint
Following the ICH E9 (R1) guidance [European Medicines Agency 2020], The primary 
estimand for the primary objective used for the Phase 2 Cohort contains 5 attributes:

The treatment condition of interest is MK-5475 or matching placebo with stable 
concomitant PAH-specific therapy, as defined in Section 5.1.
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
The population of participants targeted by the clinical question are male/female 
participants with PAH between the ages of 18 and 75 years (inclusive).

The variable to address the clinical question is PVR at Week 12.

The following are intercurrent events, along with the approaches to handle them:
o
Death: hypothetical strategy to evaluate PVR at Week 12 as though death would not 
occur.
o
Treatment discontinuation: treatment policy strategy seeking to use every 
participant’s actual Week 12 value, regardless of whether they are still taking study 
medication.
The approach to handling missing data for these intercurrent events is described 
below.

The population-level summary is mean percent change from baseline in PVR at Week 12. 
For this estimand, the primary approach will use a robust regression method to address the 
primary hypothesis. Robust regression method will be used because percent change from 
baseline in PVR is not expected to follow a normal distribution, based on other Phase 2 
clinical trials which have used non-parametric methods for analyzing PVR [Simonneau, G., 
et al 2012] [Ghofrani, H. A., et al 2010]. The robust regression model will include terms for 
treatment and WHO-FC (Class II and Class III/IV). Missing PVR observations at Week 12 
from participants in all treatment groups will be imputed following a PMM. Missing data due 
to death will be imputed as the worst outcome among all observed data. Missing data due to 
treatment discontinuation will be imputed based on the observed PVR observations at Week 
12 from the placebo group referred as J2R (detailed below). If there are missing Week 12 
data for other reasons, J2R will also be used. The randomization seed for imputations will be 
5475007.
The difference (MK-5475 minus placebo) in percent change from baseline and the associated 
95% CI and p-value will be provided. A p-value for the comparison of MK-5475 versus 
placebo <0.025 (one-sided) will be considered statistically significant contingent upon the 
multiplicity strategy (Section 9.8).  
The following steps will be taken to perform the primary analysis, including imputation for 
missing data. Percent change from baseline in PVR at Week 12 is the response variable:
1.
Define imputation model for different missingness patterns:
a.
Obtain the worst outcome among all observed data.
b. Within the placebo group, for participants with both baseline and Week 12 data, fit an 
ANCOVA model including terms for treatment and WHO-FC (Class II and 
Class III/IV). 
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2.
Impute missing data for different missingness patterns:
a.
Death: for participants (in both treatment groups) who died before Week 12, the worst 
outcome among all observed data will be used to impute the missing Week 12 values. 
b. Reasons other than death: For participants (in both treatment groups) missing the 
response variable, the fitted model in Step 1 will be used to impute the missing 
values.  
3.
Robust regression based on a Huber-type M estimator [Huber, P. J. 1973] will be 
performed for the imputed dataset. The model will include terms for treatment and 
WHO-FC (Class II and Class III/IV). 
4.
Steps 2 and 3 will be repeated 50 times to create 50 complete datasets and 50 sets of 
parameter estimates. 
5.
The final parameter estimate for the mean percent change will be the average of the 
50 parameter estimates for the mean percent change from Step 4. 
6.
Steps 1 through 5 will be repeated 200 times based on bootstrap resampling. The 
resulting standard error for the mean percent change will be the standard error of the 
resulting parameter estimates obtained in the 200 bootstrap resampled datasets. The CI 
and p-value will be derived from a normal distribution based on the final parameter 
estimate and its standard error.
Two sensitivity analyses for percent change from baseline in PVR will be performed to 
assess the impact of missing data imputation. Within the same PMM structure in the primary 
analysis, for missing data due to reasons other than death, 1 analysis will use a tipping point 
approach and the other analysis will use an approach referred to as washout imputation.
In the tipping point approach, missing values due to reasons other than death will be imputed 
based on the first step in the primary analysis with a positive adjustment Δ added for the 
MK-5475 group. The inference will be carried out for a range of values of Δ. The smallest 
value of Δ that renders the significant result into a non-significant result will be the tipping 
point value, which provides a measure of robustness of the primary result.
In the washout imputation approach, missing values due to reasons other than death in the 
MK-5475 group will be imputed from a normal distribution with the expected value set to the 
baseline value in the MK-5475 group and standard deviation computed based on the root 
mean squared error from the ANCOVA model described in the primary analysis. Missing 
values in the placebo group will be imputed in the same way as in the primary analysis.
Secondary Endpoint
The primary approach for addressing the mean change from baseline in 6MWD at Week 12 
will use the same robust regression method described above for the primary endpoint.
Summary statistics will be provided for other selected hemodynamic parameters listed in 
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Section 9.4.1. Table 5 summarizes the analysis strategy for efficacy endpoints in the Phase 2 
Cohort.
Table 5
Analysis Strategy for Primary and Secondary Efficacy Endpoints in the Phase 
2 Cohort
Endpoint
Type
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Percent Change from baseline in PVR at 
Week 12
P
Sen
Sen
RR
RR
RR
FAS
FAS
FAS
PMM-J2R
PMM-Tipping point
PMM-Washout
Secondary Endpoints
Change from baseline in 6MWD at Week 
12
P
RR
FAS
PMM-J2R
Change from baseline in selected 
hemodynamic parameters at Week 12
P
SS
FAS
N/A
6MWD=6-minute walk distance; FAS=full analysis set; J2R=jump-to-reference; N/A=not applicable; P=Primary; 
PMM=pattern mixture model; PVR=pulmonary vascular resistance; RR=robust regression; Sen=Sensitivity; 
SS=summary statistics.
9.6.1.2
Phase 3 Cohort
In the Phase 3 Cohort, efficacy endpoints will be collected during the Base and Extension 
Periods. For the Base Period, the analysis timepoint of interest is Week 12. For the Extension 
Period, the analysis timepoint of interest is Week 24. Summary statistics will be provided for 
every planned data collection timepoint described in the SoA (Section 1.3).  
Primary Endpoint
The primary estimand for the primary objective used for the Phase 3 Cohort contains 
5 attributes:

The treatment condition of interest is MK-5475 or matching placebo on background 
stable concomitant PAH-specific therapy, as defined in Section 5.1. 

The population of participants targeted by the clinical question are male/female 
participants with PAH between the ages of 18 and 75 years (inclusive).

The variable to address the clinical question is 6MWD at Week 12.

The following are intercurrent events, along with the approaches to handle them:
o
Death: hypothetical strategy to evaluate 6MWD at Week 12 as though death would 
not occur.
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o
Treatment discontinuation: treatment policy strategy seeking to use every 
participant’s actual Week 12 value, regardless of whether they are still taking study 
medication.
The approach to handling missing data for these intercurrent events is described 
below.

The population-level summary is mean change from baseline in 6MWD at Week 12.
For this estimand, the primary approach will use a robust regression method to address the 
primary hypothesis. Robust regression method will be used because change from baseline in 
6MWD is not expected to follow a normal distribution, based on other Phase 3 clinical trials 
which have used non-parametric methods for analyzing 6MWD [Rubin, L. J., et al 2002] 
[Rubin, L. J., et al 2015]. The robust regression model will include a term for treatment and 
WHO-FC (Class II and Class III/IV). Missing 6MWD observations at Week 12 from 
participants in all treatment groups will be imputed following a PMM. Missing data due to 
death will be imputed based on the worst outcome among all observed data. Missing data due 
to treatment discontinuation will be imputed based on the observed 6MWD observations at 
Week 12 from the placebo group referred as J2R (detailed below). If there are missing Week 
12 data for other reasons, J2R will also be used. The randomization seed for imputations will 
be 5475007. 
The difference in change from baseline and the associated 95% CI and p-value will be 
provided (MK-5475 minus placebo). A p-value for the comparison of MK-5475 versus 
placebo <0.025 (one-sided) will be considered statistically significant.  
The following steps will be taken to perform the primary analysis, including imputation for 
missing data. Percent change from baseline in 6MWD at Week 12 is the response variable:
1. Define imputation model for different missingness patterns:
a.
Obtain the worst outcome among all observed data. 
b. Within the placebo group, for participants with both baseline and Week 12 endpoint, 
an MMRM model including terms for treatment and WHO-FC (Class II and 
Class III/IV) will be fit. 
2. The same procedure in Steps 2 through 6 described in Section 9.6.1.1 will be used for 
analysis.  
Two sensitivity analyses of the estimand for change from baseline in 6MWD will be 
performed to assess the impact of missing data imputation. Within the same PMM structure 
in the primary analysis, for missing data due to reasons other than death, 1 analysis will use a 
tipping point approach and the other analysis will use an approach referred to as washout 
imputation. The analysis approaches are the same as in the 2 sensitivity analyses described in 
Section 9.6.1.1 except the missing data due to reasons other than death will be imputed by 
the MMRM model in the primary analysis. 
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As a supplemental analysis, the primary analysis will be repeated, excluding participants who 
participated in the Phase 2 Cohort.
Secondary Endpoint
The primary approach for addressing the mean change from baseline in 6MWD at Week 24
will use the same robust regression method in Section 9.6.1.1. Summary statistics will be 
provided for the proportion of participants whose WHO-FC is not worse at Week 12 relative 
to baseline. Table 6 summarizes the analysis strategy for efficacy endpoints in the Phase 3 
Cohort. 
Table 6
Analysis Strategy for Primary and Secondary Efficacy Endpoints in the Phase 
3 Cohort
Endpoint
Type
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Change from baseline in 6MWD at 
Week 12
P
Sen
Sen
RR
RR
RR
FAS
FAS
FAS
PMM-J2R
PMM-Tipping point
PMM-Washout
Secondary Endpoints
Change from baseline in 6MWD at 
Week 24
Proportion of participants whose WHO 
functional class does not worsen at 
Week 12 relative to baseline.
P
P
RR
SS
FAS
FAS
PMM-J2R
N/A
6MWD=6-minute walk distance; FAS=full analysis set; J2R=jump-to-reference; N/A=not applicable; P=Primary; 
PMM=pattern mixture model; RR=robust regression; Sen=Sensitivity; SS=summary statistics; WHO=World Health 
Organization.
9.6.2
Analysis Methods for Safety Analyses
Safety analyses of the Phase 2 Cohort and the Phase 3 Cohort will be performed separately. 
The analysis methods for safety analyses are the same for both cohorts. The analyses at the 
end of the Extension Period will include data collected in both the Base and Extension Period 
of each study cohort.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, PFTs, and ECG measurements. Except where noted 
otherwise, the same analyses will be performed at the end of the Base Period and at the end 
of the Extension Period.
The Treatment Period will include all data from randomization up to 14 days after the last 
dose of study medication. All safety endpoints will be analyzed for the time frame consisting 
of the treatment period + 14-day post-treatment follow-up, except SAEs. For SAEs, the 
analysis will include all post-treatment follow-up. 
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AEs will be coded using the standard MedDRA and grouped according to SOC.
9.6.2.1
Overall Safety Assessment 
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least one AE, drug-related AE, SAE, and drug-related 
SAE, as well as who discontinued from study intervention due to an AE and who had an AE 
resulting in death. Point estimates and 95% CIs for the differences between treatment groups 
in the percentages of participants with these events will be provided.
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 95% CIs for the differences between treatment groups in the percentages of 
participants with specific AEs will be provided for AEs that occur in at least 4 participants in 
any treatment group. This threshold for the numbers of events was chosen because the 95% 
CI for the between-group difference in percent incidence will always include zero when 
fewer participants per group have events and thus would add little to the interpretation of 
potentially meaningful differences.
Point estimates and 95% CIs will be provided for the percentage of participants with safety 
parameters that meet predefined limits of change based on the same criteria used above for 
the specific AEs.
CIs for between-treatment group differences will be provided using the Miettinen and 
Nurminen (M&N) method [Miettinen, O. and Nurminen, M. 1985]. These CIs will not be 
adjusted for multiplicity and should be regarded only as helpful descriptive measures for the 
review of the safety profile and not as a formal method for assessing statistical significance 
of between-group differences. Rainfall plots with point estimates and 95% CIs will be 
displayed for AEs that occur in at least 4 participants in any treatment group. 
Assessment of Safety Topics of Interest 
Safety topics of interest include AEs of symptomatic hypotension, pulmonary hemorrhage, 
and hemoptysis. The safety topics of special interest will be summarized by treatment group 
of the number and percentage of participants. Point estimates and 95% CIs for between-
group differences will be provided based on the criteria described above for specific AEs. 
A summary of the analysis strategy for safety parameters is provided in Table 7.
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Table 7
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% 
Between-
group CIa
Graphical 
Displaya
Overall Safety 
Assessment
Any AE
X
X
Any serious AE 
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to AE
X
X
Death
X
X
SOCs, PDLCs (incidence ≥4 of 
participants in any treatment 
groups)
X
X
Specific AEs (incidence ≥4 of 
participants in any treatment 
groups)
X
X
X
Specific AEs, SOCs, PDLCs
(incidence <4 of participants in 
any treatment groups)
X
Change from Baseline results 
(laboratory tests, ECGs, vital 
signs)
X
Safety Topics of 
Special Interest
Symptomatic hypotension
Pulmonary hemorrhage
Hemoptysis
X
X
X
AE=adverse event; CI=confidence interval; ECGs=electrocardiograms; PDLC=predefined limit of change; 
SOC=system organ class; X=results will be provided.
a 95% between-group CI and graphical display will not be provided for the analysis of the Phase 2 Cohort 
Extension Period.
9.6.3
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed separately for each cohort by the use of tables and/or graphs. 
No statistical hypothesis tests will be performed on these characteristics. The number and 
percentage of participants screened and randomized and the primary reasons for screening 
failure and discontinuation will be displayed. Demographic variables (eg, age), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
For analysis purposes, the baseline assessment is considered the one closest to but before or 
on the day of randomization (Day 1).
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9.7
Interim Analyses
Analyses of data to be performed while the study is in progress are described below. 
The O'Brien–Fleming alpha-spending function [Lan, K. K. G. and DeMets, D. L. 1983] will 
be used for the efficacy IA to assess the superiority of MK-5475 versus placebo. The 
spending function can be expressed as
where ‘t’ denotes the percentage of information included at the IA, and ‘Ф’ denotes the 
standard normal cumulative distribution function.
With this alpha spending approach, the cumulative significance level will be approximately 
 (one-sided) at the IA and 
 at the final analysis of the Phase 2 Cohort Base Period, 
respectively. This testing approach controls the one-sided alpha between the efficacy IA and 
final analysis at 0.025. The operating characteristics for the interim efficacy analysis are 
shown in Table 8.
Table 8
Power to Demonstrate Superiority of MK-5475 vs placebo on the Primary 
Endpoint of % Change in PVR in Phase 2 Cohort Base Period at the Interim Analysis
Analysis timepoint
Cumulative α Spent 
(one-sided)
Power (%) for Various True Effect Sizes
-30%
-35%
-40%
-45%
-50%
 
59.5
75.0
86.7
93.9
97.6
IA=interim analysis; PVR=pulmonary vascular resistance.
 
 
CCI
CCI
CCI
CCI
CCI
CC
I
CCI
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Study enrollment will not be paused while the IA is being conducted. Blinding to treatment 
assignment will be maintained at all investigational sites. Participant-level unblinding will be 
restricted to an internal unblinded statistician and a scientific programmer performing the IA. 
Treatment-level results and/or participant-level data from the IA will be provided by the 
unblinded statistician to the eDMC. Limited additional Sponsor personnel may be unblinded 
to the treatment-level results of the IA, if required, to act on the recommendations of the 
eDMC. The processes by which recommendations and decisions are reached and 
communicated will be documented in the DMC charter. Before final study unblinding, 
individuals who have been unblinded at any level will not be involved in any discussions 
regarding modifications to the protocol, statistical methods, identification of protocol 
deviations, or data validation efforts after the IA. The results of the IA will not be shared 
with the investigators before completion of the Phase 2 Cohort.
Phase 2 Cohort Base Period
If the IA is cancelled, at the end of the Phase 2 Cohort Base Period, selected members of the 
Sponsor study team and management will be unblinded to comprehensive results from the 
Phase 2 Cohort Base Period to evaluate the efficacy and safety profile of MK-5475 for 
selecting a dose for the Phase 3 Cohort. The MCP-Mod method [Center for Drug Evaluation 
and Research 2015] may be used to support the finding of a suitable dose for Phase 3 Cohort. 
Details will be described in the sSAP. This study may stop if analysis of the data collected at 
the end of the Phase 2 Cohort Base Period shows that none of the MK-5475 doses has a 
desirable efficacy and safety profile. 
CCI
CCI
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Phase 3 Cohort Base Period
The analysis at the end of Phase 3 Cohort Base Period represents the final analysis for 
Phase 3 Cohort Base Period. At the end of the Phase 3 Cohort Base Period, selected members 
of the Sponsor study team and management will be unblinded to comprehensive Base Period 
results from the Phase 3 Cohort, for preparing a CSR and regulatory submissions. For the 
Extension Period of Phase 3 Cohort, a separate blinded Sponsor study team will monitor the 
ongoing study. Individuals directly involved with study conduct will not be unblinded. 
Data Monitoring Committee 
To supplement the routine trial monitoring outlined in this study, an external DMC will 
monitor the interim data. The DMC will not be involved in the dose selection decision. More 
details are described in Section 10.1.4.3.
9.8
Multiplicity
Multiplicity for the Phase 2 Cohort and the Phase 3 Cohort will be considered separately in 
this operationally seamless adaptive design study.
Phase 2 Cohort
For the Phase 2 Cohort Base Period, there are 3 treatment group comparisons that may be 
tested to address the primary hypothesis. Testing will be done in a sequential manner in 
descending order of MK-5475 randomized dose group, stopping at the point statistical 
significance is not achieved. 
The multiplicity strategy strongly controls the Type I error at 2.5% (one-sided) to address the 
primary hypothesis.
Phase 3 Cohort
As there is a single hypothesis involving a single comparison, no multiplicity control is 
required in the Phase 3 Cohort.
9.9
Sample Size and Power Calculations
Sample size and power calculations for the Phase 2 Cohort and the Phase 3 Cohort have been 
performed separately in this operationally seamless adaptive design study.
9.9.1
Efficacy
Phase 2 Cohort
The study design assumptions are based on results from other Phase 2 clinical trials in the 
literature for PAH participants with similar design. In the Phase 2 study assessing selexipag, 
the observed mean percent change from baseline PVR was 33% with standard deviation 0.34, 
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and the overall study completion rate was 91% [Simonneau, G., et al 2012]. Comparable 
results were reported in a Phase 2 study assessing riociguat [Ghofrani, H. A., et al 2010]. 
Through 12 weeks post-randomization, drop-out is expected to be approximately 10% in 
each treatment group. However, based on the approach to missing data, all randomized 
participants per group are expected to be included in the primary analysis and are the basis 
for sample size and power calculations, accounting for imputation of missing data. 
Power and sample size are based on the percent change from baseline in PVR at Week 12. 
Assuming the true percent change from baseline in PVR at Week 12 is -30% for each 
MK-5475 dose versus 0% for placebo, the assumed percent change from baseline in PVR at 
Week 12 using J2R to impute missing data would be 27% for each MK-5475 dose versus 0% 
for placebo. The assumed standard deviation of the difference of percent change from 
baseline in PVR at Week 12 between each MK-5475 and placebo is 0.4. Under these 
assumed percent change and standard deviation, a sample size of 41/group provides more 
than 85% power (approximately 86.4%) to demonstrate superiority for each of the MK-5475 
treatment comparisons using a one-sided alpha=0.025. 
With respect to the secondary endpoint of change from baseline in 6MWD at Week 12, a 
sample size of 41/group will provide a half-width of the 95% CI to be 30 meters, assuming 
the standard deviation of the change from baseline in 6MWD is 70.
Phase 3 Cohort
The study design assumptions are based on results from Phase 3 PAH clinical studies in the 
literature with similar design [Ghofrani, H. A., et al 2013] [Galie, N., et al 2008] [Galie, N., 
et al 2005] [Rubin, L. J., et al 2002]. A clinically relevant increase in 6MWD (>30 meters)
correlates with improved clinical outcomes in PAH (Section 4.2.1.1).
Through 12 weeks post-randomization, drop-out is expected to be approximately 10% in 
each treatment group. However, based on the approach to missing data, all randomized 
participants per group are expected to be included in the primary analysis and are the basis 
for sample size and power calculations, accounting for imputation of missing data. 
Power and sample size are based on the change from baseline in 6MWD at Week 12. 
Assuming the true change from baseline in 6MWD at Week 12 is 30 meters for MK-5475 
versus 0 meters for placebo, the assumed change from baseline in 6MWD at Week 12 using 
J2R to impute missing data would be 27 meters for MK-5475 versus 0 meters for placebo. 
The assumed standard deviation of the difference of change from baseline in 6MWD at 
Week 12 between each MK-5475 and placebo is 70 meters. Under these assumed change and 
standard deviation, a sample size of 143/group provides 90% power to demonstrate
superiority for each of the MK-5475 treatment comparisons using a one-sided alpha=0.025. 
9.10
Subgroup Analyses
Analyses of the Phase 2 Cohort and the Phase 3 Cohort will be performed separately. The 
subgroups analyzed will be the same for both cohorts, except PVR at baseline.
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To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of each subgroup. The following 
are examples of classification variables (the subgroup categories will be defined in the sSAP 
and other subgroups may be defined and described in the sSAP):

Age 

Sex 

PAH subtypes 

Number of background PAH-specific therapies 

Type of background PAH-specific therapy

6MWD at baseline 

PVR at baseline (Phase 2 Cohort only)
9.11
Compliance (Medication Adherence)
Analyses for the Phase 2 Cohort and the Phase 3 Cohort will be performed separately. The 
approach to summarizing compliance will be the same for both cohorts. Analysis details will 
be provided in the sSAP.
9.12
Extent of Exposure
Analyses of the Phase 2 Cohort and the Phase 3 Cohort will be performed separately. The 
approach to summarizing exposure will be the same for both cohorts.
The extent of exposure will be summarized as duration of treatment in terms of number of 
puffs. Dose interruption will be summarized. Summary statistics will be provided on the 
extent of exposure for the APaT population. Further detail will be provided in the sSAP.
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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 his/her 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 his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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 
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.
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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
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.2
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee may be composed of some or all of the following members:
•
Sponsor personnel,
•
Investigators participating in the study, and
•
Consulting therapeutic-area experts and clinical trialists.
The Steering Committee will provide guidance on the operational aspects of the study, 
evaluate recommendations from the DMC, and make recommendations to the EOC.
Specific details regarding responsibilities and governance of the Steering Committee will be 
described in a separate charter.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
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Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.4
Clinical Adjudication Committee (CAC)
A CAC will evaluate the following events (including events from participants who continue 
to be followed after discontinuation of double-blinded study intervention) for the purposes of 
confirming them according to the criteria in Section 8.2.6, as well as evaluating the presence 
of confounding factors.
TTCW composite endpoint components: 

PAH-related mortality TTCW:
1. PAH-related death
2. PAH-related hospitalization
3. Disease progression as assessed by WHO-FC, 6MWD, and need for additional 
treatment.

All-cause mortality TTCW:
1. All-cause death
2. PAH-related hospitalization
3. Disease progression as assessed by WHO-FC, 6MWD, and need for additional 
treatment
All personnel involved in the adjudication process will remain blinded to study intervention 
allocation throughout the study.
Specific details regarding endpoint definitions can be found in the CAC Charter.
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.
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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.
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.
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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.
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 
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.
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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 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
Previous medical records or transfer records including, but not limited to, echocardiogram 
results, pulmonary function test results, and RHC results will be retained in the participant’s 
source document at the study site.
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
The tests detailed in Table 10 will be performed by the central laboratory, with the exception 
of routine urinalysis, pregnancy testing, and screening laboratory tests, which will be 
performed by the local laboratory.
•
Local laboratory results are only required if the central laboratory results are not available 
in time for either study intervention administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the eCRF.
•
Protocol-specific requirements for I/E of participants are detailed in Sections 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 10
Protocol-required Laboratory Assessments
Laboratory Assessments
Hematology
Chemistry
Other Tests
Routine Urinalysis
Hemoglobin
Hematocrit
RBC count
RBC indices:

MCV

MCH

%Reticulocytes
Platelet count
WBC count with 
differential:

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
Coagulation tests: 

PT

aPTT

INR

NT-proBNPa

BUN

Serum creatinineb
and eGFR

Uric acid 

Sodium

Potassium

Chloride

Calcium

PG

ALP

ALT/SGPT

AST/SGOT

Albumin

Total protein

Total bilirubin 

Direct 
(conjugated) bilirubin

Indirect 
(unconjugated) 
bilirubin
Highly sensitive urine
hCG pregnancy test,
for WOCBP only
β-hCG pregnancy test 
(serum), as needed for 
WOCBP only
FSH (as needed, to 
confirm 
postmenopausal state)
By dipstick:
Blood
Glucose
Protein
pH
Ketones
Bilirubin
Urobilinogen
Nitrite 
Leukocyte esterase
Specific gravity
Microscopic 
examination (if 
blood or protein 
abnormal results 
are noted)
6MWT=6-minute walk test; ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial 
thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration 
rate; FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; INR=International Normalized Ratio; 
MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; MDRD=Modification of Diet in Renal Disease; 
NT-proBNP=N-terminal pro b-type natriuretic peptide; PG=plasma glucose; PT=prothrombin time; RBC=red blood 
cells; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=white 
blood cells; WOCBP=women of childbearing potential; 
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Laboratory Assessments
Hematology
Chemistry
Other Tests
Routine Urinalysis
NOTES: 
All study-required laboratory assessments will be performed by a central laboratory, with the exception of routine 
urinalysis, pregnancy testing and the Screening laboratory assessments.
a. Blood samples for NT-proBNP should be obtained prior to the 6MWT. As NT-proBNP may be affected by recent 
exercise, participants should be advised to abstain from exercise before each study visit requiring blood collection for 
clinical laboratory tests.
b. eGFR to be calculated using the MDRD formula.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
NT-proBNP results will not be reported to investigative sites until the study has been 
unblinded.
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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.”
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.
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.
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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.
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.
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•
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
•
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).
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?
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-
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 
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.
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-
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.
•
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.
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•
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
The recording and follow-up procedures described in this protocol apply to the drug-device 
combination product intended to be used by a study participant according to the study 
protocol. Product Quality Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product – A product comprised of 2 or more regulated components (ie, a drug 
and a device; a biologic and device; a biologic and a drug; or a drug, a device, and a 
biologic). Combination products can be single entity, copackaged, or colabeled.
Complaint – Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. This would include PQC, AE, and customer feedback.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part – A drug, device, or biological product that is part of a combination 
product.
Customer Feedback – A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark that may suggest an improvement in the 
functionality or quality of a medical device, or device like features of a drug delivery 
system).
Malfunction – The failure of a device to meet its performance specifications or otherwise 
perform as intended.
Medical Device – Any instrument, apparatus, appliance, material, or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 
•
diagnosis, prevention, monitoring, treatment, or alleviation of disease,
•
diagnosis, monitoring, treatment, alleviation of, or compensation for an injury or
handicap,
•
investigation, replacement, or modification of the anatomy or of a physiological process,
•
control of conception,
and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological, or metabolic means, but which may be assisted in its 
function by such means.
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PQC – Any communication that describes a potential defect related to the identity, strength, 
quality, purity, or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
Serious Injury – An injury or illness that:
1. Is life-threatening,
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, or
3. Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
When a complaint including PQC/malfunction occurs it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.
Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug-device combination product information will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 8.4.1
via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
Assessing Causality
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
The investigator will use clinical judgment to determine the relationship.
Alternative causes such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration should 
be considered and investigated.
Follow-up
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and 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.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female 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, Mullerian 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 female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females 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 Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant b,c
IUS b,d
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the WOCBP 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.
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception b,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception b,c
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner 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.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Penile/external or vaginal/internal condom with or without spermicidee
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
Penile/external condoms must be used in addition to the WOCBP’s hormonal contraception
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
d
IUS is a progestin releasing IUD
e
Vaginal/internal condom used for contraceptive purposes
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction) e  
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
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.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
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.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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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.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
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
10.7.1
Argentina-specific Requirements
Section 1.3 Schedule of Activities, Section 8.3.7 Pregnancy Testing
Pregnancy testing must be performed monthly during treatment as well as at the end of study 
intervention.
10.7.2
France-specific Requirements
Section 8.4.4 Regulatory Reporting Requirements for SAE
According to the French regulations regarding the timeline of safety data reporting for SAE 
and AESI: 

The investigator must notify the Sponsor of all SAEs immediately without exceeding 
24 hours.

In the event of premature termination of the trial for safety reasons, the Sponsor will 
inform the ANSM and the CPP without delay within a maximum period of 15 days.
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10.8
Appendix 8: Approximate Blood Volume Tables
Table 11
Phase 2 Cohort Approximate Blood Volumes Drawn/Collected by Trial Visit 
and by Sample Types
Phase 2 Cohort 
Base Period
Phase 2 Cohort 
Extension Period
Early 
DC Follow-up
Phase 2 Cohort/
Trial Visit
Screening 
Visit
Rand/
Visit 2/
Day 1
Visit 3/
Day 7
Visit 4/
Week 4
Visit 5/
Week 8
Visit 6/
Week 12
TC
1 Day 
After 
Visit 6
Visit X
Every 6
Weeks
Final 
Visit
DC 
Visit
14 days 
After 
Final Visit
Approximate Blood Volume (mL)
NT-proBNP
3
3
3a
3b
Serum β-Human 
Chorionic 
Gonadotropin 
(β-hCG) (WOCBP 
only)
If required, 
included 
with the 
Chemistry 
Sample
Serum Follicle-
Stimulating 
Hormone (FSH) 
(WOCBP only) 
If required, 
included 
with the 
Chemistry 
Sample
Hematology
2
2
2
2
2d
2
2
PT/INR, aPTT
3
3
3
3
3d
3
3
Chemistry 
3
3
3
3
3d
3
3
Screening CBC 
Local laboratory
2
Screening 
Chemistry 
(including eGFR, 
ALT, AST, ALP 
and bilirubin) 
Local laboratory 
3
Pharmacokinetic 
Samples 
6+6c
6
6
6
6d
6
6
Blood for Planned 
Genetic Analysis 
9
Blood (Serum) for 
FBR
10
10
Blood (Plasma) for 
FBR
10
10
Expected Total 
(mL)
5
52c
14
14
37
17a,d
14
17b
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; β-hCG=β-human chorionic gonadotropin; CBC=complete blood count test; DC=discontinuation; 
eGFR=estimated glomerular filtration rate (calculated using MDRD equation); FBR=future biomedical research; 
FSH=follicle-stimulating hormone; INR=International Normalized Ratio; MDRD=Modification of Diet in Renal Disease; 
mL=milliliters; NT-proBNP=N-terminal pro b-type natriuretic peptide; PT=prothrombin time; Rand=randomization; 
TC=telephone contact; WOCBP=women of childbearing potential.
a Sample collected only at Week 24.
b Sample collected during the DC Visit only if the DC occurs prior to Week 24.
c One sample collected predose, one sample collected postdose (See Sec. 8.6.1).
d Sample collected every 12 weeks until Final Visit.
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Table 12
Phase 3 Cohort Approximate Blood Volumes Drawn/Collected by Trial Visit 
and by Sample Types
Phase 3 Cohort Base Period
Phase 3 Cohort 
Ext Period
Early 
DC
Follow
-up
Phase 3 Cohort/
Trial Visit
Screening 
Visit
Rand/
Visit 2/
Day 1
Visit 
3/
Day 7
Visit 4/
Week 4
Visit 5/
Week 8
Visit 6/
Week 12
Visit X/
Every 12 
weeks
Final 
Visit/
DC 
Visit
14 
days 
post-
FV
Approximate Blood Volume (mL)
NT-proBNP
3
3
3a
3
3
-
Serum β-Human 
Chorionic 
Gonadotropin 
(β-hCG) (WOCBP 
only)
If required, 
included 
with the 
Chemistry 
Sample
-
Serum Follicle-
Stimulating 
Hormone (FSH) 
(WOCBP only) 
If required, 
included 
with the 
Chemistry 
Sample
Hematology
-
2
-
2
2
2
2
2
2
-
PT/INR, aPTT
3
3
3
3
3
3
3
Chemistry 
-
3
-
3
3
3
3
3
3
-
Screening CBC 
Local laboratory
2
-
Screening 
Chemistry 
(including eGFR, 
ALT, AST, ALP 
and bilirubin) Local 
laboratory 
3
-
Pharmacokinetic 
Samples 
6 + 6b
6
6
6
6a
6
6
-
Blood for Planned 
Genetic Analysis/
9
-
Blood (Serum) for 
FBR
10
10
Blood (Plasma) for 
FBR
10
10
Expected Total 
(mL)
5
52b
14
14
37
17a
17
17
-
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; β-hCG=β-human chorionic gonadotropin; CBC=complete blood count test; DC=discontinuation; 
eGFR=estimated glomerular filtration rate (calculated using MDRD equation); Ext=Extension; FBR=future biomedical 
research; FSH=follicle-stimulating hormone; FV=Final Visit; INR=International Normalized Ratio; 
MDRD=Modification of Diet in Renal Disease; mL=milliliters; NT-proBNP=N-terminal pro b-type natriuretic peptide; 
PT=prothrombin time; Rand=randomization; WOCBP=women of childbearing potential.
a Starting at Week 24, will be collected at every other visit until the Final Visit 
  b One sample collected predose, one sample collected postdose (See Sec. 8.6.1).
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
6MWD
6-minute walk distance
6MWT
6-minute walk test
AE
adverse event 
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANSM
Agence nationale de sécurité du médicament et des produits de santé 
(French National Agency for the Safety of Medicines and Health 
Products)
APaT
All Participants as Treated
AST
aspartate aminotransferase
ATS
American Thoracic Society
AUC
area under the curve
AUC0-24
area under the curve over 24 hours
BMI
body mass index
BNP
brain natriuretic peptide, B-type natriuretic peptide
BP
blood pressure
CAC
Clinical Adjudication Committee
CCB
calcium channel blocker(s)
CD4+
cluster of differentiation 4 positive
cGMP
cyclic guanosine monophosphate
CI
confidence interval
Cmax
maximum plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
CPP
Comités de Protection des Personnes (Committees of Protection of 
Persons)
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
CT
computed tomography
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Abbreviation
Expanded Term
CTFG
Clinical Trial Facilitation Group 
CV
cardiovascular
D
day
DBL
database lock
DDI
drug-drug interaction
DLCO
diffusing capacity of the lungs for carbon monoxide
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DPI
dry powder inhaler
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
Electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
ePROs
electronic patient-reported outcomes
ERA
endothelin receptor antagonist
ERS
European Respiratory Society
EU CT
European Union Clinical Trial
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
Full Analysis Set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FEF25-75
forced expiratory flow at 25% to 75% of FVC
FEV1
forced expiratory volume in 1 second
FMF
Final Market Formulation
FRI
functional respiratory imaging
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Abbreviation
Expanded Term
FSH
follicle-stimulating hormone 
FSR
first site ready
FVC
forced vital capacity
GCP
Good Clinical Practice 
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation
I/E
inclusion/exclusion
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug 
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
J2R
jump-to-reference
JRCT
Japan Registry of Clinical Trials
LAM
lactation amenorrhea method
LPH
Living with Pulmonary Hypertension questionnaire
LVEDP
left ventricular end diastolic pressure
MAD
multiple ascending dose
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
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Abbreviation
Expanded Term
M&N
Miettinen and Nurminen
mRAP
mean right arterial pressure
NCT
National Clinical Trial
NIH
National Institutes of Health
NO
nitric oxide
NOAEL
no observed adverse effect level 
NT-proBNP
N-terminal fragment of prohormone B-type natriuretic peptide
OSA
obstructive sleep apnea
OTC
over-the-counter
PAH
pulmonary arterial hypertension
PBV
pulmonary blood volume
PCH
pulmonary capillary hemangiomatosis
PCWP
pulmonary capillary wedge pressure
PDE5
phosphodiesterase type 5
PDE5i
phosphodiesterase type 5 inhibitor
PDLC
predefined limit of change
PEF
peak expiratory flow
PFT
pulmonary function tests
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity 
PH
pulmonary hypertension
PK
pharmacokinetic(s)
PMM
pattern mixture model
PN
protocol number
PQC
product quality complaint(s)
PRO
patient-reported outcome
PVOD
pulmonary veno-occlusive disease 
PVR
pulmonary vascular resistance
QoL
quality of life
REVEAL
Registry to Evaluate Early and Long-Term PAH Disease Management
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Abbreviation
Expanded Term
RHC
right heart catheterization
RNA
ribonucleic acid
SAD
single ascending doses
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SaO2
arterial oxygen saturation
SC
subcutaneous
sGC
soluble guanylate cyclase
SoA
schedule of activities
SOC
system organ class
SOPs
standard operating procedures
SpO2
oxygen saturation measured by pulse oximetry
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
SVI
stroke volume index
SvO2
mixed venous oxygen saturation
t1/2
terminal half-life
T cells
T-type lymphocytes
TLC
total lung capacity
Tmax
time to maximum plasma concentration
TTCW
time to clinical worsening
ULN
upper limit of normal
UTN
Universal Trial Number
VA
alveolar volume
WHO
World Health Organization
WHO-FC
World Health Organization functional class
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of nonchildbearing potential
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REFERENCES
[Bonner, N., et al 2013]
Bonner N, Abetz L, Meunier J, Sikirica 
M, Mathai SC. Development and 
validation of the living with pulmonary 
hypertension questionnaire in pulmonary 
arterial hypertension patients. Health 
Qual Life Outcomes. 2013 Oct 3;11:161.
[05JPLL]
[Center for Drug Evaluation 
and Research 2015]
Center for Drug Evaluation and Research. 
Request for qualification of MCP-Mod as 
an efficient statistical methodology for 
model-based design and analysis of phase 
II dose finding studies under model 
uncertainty. Silver Spring (MD): Food 
and Drug Administration (FDA); 2015 
Apr 22. 31 p.
[05L5TN]
[Divers, C., et al 2017]
Divers C, Platt D, Wang E, Lin J, 
Lingohr-Smith M, Mathai SC. A review 
of clinical trial endpoints of patients with 
pulmonary arterial hypertension and 
chronic thromboembolic pulmonary 
hypertension and how they relate to 
patient outcomes in the United States. J 
Manag Care Spec Pharm. 2017 
Jan;23(1):92-104.
[05JPLN]
[Dubroff, J., et al 2020]
Dubroff J, Melendres L, Lin Y, Beene 
DR, Ketai L. High geographic prevalence 
of pulmonary artery hypertension: 
associations with ethnicity, drug use, and 
altitude. Pulm Circ. 
2020;10(1):2045894019894534.
[05LKQH]
[European Medicines Agency 
2020]
European Medicines Agency. ICH E9 
(R1) addendum on estimands and 
sensitivity analysis in clinical trials to the 
guideline on statistical principles for 
clinical trials: step 5. London (England): 
European Medicines Agency (EMA); 
2020. 19 p. 
EMA/CHMP/ICH/436221/2017.
[05G4BV]
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[Fenstad, E. R., et al 2019]
Fenstad ER, Bonfig N, Mirfakhraie L, 
Ebnet S, Eckman P, Cabuay B, et al. 
Pulmonary hypertension in rural 
minnesota: prevalence and clinical 
classification [abstract]. Presented at: 
International Society for Heart and Lung 
Transplantation (ISHLT) 39th Annual 
Meeting and Scientific Sessions; 2019 
Apr 3-6; Orlando (Florida). J Heart Lung 
Transplant. 2019;38(4 suppl):S488. 
Abstract no. 1231.
[05LKJ9]
[Food and Drug 
Administration 2019]
Food and Drug Administration. Adaptive 
designs for clinical trials of drugs and 
biologics: guidance for industry. Silver 
Spring, MD. Nov 2019.
[05K0YQ]
[Frost, A. E., et al 2011]
Frost AE, Badesch DB, Barst RJ, Benza 
RL, Elliott CG, Farber HW, et al. The 
changing picture of patients with 
pulmonary arterial hypertension in the 
United States: how REVEAL differs 
from historic and non-US contemporary 
registries. Chest. 2011;139(1):128-37. 
Erratum in: Chest. 2011 Oct;140(4):1106.
[05K3C9]
[Frost, A., et al 2019]
Frost A, Badesch D, Gibbs JSR, Gopalan 
D, Khanna D, Manes A, et al. Diagnosis 
of pulmonary hypertension. Eur Respir J. 
2019;53:1801904.
[05J4QX]
[Galie, N., et al 2005]
Galie N, Ghofrani HA, Torbicki A, Barst 
RJ, Rubin LJ, Badesch D, et al. Sildenafil 
citrate therapy for pulmonary arterial 
hypertension. N Engl J Med. 2005 Nov
17;353(20):2148-57. Erratum in: N Engl 
J Med. 2006 Jun 1;354(22):2400-1.
[05D3ZP]
08P53K


PRODUCT: MK-5475
154
PROTOCOL/AMENDMENT NO.: 007-03
MK-5475-007-03 FINAL PROTOCOL
07-NOV-2023
[Galie, N., et al 2008]
Galie N, Olschewski H, Oudiz RJ, Torres 
F, Frost A, Ghofrani HA, et al. 
Ambrisentan for the treatment of 
pulmonary arterial hypertension: results 
of the ambrisentan in pulmonary arterial 
hypertension, randomized, double-blind, 
placebo-controlled, multicenter, efficacy 
(ARIES) study 1 and 2. Circulation. 2008 
Jun 10;117:3010-9.
[05MKZQ]
[Galie, N., et al 2015]
Galie N, Barbera JA, Frost AE, Ghofrani 
HA, Hoeper MM, McLaughlin VV, et al. 
Initial use of ambrisentan plus tadalafil in 
pulmonary arterial hypertension. N Engl J 
Med. 2015 Aug 27;373(9):834-44.
[05JMNQ]
[Ghofrani, H. A., et al 2010]
Ghofrani HA, Hoeper MM, Halank M, 
Meyer FJ, Staehler G, Behr J, et al. 
Riociguat for chronic thromboembolic 
pulmonary hypertension and pulmonary 
arterial hypertension: a phase II study. 
Eur Respir J 2010;36(4):792-9.
[03RRL7]
[Ghofrani, H. A., et al 2013]
Ghofrani HA, Galie N, Grimminger F, 
Grunig E, Humbert M, Jing ZC, et al. 
Riociguat for the treatment of pulmonary 
arterial hypertension. N Engl J Med. 2013 
Jul 25;369(4):330-40.
[04GB0S]
[Graham, B. L., et al 2017]
Graham BL, Brusasco V, Burgos F, 
Cooper BG, Jensen R, Kendrick A, et al. 
2017 ERS/ATS standards for single-
breath carbon monoxide uptake in the 
lung. Eur Respir J. 2017;49:1600016. 
Erratum in: Eur Respir J. 
2018;52:1650016.
[05MWZ5]
[Graham, B. L., et al 2019]
Graham BL, Steenbruggen I, Miller MR, 
Barjaktarevic IZ, Cooper BG, Hall GL, et 
al. Standardization of spirometry 2019 
update: an official American Thoracic 
Society and European Respiratory 
Society technical statement. Am J Respir 
Crit Care Med. 2019 Oct 15;200(8):e70-
88.
[05MW53]
08P53K


PRODUCT: MK-5475
155
PROTOCOL/AMENDMENT NO.: 007-03
MK-5475-007-03 FINAL PROTOCOL
07-NOV-2023
[Hoeper, M. M., et al 2016]
Hoeper MM, Huscher D, Pittrow D. 
Incidence and prevalence of pulmonary 
arterial hypertension in Germany 
[correspondence]. Int J Cardiol. 
2016;203:612-3.
[05LF7B]
[Holland, A. E., et al 2014]
Holland AE, Spruit MA, Troosters T, 
Puhan MA, Pepin V, Saey D, et al. An 
official European Respiratory 
Society/American Thoracic Society 
technical standard: field walking tests in 
chronic respiratory disease. Eur Respir J. 
2014;44:1428-46.
[05LZYN]
[Huber, P. J. 1973]
Huber PJ. Robust regression:  
asymptotics, conjectures and Monte 
Carlo. The Annals of Statistics 
1973;1(5):799-821.
[03PC72]
[Humbert, M., et al 2006]
Humbert M, Sitbon O, Chaouat A, 
Bertocchi M, Habib G, Gressin V, et al. 
Pulmonary arterial hypertension in 
France - Results from a national registry. 
Am J Respir Crit Care Med 
2006;173:1023-30.
[00WDQY]
[Kirson, N. Y., et al 2011]
Kirson NY, Birnbaum HG, Ivanova JI, 
Waldman T, Joish V, Williamson T. 
Prevalence of pulmonary arterial 
hypertension and chronic 
thromboembolic pulmonary hypertension 
in the United States. Curr Med Res Opin. 
2011 Sep;27(9):1763-8.
[05LF7T]
[Lan, K. K. G. and DeMets, 
D. L. 1983]
Lan KKG, DeMets DL. Discrete 
sequential boundaries for clinical trials. 
Biometrika 1983;70(3):659-63.
[03PF2K]
[Lewis, R. A., et al 2020]
Lewis RA, Durrington C, Condliffe R, 
Kiely DG. BNP/NT-proBNP in 
pulmonary arterial hypertension: time for 
point-of-care testing? Eur Respir Rev. 
2020;29:200009.
[05MWZ6]
08P53K


PRODUCT: MK-5475
156
PROTOCOL/AMENDMENT NO.: 007-03
MK-5475-007-03 FINAL PROTOCOL
07-NOV-2023
[Ling, Y., et al 2012]
Ling Y, Johnson MK, Kiely DG, 
Condliffe R, Elliot CA, Gibbs JSR, et al. 
Changing demographics, epidemiology, 
and survival of incident pulmonary 
arterial hypertension: results from the 
pulmonary hypertension registry of the 
United Kingdom and Ireland. Am J 
Respir Crit Care Med. 2012 Oct 
15;186(8):790-6.
[05LF82]
[Mathai, S. C., et al 2012]
Mathai SC, Puhan MA, Lam D, Wise 
RA. The minimal important difference in 
the 6-minute walk test for patients with 
pulmonary arterial hypertension. Am J 
Respir Crit Care Med. 2012 Sep 
1;186(5):428-33.
[05MCFM]
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O, Nurminen M. Comparative 
analysis of two rates. Stat Med 
1985;4:213-26.
[03NV0C]
[Miller, M. R., et al 2005]
Miller MR, Hankinson J, Brusasco V, 
Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir 
J 2005;26:319-38.
[03PYPH]
[Peacock, A. J., et al 2007]
Peacock AJ, Murphy NF, McMurray JJV, 
Caballero L, Stewart S. An 
epidemiological study of pulmonary 
arterial hypertension. Eur Respir J. 
2007;30(1):104-9.
[05LKQJ]
[Pulido, T., et al 2013]
Pulido T, Adzerikho I, Channick RN, 
Delcroix M, Galie N, Ghofrani HA, et al. 
Macitentan and morbidity and mortality 
in pulmonary arterial hypertension. N 
Engl J Med. 2013 Aug 29;369(9):809-18.
[05JMNN]
[Rubin, L. J., et al 2002]
Rubin LJ, Badesch DB, Barst RJ, Galie 
N, Black CM, Keogh A, et al. Bosentan 
therapy for pulmonary arterial 
hypertension. N Engl J Med. 2002 Mar 
21;346(12):896-903. Erratum in: N Engl 
J Med 2002 Apr 18;346(16):1258.
[05D3ZJ]
08P53K


PRODUCT: MK-5475
157
PROTOCOL/AMENDMENT NO.: 007-03
MK-5475-007-03 FINAL PROTOCOL
07-NOV-2023
[Rubin, L. J., et al 2015]
Rubin LJ, Galie N, Grimminger F, 
Grunig E, Humbert M, Jing ZC, et al. 
Riociguat for the treatment of pulmonary 
arterial hypertension: a long-term 
extension study (PATENT-2). Eur Respir 
J. 2015 May;45(5):1303-13.
[04GB0W]
[Savarese, G., et al 2013]
Savarese G, Musella F, D’Amore C, 
Losco T, Marciano C, Gargiulo P, et al. 
Haemodynamics, exercise capacity and 
clinical events in pulmonary arterial 
hypertension. Eur Respir J. 2013;42:414-
24.
[05MCFL]
[Simonneau, G., et al 2012]
Simonneau G, Torbicki A, Hoeper MM, 
Delcroix M, Karlocai K, Galie N, et al. 
Selexipag: an oral, selective prostacyclin 
receptor agonist for the treatment of 
pulmonary arterial hypertension. Eur 
Respir J. 2012;40(4):874-80.
[05G4DB]
[Simonneau, G., et al 2019]
Simonneau G, Montani D, Celermajer 
DS, Denton CP, Gatzoulis MA, Krowka 
M, et al. Haemodynamic definitions and 
updated clinical classification of 
pulmonary hypertension. Eur Respir J. 
2019;53:1801913.
[05J4R0]
[Sitbon, O., et al 2015]
Sitbon O, Channick R, Chin KM, Frey A, 
Gaine S, Galie N, et al. Selexipag for the 
treatment of pulmonary arterial 
hypertension. N Engl J Med. 2015 Dec 
24;373(26):2522-33.
[05G4DC]
[Stuart, R. 1998]
Stuart R, editor (2nd World Symposium 
on Pulmonary Hypertension, Evian 
(France)). Primary pulmonary 
hypertension: executive summary from 
the World Symposium - Primary 
Pulmonary Hypertension 1998. Geneva 
(Switzerland): World Health 
Organization (WHO); 1998. 30 p.
[05JPLP]
08P53K


PRODUCT: MK-5475
158
PROTOCOL/AMENDMENT NO.: 007-03
MK-5475-007-03 FINAL PROTOCOL
07-NOV-2023
[Swinnen, K., et al 2019]
Swinnen K, Quarck R, Godinas L, Belge 
C, Delcroix M. Learning from registries 
in pulmonary arterial hypertension: 
pitfalls and recommendations. Eur Respir 
Rev. 2019;28:190050.
[05K3C6]
[Tiede, H., et al 2013]
Tiede H, Sommer N, Milger K, 
Voswinckel R, Bandorski D, Schermuly 
RT, et al. Short-term improvement in 
pulmonary hemodynamics is strongly 
predictive of long-term survival in 
patients with pulmonary arterial 
hypertension. Pulm Circ. 2013 
Sep;3(3):523-32.
[05G4DD]
[Waxman, A. B. 2015]
Waxman AB, Farber HW. Using clinical 
trial end points to risk stratify patients 
with pulmonary arterial hypertension. 
Circulation. 2015 Dec 1;132:2152-61.
[05MWZ7]
[Weatherald, J., et al 2018]
Weatherald J, Boucly A, Chemla D, 
Savale L, Peng M, Jevnikar M, et al. 
Prognostic value of follow-up 
hemodynamic variables after initial 
management in pulmonary arterial 
hypertension. Circulation. 2018 Feb 
13;137:693-704.
[05GDKS]
08P53K