Clinical trial NCT04370873
Conditions: Pulmonary Hypertension
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-06-05; Completion date: 2022-01-12
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are to assess the safety/tolerability and efficacy (by evaluating changes in pulmonary vascular resistance \[PVR\] and pulmonary blood volume \[PBV\]) of frespaciguat in participants with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). The primary hypothesis is that 28 days of frespaciguat treatment is superior to placebo treatment in reduction of PVR.

Detailed description:
Part 1 of this study will assess safety, tolerability, and PK of frespaciguat compared to placebo. Part 2 will assess safety, tolerability, PK, and changes in PVR and PBV of frespaciguat compared to placebo.

Arms: arm 1: Participants receive frespaciguat 360 μg once daily (QD) via inhalation from Days 1-7. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data in these participants. arm 2: Participants receive placebo QD via inhalation from Days 1-7. arm 3: Participants receive frespaciguat 32 µg, 100 µg, 195 µg or 380 μg QD via inhalation from Days 1-28. arm 4: Participants receive placebo QD via inhalation from Days 1-28.
Interventions: intervention 1: Frespaciguat intervention 2: Placebo
Intervention descriptions: intervention 1: Frespaciguat 32 µg, 100 µg, 195 µg, 360 µg or 380 µg administered as dry powder inhalation according to randomization. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data. Dosage may be adjusted downwards in Part 2, if indicated by PK results in Part 1. intervention 2: Placebo administered as dry powder inhalation according to randomization

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04370873 
Document Date: 
24-Sep-2021
A Study to Assess the Safety, Tolerability, Pharmacokinetics and
Pharmacodynamics of Multiple Dose MK-5475 in Participants with 
Pulmonary Hypertension Associated with COPD


PRODUCT: MK-5475  
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PROTOCOL/AMENDMENT NO.: 006-05 
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24-SEP-2021
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Multiple Dose MK-5475 in Participants with Pulmonary Hypertension 
Associated with COPD
Protocol Number: 006-05
Compound Number: MK-5475
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
146752
EudraCT
2020-000488-22
Approval Date: 24 September 2021
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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
MK-5475-006-05
24-SEP-2021
Part 3 added. The purpose of this amendment is to allow enrollment of participants 
unwilling or unable to undergo RHC and to increase the sample size for FRI and 
CPET to allow more robust statistical analyses of these 2 PD assessments. Part 3 
eliminates RHC.
MK-5475-006-04
14-SEP-2021
Country Specific: Hepatitis B surface antigen exclusion criteria updated by 
making it less restrictive. This will allow participants with stable chronic hepatitis 
B to participate in the study. No additional risk to these participants will be 
incurred, as their disease is stable and those with significant liver disease would 
still be excluded.
MK-5475-006-03
04-JUN-2021
Exercise exclusion criteria removed to improve screening and enrollment.
MK-5475-006-02
01-FEB-2021
Changes to multiple inclusion and exclusion criteria to improve screening and 
enrollment 
MK-5475-006-01
11-SEP-2020
Dosing of MK-5475 in Part 2 of the study will be with the For Market 
Formulation (FMF) which has a potency of 380µg and will be used in later phase 
trials
Original Protocol
13-MAR-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
Part 3 added. Part 3 allows for enrollment of an additional 15 participants, who will have pharmacodynamic measurements done at 
baseline and then again after 4 weeks of dosing with MK-5475. Measurements will include FRI and CPET testing but will not include 
RHC. The purpose is to increase the sample size for FRI and CPET to allow more robust statistical analyses, while allowing 
enrollment of participants who are unwilling or unable to undergo RHC.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
Objectives Table, Estimated Duration, 
Number of Participants, and Intervention 
Groups updated.
Updated to reflect objectives that apply to addition of 
Part 3. Estimated duration and number of participants 
adjusted to account for Part 3. To define Intervention 
groups that will apply to Part 3.
1.2 Schema
Part 3 Schema added
To provide a diagram of the Part 3 design which 
eliminates RHC.
1.3 Schedule of Activities
Part 3 study procedures table added
HR and BP timing updated to within 15 
minutes before and after 6 -minute walk 
test.
To provide list of procedures that apply only to Part 3.
To provide clarification as to timing of measurements 
related to 6-minute walk test.
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Section # and Name
Description of Change 
Brief Rationale 
2.1 Study Rationale
Changed to a 3-Part study, updated PVR 
data from PN 002. Added age range and 
rationale for Part 3
Reflects addition of Part 3. To provide most current 
results of PVR from PN 002. Increased age range since 
invasive RHC procedure will not be performed in 
Part 3.
2.2 Background
Updated name of drug delivery device to 
dry powder inhaler (DPI). Moved protocol 
002 and 004 narratives to completed 
studies section. Added high level summary 
of PN006 safety results for Part 2, to date.
Added protocol summary for PN 007 to 
Ongoing Studies Section.
Name change to DPI as per internal decision. To 
provide most current program and safety data.
3.0 Hypothesis, Objectives 
and Endpoints
Updated objectives that will also be 
applied to Part 3.
To reflect addition of Part 3.
4.1 Overall Study Design
Part 3 study design added, which includes 
removal of RHC procedure, sample size 
for Part 3 and randomization ratio.
To enhance patient recruitment by eliminating RHC, 
while bolstering dataset for FRI and CPET.
4.2 Scientific Rationale for 
Study Design
Rationale for Part 3 added.
To eliminate the need for RHC and to provide a more 
robust dataset for PD analysis associated with FRI and 
CPET, if needed.
4.3.3 Rationale for Dose and 
Dose Interval
Updated to include Part 3.
To reflect addition of Part 3.
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Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Criteria #4: Age range for Part 3 adjusted 
to upper age of 85. Criteria #14 indicates 
echo applies to parts 1 and 2 only. Part 3 
participants require historical RHC.
To enhance enrollment in Part 3. To ensure participants 
have confirmed PH diagnosis.
5.2 Exclusion Criteria
Criteria #s 7, 10, 17 and 18 updated to 
include Part 3. Criteria # 6: A positive 
hepatitis B surface antigen will be 
permitted provided it is not an acute 
infection. 
To reflect addition of Part 3.
To expand pool to include chronic hepatitis B patients 
that would otherwise be good PH-COPD candidates for 
enrollment into the trial.
5.3 Lifestyle Considerations
Part 3 included for dietary, caffeine and 
alcohol restrictions.
To reflect addition of Part 3.
6.1 Study Interventions 
Administered
Part 3 added to Study Interventions Table
To reflect addition of Part 3.
6.3 Blinding
Part 3 sample allocation schedule added.
To describe sample allocation based on sample size 
and treatment group for Part 3.
6.4 Study Intervention 
Compliance
Device name changed to DPI.
Per internal decision in device name description.
6.6 Dose Modification 
(Escalation/Titration/Other)
Preliminary Part 2 PD data will be used to 
trigger the start of Part 3. Part 2 and 3 may
run in parallel, if needed
To allow for continued assessment of CPET and FRI
measures depending on outcome of preliminary review 
of PD data from Part 2.
8.1.8 Study Intervention 
Administration
Updated to include Part 3 and dosing 
window expanded to +/- 2 hours.
To reflect addition of Part 3.  To provide more 
flexibility for dosing.
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Section # and Name
Description of Change 
Brief Rationale 
8.1.11 Domiciling
Updated to include Part 3.
To reflect addition of Part 3.
8.3.1 Physical Examinations
Updated to include Part 3.
To reflect addition of Part 3.
8.6.1 Blood Collection for 
Plasma MK-5475
Updated to indicate that PK samples done 
at time of RHC applies only in Part 2.
To ensure appropriate draw of PK samples in Part 2.
8.7 Pharmacodynamics
Updated to indicate RHC applies to Part 2
only.
RHC will not be performed in Part 3.
8.7.2 CT Scan for Functional 
Respiratory Imaging
Updated to include Part 3.
To reflect addition of Part 3.
8.7.3 Cardiopulmonary 
Exercise Testing
Updated to include Part 3.
Baseline CPET interval extended to 10 
weeks from Day 1 in the event the 
participant is not randomized within 35 
days of Day 1.
To reflect addition of Part 3.
To enable rescreening of participants that had baseline 
CPET performed but were not randomized within 35 
days of Visit 1.
8.11.2 Treatment Period
Description of Part 3 Treatment Period 
was added.
To reflect addition of Part 3.
8.11.5 Critical Procedures 
Based on Study Objectives
Updated for the addition of Part 3.  Time 
windows associated with RHC apply to 
Part 2 only. FRI defined as critical 
procedure in Part 3.
To reflect addition of Part 3. To define RHC applies 
only to Part 2.
9.1 Statistical Analysis Plan 
Summary
Added that Part 3 will be part of secondary 
and exploratory analysis.
Updated to account for the inclusion of Part 3.
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Section # and Name
Description of Change 
Brief Rationale 
9.4 Analysis Endpoints
Secondary and Exploratory Analysis 
endpoints updated to include Part 3
Updated to account for the inclusion of Part 3.
9.6 Statistical Methods
Updated to include Part 3.
Updated to account for the inclusion of Part 3.
9.7 Interim Analysis
Part 2 CPET and FRI data will be analyzed 
to determine adequate sample size timing 
for triggering Part 3
A more robust dataset for FRI and CPET may or may 
not be needed depending on outcome preliminary 
analysis. This will determine timing to trigger Part 3.
10.8 Appendix 8 Blood 
Volume Table
Blood Volume Table for Part 3 added
Hepatitis B DNA sample, if needed, has 
been added to blood volume table
Blood volume requirements differ for Part 3 due to 
elimination of RHC.
To confirm Hepatitis B is chronic.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................21
2
INTRODUCTION..........................................................................................................49
2.1
Study Rationale....................................................................................................49
2.2
Background ..........................................................................................................49
2.2.1
Pharmaceutical and Therapeutic Background .............................................49
2.2.2
Preclinical and Clinical Studies ...................................................................50
2.2.3
Ongoing Clinical Studies.............................................................................52
2.2.4
Information on Other Study-related Therapy ..............................................54
2.3
Benefit/Risk Assessment......................................................................................54
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................54
4
STUDY DESIGN............................................................................................................57
4.1
Overall Design......................................................................................................57
4.2
Scientific Rationale for Study Design.................................................................59
4.2.1
Rationale for Endpoints ...............................................................................60
4.2.1.1
Efficacy Endpoints.............................................................................60
4.2.1.2
Safety Endpoints................................................................................60
4.2.1.3
Pharmacokinetic Endpoints ...............................................................60
4.2.1.4
Pharmacodynamic Endpoints.............................................................60
4.2.1.5
Planned Exploratory Biomarker Research.........................................61
4.2.1.5.1
Planned Genetic Analysis ........................................................61
4.2.1.6
Future Biomedical Research..............................................................61
4.2.2
Rationale for the Use of Comparator/Placebo .............................................62
4.3
Justification for Dose...........................................................................................62
4.3.1
Starting Dose for This Study........................................................................62
4.3.2
Maximum Dose/Exposure for This Study ...................................................63
4.3.3
Rationale for Dose Interval and Study Design ............................................64
4.4
Beginning and End of Study Definition .............................................................64
4.4.1
Clinical Criteria for Early Study Termination .............................................64
5
STUDY POPULATION ................................................................................................65
5.1
Inclusion Criteria.................................................................................................65
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5.2
Exclusion Criteria................................................................................................68
5.3
Lifestyle Considerations......................................................................................73
5.3.1
Meals and Dietary Restrictions....................................................................73
5.3.1.1
Diet Restrictions.................................................................................73
5.3.1.2
Fruit Juice Restrictions ......................................................................74
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................74
5.3.2.1
Caffeine Restrictions..........................................................................74
5.3.2.2
Alcohol Restrictions...........................................................................74
5.3.2.3
Tobacco Restrictions..........................................................................74
5.3.3
Activity Restrictions ....................................................................................75
5.4
Screen Failures.....................................................................................................75
5.5
Participant Replacement Strategy......................................................................75
6
STUDY INTERVENTION............................................................................................75
6.1
Study Intervention(s) Administered...................................................................75
6.2
Preparation/Handling/Storage/Accountability .................................................78
6.2.1
Dose Preparation..........................................................................................78
6.2.2
Handling, Storage, and Accountability........................................................78
6.3
Measures to Minimize Bias: Randomization and Blinding..............................79
6.3.1
Intervention Assignment..............................................................................79
6.3.2
Stratification.................................................................................................79
6.3.3
Blinding........................................................................................................79
6.4
Study Intervention Compliance..........................................................................80
6.5
Concomitant Therapy..........................................................................................80
6.5.1
Rescue Medications and Supportive Care ...................................................82
6.6
Dose Modification (Escalation/Titration/Other)...............................................82
6.6.1
Stopping Rules.............................................................................................83
6.7
Intervention After the End of the Study............................................................83
6.8
Clinical Supplies Disclosure................................................................................83
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................84
7.1
Discontinuation of Study Intervention...............................................................84
7.2
Participant Withdrawal From the Study...........................................................85
7.3
Lost to Follow-up .................................................................................................85
8
STUDY ASSESSMENTS AND PROCEDURES........................................................85
8.1
Administrative and General Procedures ...........................................................86
8.1.1
Informed Consent.........................................................................................86
8.1.1.1
General Informed Consent.................................................................86
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................87
8.1.2
Inclusion/Exclusion Criteria ........................................................................87
8.1.3
Participant Identification Card.....................................................................87
8.1.4
Medical History ...........................................................................................87
8.1.5
Prior and Concomitant Medications Review...............................................88
8.1.5.1
Prior Medications...............................................................................88
8.1.5.2
Concomitant Medications..................................................................88
8.1.6
Assignment of Screening Number...............................................................88
8.1.7
Assignment of Treatment/Randomization Number.....................................88
8.1.8
Study Intervention Administration ..............................................................88
8.1.8.1
Timing of Dose Administration.........................................................88
8.1.9
Discontinuation and Withdrawal .................................................................89
8.1.9.1
Withdrawal From Future Biomedical Research ................................89
8.1.10
Participant Blinding/Unblinding..................................................................89
8.1.11
Domiciling ...................................................................................................90
8.1.12
Calibration of Equipment.............................................................................91
8.2
Efficacy Assessments ...........................................................................................91
8.3
Safety Assessments...............................................................................................91
8.3.1
Physical Examinations.................................................................................91
8.3.2
Vital Signs....................................................................................................92
8.3.2.1
Resting Vital Signs ............................................................................92
8.3.2.2
Orthostatic Vital Signs.......................................................................93
8.3.2.3
Oxygen Saturation .............................................................................93
8.3.3
Electrocardiograms ......................................................................................93
8.3.4
Clinical Safety Laboratory Assessments .....................................................94
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................94
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................95
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......97
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...97
8.4.4
Regulatory Reporting Requirements for SAE .............................................97
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................97
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................98
8.4.7
Events of Clinical Interest............................................................................98
8.5
Treatment of Overdose........................................................................................98
8.6
Pharmacokinetics.................................................................................................98
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8.6.1
Blood Collection for Plasma MK-5475 .......................................................99
8.7
Pharmacodynamics..............................................................................................99
8.7.1
Right Heart Catheterization Procedure (Part 2)...........................................99
8.7.2
CT Scan for Functional Respiratory Imaging (Parts 2 and 3) ...................100
8.7.3
Cardiopulmonary Exercise Testing (CPET)..............................................100
8.7.4
Pulmonary Function Tests (PFTs- Spirometry).........................................101
8.7.5
Inspiratory Flow Meter Assessment ..........................................................102
8.8
Biomarkers .........................................................................................................102
8.8.1
Planned Genetic Analysis Sample Collection............................................102
8.9
Future Biomedical Research Sample Collection.............................................102
8.10
Health Economics Medical Resource Utilization and Health Economics.....102
8.11
Visit Requirements.............................................................................................102
8.11.1
Screening....................................................................................................103
8.11.2
Treatment Period........................................................................................103
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ........105
8.11.4
Poststudy....................................................................................................105
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.....105
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters ...................................................................................107
9
STATISTICAL ANALYSIS PLAN ...........................................................................108
9.1
Statistical Analysis Plan Summary...................................................................108
9.2
Responsibility for Analyses...............................................................................109
9.3
Hypotheses/Estimation ......................................................................................109
9.4
Analysis Endpoints.............................................................................................109
9.5
Analysis Populations..........................................................................................110
9.6
Statistical Methods.............................................................................................110
9.7
Interim Analyses ................................................................................................112
9.8
Multiplicity .........................................................................................................112
9.9
Sample Size and Power Calculations ...............................................................112
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................113
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......113
10.1.1
Code of Conduct for Clinical Trials...........................................................113
10.1.2
Financial Disclosure...................................................................................115
10.1.3
Data Protection...........................................................................................115
10.1.3.1
Confidentiality of Data ....................................................................116
10.1.3.2
Confidentiality of Participant Records.............................................116
10.1.3.3
Confidentiality of IRB/IEC Information..........................................116
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10.1.4
Publication Policy......................................................................................116
10.1.5
Compliance with Study Registration and Results Posting Requirements .117
10.1.6
Compliance with Law, Audit, and Debarment ..........................................117
10.1.7
Data Quality Assurance .............................................................................118
10.1.8
Source Documents .....................................................................................119
10.1.9
Study and Site Closure...............................................................................119
10.2
Appendix 2: Clinical Laboratory Tests............................................................120
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................122
10.3.1
Definition of AE ........................................................................................122
10.3.2
Definition of SAE ......................................................................................123
10.3.3
Additional Events Reported.......................................................................124
10.3.4
Recording AE and SAE .............................................................................124
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................128
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................129
10.5
Appendix 5: Contraceptive Guidance..............................................................130
10.5.1
Definitions..................................................................................................130
10.5.2
Contraception Requirements......................................................................131
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................132
10.7
Appendix 7: Country-specific Requirements..................................................137
10.8
Appendix 8: Blood Volume Table ....................................................................138
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....140
10.10 Appendix 10: Hemodynamic Stopping Criteria..............................................141
10.11 Appendix 11: Guidelines for the Treatment of Hypo/Hypertension.............143
10.12 Appendix 12: Abbreviations .............................................................................145
11
REFERENCES.............................................................................................................148
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LIST OF TABLES
Table 1
Geometric Mean AUC0-24 Actual and Predicted .....................................63
Table 2
Study Interventions....................................................................................76
Table 3
Sample Allocation schedule (Parts 1 and 2) ..............................................79
Table 4
Sample Allocation schedule (Part 3)..........................................................79
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................96
Table 6
Pharmacokinetic (Blood) Collection Windows .......................................106
Table 7
Protocol-required Laboratory Assessments.............................................121
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LIST OF FIGURES
Figure 1
Part 1 Study Design ...................................................................................19
Figure 2
Part 2 Study Design ...................................................................................20
Figure 3
Part 3 Study Design ...................................................................................20
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Multiple Dose MK-5475 in Participants with Pulmonary Hypertension 
Associated with COPD
Short Title: MK-5475 PH-COPD Study
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
This study is to be conducted in male and female participants diagnosed with PH-COPD.
Primary Objectives
Primary Endpoints
- Objective: To assess the safety and 
tolerability of MK-5475 in participants 
with pulmonary hypertension associated 
with chronic obstructive pulmonary 
disease following 7 and 28 days of dosing. 
(Parts 1, 2 and 3)
- Safety and tolerability will be evaluated 
during clinical assessments that include 
vital signs, safety laboratory testing, 
physical examinations, ECG readings, and 
review of adverse events (AEs). (Parts 1, 
2 and 3)
- Objective: To assess the effect of MK-
5475 on pulmonary vascular resistance 
following 28 days of dosing in 
participants with pulmonary hypertension 
associated with chronic obstructive 
pulmonary disease. (Part 2)
- Hypothesis: MK-5475 reduces mean 
pulmonary vascular resistance following 
28 days of dosing in participants with 
pulmonary hypertension associated with 
chronic obstructive pulmonary disease 
when compared to placebo. A true mean 
difference (MK-5475-placebo) of 15% is 
considered clinically meaningful. (Part 2)
- Percent change from baseline for PVR of 
MK-5475/placebo on Day 28 in Part 2.
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Secondary Objectives
Secondary Endpoints
- To obtain preliminary plasma 
pharmacokinetic data of MK -5475 (e.g 
AUC0-24, AUC0-inf, Cmax, Tmax, 
terminal half-life, accumulation ratio) in 
participants with pulmonary hypertension 
associated with chronic obstructive 
pulmonary disease (Parts 1, 2 and 3)
- AUC0-inf, AUC0-24, Cmax, C24, Tmax, 
apparent terminal half-life, accumulation 
ratio
- To assess the effect of multiple inhaled 
doses of MK-5475 on pulmonary blood 
volume in participants with pulmonary 
hypertension associated with chronic 
obstructive pulmonary disease (Parts2 
and 3)
- Percent change from baseline for PBV of 
MK-5475/placebo on Day 28 in Parts 2 
and 3.
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Pulmonary Hypertension
Population
Participants with pulmonary hypertension associated with COPD
Study Type
Interventional
Intervention Model
Sequential
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration 
of Study
The Sponsor estimates that the study will require approximately
12 to 21 months 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 24-48 participants will be allocated/randomized such that evaluable 
participants complete the study as described in Section 9.5.
Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group Part
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen 
Treatment 
Period
Use
Part 1
MK-5475
360 µg
Once Daily
Inhalation
Days 1-7a
Experimental
Pbo
0 µg
Once Daily
Inhalation
Days 1-7
Pbo control
Pbo
0 µg
Once
Inhalation
Screening 2
Training
Parts 2 and 3
MK-5475 
380 µgb
Once Daily
Inhalation
Days 1-28
Experimental
Pbo
0 µg
Once Daily
Inhalation
Days 1-28
Pbo control
Pbo
0 µg
Once
Inhalation
Screening 2
Training
Abbreviations: Pbo = Placebo, µg = micrograms
a Following review of PK and safety data, a second 7 days of dosing may be initiated A dose of up 
to 360 µg up to twice a day may be administered based on PK data in this population. 
b Dose strength may be adjusted downwards, if indicated. 
Total 
Number
4
Duration of 
Participation
Each participant will participate in the study for approximately 10 to 16
weeks from the time the participant provides documented informed consent
through the final contact. After a screening phase of up to 5 weeks, each 
participant in Part 1 will be receiving assigned intervention for 
approximately 7 to 14 days and each participant in Parts 2 and 3 will be 
receiving assigned intervention for approximately 27 to 32 days. Participants 
in Part 1 may participate in Part 2 or 3 upon SPONSOR agreement. 
Participants in Part 2 may not participate in Part 3. After the end of 
treatment, each participant will be followed for 14 days.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 13.
1.2
Schema
A high-level study design is depicted in Figure 1, Figure 2 and Figure 3. Refer to SOA 
(Section 1.3) for full details.
Figure 1
Part 1 Study Design
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Figure 2
Part 2 Study Design
Figure 3
Part 3 Study Design
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1.3
Schedule of Activities
Part 1 (Period 1)
Study Period:
Screening
Intervention
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Screening 1
≤35 days
prerandomization
Screening 2
≤7 days 
prerandomization
Predose Day 1
D1
D2
D3
D4
D5
D6 D7
Post-studya
A second 7-day dosing period 
may be implemented following 
review of safety and PK data.
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research (optional)
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
X
X
Medical History
X
X
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
Assignment of Screening Number
X
Assignment of 
Treatment/Randomization Number
X
MK-5475/Placebo Witness Dosing
X
X
X
X
X
X
X
Domiciling
X
X
X
See Section 8.1.11 for 
domiciling details
Standard Meals
X
X
Days 1 and 7:  Meals 4 and 10 
hrs postdose. Snacks at 7 and 
13 hrs postdose.
See Section 5.3.1 additional 
meal details
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Part 1 (Period 1)
Study Period:
Screening
Intervention
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Screening 1
≤35 days
prerandomization
Screening 2
≤7 days 
prerandomization
Predose Day 1
D1
D2
D3
D4
D5
D6 D7
Post-studya
A second 7-day dosing period 
may be implemented following 
review of safety and PK data.
Inhaler Training/placebo 
administration
X
Preferably done at Screening 2 
but, may be done at screening 1 
if within 7 days of Predose Day 
1. Retraining may occur during 
dosing period, at discretion of 
investigator
Training with Spirometry Device
X
Training will be done for each 
participant at one occasion for 
site spirometry measures
Inspiratory Flow Meter Assessment
X
X
X
X
X
X
X
X
Preferably done at Screening 2 
but, may be done at screening 1 
if within 7 days of Day 1. 
Days 1-7: Predose First daily
dose only
Safety Procedures
Full physical examination
X
X
X
X
Day 1: Predose
Day 7: 24 hr post dose. 
See Section 8.3.1 for PE
procedure: 
See Section 8.11.5 for timing 
window.
Height
X
See Section 8.3.1 for height and 
weight procedures
Weight
X
X
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Part 1 (Period 1)
Study Period:
Screening
Intervention
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Screening 1
≤35 days
prerandomization
Screening 2
≤7 days 
prerandomization
Predose Day 1
D1
D2
D3
D4
D5
D6 D7
Post-studya
A second 7-day dosing period 
may be implemented following 
review of safety and PK data.
Heart Rate (HR), Blood Pressure 
(BP)
X
X
X
X
X
X
X
X
X
X
Days 1: Predose and 3 hrs post 
dose
Days 2 -6:  Predose
Day 7: Predose, 1, 3 and 24 hrs 
post dose. 
Take before and after 6MWT
on Days 1 and 7. See operations 
manual for 6MWT.
See Section 8.3.2 for all vital 
sign procedures. 
See Section 8.11.5 for timing 
window.
Orthostatic Vital Signs
X
X
X
X
Days 1 and 4:  Predose
Day 7: Predose and 24 hrs 
postdose
Respiratory Rate (RR)
X
X
X
X
X
X
X
X
X
X
Day 1: Predose and 3 hrs 
postdose
Days 2 -6: Predose
Day 7: Predose and 24hrs 
postdose
Body Temperature 
X
X
X
X
Day 1: Predose
Day 7: 24 hrs postdose
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Part 1 (Period 1)
Study Period:
Screening
Intervention
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Screening 1
≤35 days
prerandomization
Screening 2
≤7 days 
prerandomization
Predose Day 1
D1
D2
D3
D4
D5
D6 D7
Post-studya
A second 7-day dosing period 
may be implemented following 
review of safety and PK data.
12-lead ECG
X
X
X
X
X
X
Day 1: Predose and 3 hrs 
postdose
Day 4:  Predose
Day 7: Predose, 3 and 24 hrs 
postdose
See Section 8.3.3 for all 
appropriate ECG procedures.
See Section 8.11.5 for timing 
window.
Echocardiogram (if needed)
X
Follow site SOP for assessment 
High Resolution CT Scan (if needed) X
Follow site SOP for CT 
procedure
PFTs
X
X
X
Day1: Predose
Day 7: Predose and 24 hr 
postdose.
See Section 8.7.4 for 
parameters to be performed at 
screening and during 
intervention period. 
See Section 8.11.5 for timing 
window.
Serum
(β-hCG; WOCBP only)
X
X
Urine Pregnancy Test (WOCBP 
only)
X
Serum FSH - (WONCBP only)
X
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Part 1 (Period 1)
Study Period:
Screening
Intervention
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Screening 1
≤35 days
prerandomization
Screening 2
≤7 days 
prerandomization
Predose Day 1
D1
D2
D3
D4
D5
D6 D7
Post-studya
A second 7-day dosing period 
may be implemented following 
review of safety and PK data.
HIV, hepatitis B and C screen (per 
site SOP)
X
UDS or BDS (per site SOP)
X
X
Screening and D1 predose UDS 
or BDS is mandatory, any 
additional UDS or BDS are 
conducted per site SOP
ABGs
X
X
On room air, if tolerated by 
participant.
Follow site SOP for ABG 
procedure.
Day 1: Predose 
Day 7: 24 hrs postdose
Oxygen Saturation (Pulse Oximetry)
X
X
X
X
X
On room air, if tolerated by 
participant.
Day 1: Predose
Day 2: Predose
Day 4: Predose
Day 7: Predose and 24 hrs 
postdose.
Before and after 6MWT
Hematology
X
X
X
X
Day 1: Predose
Day 7: 24 hrs postdose
See Appendix 2 for laboratory 
test details
Urinalysis
X
X
X
X
Chemistry
X
X
X
X
PT/ aPTT
X
X
X
X
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
See all sections under 8.4
AE/SAE review via contact
X
Contact 14 days post Day 7 to 
assess for AEs 
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Part 1 (Period 1)
Study Period:
Screening
Intervention
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Screening 1
≤35 days
prerandomization
Screening 2
≤7 days 
prerandomization
Predose Day 1
D1
D2
D3
D4
D5
D6 D7
Post-studya
A second 7-day dosing period 
may be implemented following 
review of safety and PK data.
Pharmacokinetics
Blood for Plasma MK-5475 and or 
Metabolites Assay
X
X
X
X
X
X
X
X
Days 1: Predose, 5 min, 15 min, 
0.5, 1, 2, 3, 4 and 8 hrs 
postdose
Day 2 - 6: 1 hr post dose
Day 7: Predose, 5 min, 15 min, 
0.5, 1, 2, 3, 4. 8 and 24 hrs 
postdose
See operations manual for 
sample processing details.
Pharmacodynamics
MMRC Breathlessness Scale
X
Borg Dyspnea Scale
X
X
Day 1: Predose
Day 7: 24 hrs postdose
To be performed before and 
after 6MWT
Shortness of Breath Questionnaire 
(SOBQ)
X
X
Day 1:  Predose
Day 7: 24 hrs postdose
6 MWT
X
X
Day 1 Predose
Day 7: 24 hrs postdose
Biomarkers
Blood for Genetic Analysis 
X
Collect predose. See sections 
8.8 and 8.9
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Part 1 (Period 1)
Study Period:
Screening
Intervention
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Screening 1
≤35 days
prerandomization
Screening 2
≤7 days 
prerandomization
Predose Day 1
D1
D2
D3
D4
D5
D6 D7
Post-studya
A second 7-day dosing period 
may be implemented following 
review of safety and PK data.
a Post study visit will occur at the completion of the final dosing period (Period 1 or Period 2, if needed). The decision to move to Period 2, if needed will be communicated 
through a Protocol Clarification Letter. If Period 2 is not needed, the poststudy visit after Period 1 will occur within approximately 14 days after the decision being communicated.
6 MWT = 6 Minute Walk Test; ABG=Arterial Blood Gas; AE=adverse event;  β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen;  CT = computed 
tomography ECG = electrocardiogram; FSH=follicle stimulating hormone; hr= hour; ID=identification; min=minutes; MMRC= Modified Medical Research Council; PE = 
physical exam; PFT=Pulmonary Function Test; PH = pulmonary hypertension; PK= pharmacokinetic; PT = Prothrombin time; aPTT = activated partial thromboplastin time; 
SAE=serious adverse event; SOBQ = Shortness of Breath Questionnaire; SOP=standard operating procedure; UDS=Urine Drug Screen; WOCBP = women of childbearing 
potential; WONCBP = women of non-childbearing potential
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Part 1 (Period 2, if needed)
Study Period:
Intervention 
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Predose Day 1
D1
D2
D3
D4
D5
D6
D7
Post-study
Administrative Procedures
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
X
MK-5475/Placebo Witness Dosing
X
X
X
X
X
X
X
If Period 2 requires twice a day 
dosing, witness dosing will occur for
at least the first dose each day. 
MK-5475/placebo at home dosing (second 
dose only, if needed)
X
X
X
X
X
If there is twice a day dosing and 
time between first and second is 
more than 1 hour, home dosing may 
be appropriate at the discretion of the 
investigator. In this case, the 
participant is to bring DPI and dosing 
diary to CRU for witness dosing and 
diary review
MK-5475/Placebo and Dose Diary 
Dispensing (if needed)
X
DPI used for witness dosing will be 
sent with participant for at home 
dosing
Domiciling
X
X
X
See Section 8.1.11 for domiciling 
details
Standard Meals
X
X
Days 1 and 7:  Meals 4 and 10 hrs 
postdose. Snacks at 7 and 13 hrs 
postdose.
See Section 5.3.1 additional meal 
details
Inspiratory Flow Meter Assessment
X
X
X
X
X
X
X
Days 1-7: Predose First daily dose 
only
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Part 1 (Period 2, if needed)
Study Period:
Intervention 
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Predose Day 1
D1
D2
D3
D4
D5
D6
D7
Post-study
Safety Procedures
Full physical examination
X
X
X
Day 1: Predose
Day 7: 24 hr post dose. 
See Section 8.3.1 for PE procedure: 
See Section 8.11.5 for timing 
window.
Weight
X
Heart Rate (HR), Blood Pressure (BP)
X
X
X
X
X
X
X
X
X
Days 1: Predose and 3 hrs post dose
Days 2 -6:  Predose
Day 7: Predose, 1, 3 and 24 hrs post 
dose. 
Take before and after 6MWT on 
Days 1 and 7. See operations manual 
for 6MWT.
See Section 8.3.2 for all vital sign 
procedures. 
See Section 8.11.5 for timing 
window.
Orthostatic Vital Signs
X
X
X
Days 1 and 4:  Predose
Day 7: Predose and 24 hrs postdose
Respiratory Rate (RR)
X
X
X
X
X
X
X
X
X
Day 1: Predose and 3 hrs postdose
Days 2 -6: Predose
Day 7: Predose and 24hrs postdose
Body Temperature 
X
X
X
Day 1: Predose
Day 7: 24 hrs postdose
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Part 1 (Period 2, if needed)
Study Period:
Intervention 
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Predose Day 1
D1
D2
D3
D4
D5
D6
D7
Post-study
12-lead ECG
X
X
X
X
X
Day 1: Predose and 3 hrs postdose
Day 4:  Predose
Day 7: Predose, 3 and 24 hrs 
postdose
See Section 8.3.3 for all appropriate 
ECG procedures.
See Section 8.11.5 for timing 
window.
PFTs
X
X
Day1: Predose
Day 7: Predose and 24 hr postdose.
See Section 8.7.4 for parameters to 
be performed at screening and during 
intervention period. 
See Section 8.11.5 for timing 
window.
Serum
(β-hCG; WOCBP only)
X
Urine Pregnancy Test (WOCBP only)
X
UDS or BDS (per site SOP)
X
Screening and D1 predose UDS or 
BDS is mandatory, any additional 
UDS or BDS are conducted per site 
SOP
ABGs
X
X
On room air, if tolerated by 
participant.
Follow site SOP for ABG procedure.
Day 1: Predose 
Day 7: 24 hrs postdose
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Part 1 (Period 2, if needed)
Study Period:
Intervention 
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Predose Day 1
D1
D2
D3
D4
D5
D6
D7
Post-study
Oxygen Saturation (Pulse Oximetry)
X
X
X
X
On room air, if tolerated by 
participant.
Day 1: Predose  
Day 2: Predose
Day 4: Predose
Day 7: Predose and 24 hrs postdose.
Before and after 6MWT 
Hematology
X
X
X
Day 1: Predose
Day 7: 24 hrs postdose
See Appendix 2 for laboratory test 
details
Urinalysis
X
X
X
Chemistry
X
X
X
PT/ aPTT
X
X
X
AE/SAE review
X
X
X
X
X
X
X
X
X
See all sections under 8.4
Pharmacokinetics
Blood for Plasma MK-5475 and or 
Metabolites Assay
X
X
X
X
X
X
X
X
Days 1: Predose, 5 min, 15 min, 0.5, 
1, 2, 3, 4 and 8 hrs postdose
Day 2 - 6: 1 hr post dose
Day 7: Predose, 5 min, 15 min, 0.5, 
1, 2, 3, 4. 8 and 24 hrs postdose
See operations manual for sample 
processing details.
Pharmacodynamics
Borg Dyspnea Scale
X
X
Day 1: Predose
Day 7: 24 hrs postdose
To be performed before and after 
6MWT
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Part 1 (Period 2, if needed)
Study Period:
Intervention 
Post-study
Notes
Scheduled Hour, Day, Week, etc.
Predose Day 1
D1
D2
D3
D4
D5
D6
D7
Post-study
Shortness of Breath Questionnaire 
(SOBQ)
X
X
Day 1:  Predose
Day 7: 24 hrs postdose
6 MWT
X
X
Day 1 Predose
Day 7: 24 hrs postdose
a Post study visit will occur at the completion of the final dosing period (Period 1 or Period 2, if needed). 
6 MWT = 6 Minute Walk Test; ABG=Arterial Blood Gas; AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen;   ECG = 
electrocardiogram; hr= hour; min=minutes; PE = physical exam; PFT=Pulmonary Function Test; PH = pulmonary hypertension; PK= pharmacokinetic; PT = Prothrombin 
time; aPTT = activated partial thromboplastin time; SAE=serious adverse event; SOBQ = Shortness of Breath Questionnaire; SOP=standard operating procedure; UDS=Urine 
Drug Screen; WOCBP = women of childbearing potential; 
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
(optional)
X
Inclusion/Exclusion Criteria
X
X
X
X
Participant Identification Card
X
Medical History
X
X
X
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
Days 2-14 and 16-27: Conmed review 
will occur at least 2x/week via phone 
call. May occur more often at 
investigator discretion.
Assignment of Screening 
Number
X
Assignment of 
Treatment/Randomization 
Number
X
MK-5475/Placebo and Dose 
Diary Dispensing
X
DPI used for Day 1 witness dosing will 
be sent with participant for at home 
dosing
MK-5475/Placebo Witness 
Dosing
X
X
X
Participant is to bring DPI and dosing 
diary to CRU for witness dosing and 
diary review
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
MK-5475/pbo Drug 
Accountability
X
X
Cross check of dose counter to dose 
diary to be performed by site staff
Telephone/Virtual Technology 
Contact for at Home Dosing
X
X
To be performed each day +/- 2 hour of 
the Day 1 dosing actual time
Inhaler Training/placebo 
administration
X
Preferably done at Screening 2 but, 
may be done at screening 1 if within 7 
days of Day 1. Retraining may occur 
during dosing period, at discretion of 
investigator
Inspiratory Flow Meter 
Assessment
X
X
X
X
Preferably done at Screening 2 but, 
may be done at screening 1 if within 7 
days of Day 1.
Days 1, 15 and 28: Predose
Safety Procedures
Full physical examination
X
X
See Section 8.3.1 for PE procedure
Targeted physical examination
X
X
Baseline: Prior to the first of 3 PD 
procedures (RHC, FRI or CPET) 
Day 28 : Predose
Targeted PE consists of CV and 
respiratory examination. 
Height
X
See Section 8.3.1 for height and weight 
procedures
Weight
X
X
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Heart Rate (HR), Blood 
Pressure (BP)
X
X
X
X
X
X
X
Baseline Day: Prior to each of the 3 PD 
procedures (RHC, FRI and CPET)
Day 1: Predose, 1 and 3 hrs postdose.
Day 15: Predose
Day 28 (D27-32): Predose, 1 and 3 hrs 
postdose at RHC day    
Pre-RHC procedure and at least every 
5 mins when RHC measures are 
performed.  
If FRI is performed on a separate day 
from RHC, HR/BP will be performed 
prior to the FRI procedure as well. 
-Refer to operations manual for timing 
of HR/BP measures during CPET at 
baseline and on Day 28 (Day 27-32).
-Take before and after 6MWT on Days 
1, 15 and 28 (at RHC day). (Taken 
within 15 minutes of the 6MWT)
See operations manual for 6MWT vital 
sign requirements.
See Section 8.3.2 for vital signs 
procedure.
See Section 8.11.5 for timing window
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Orthostatic Vital Signs
X
X
X
X
Days 1 and 15: Predose
Respiratory Rate (RR)
X
X
X
X
X
X
X
Baseline Day: Prior to the first of the 3 
PD procedures (RHC, FRI and CPET).
Day 1: Predose and 3 hrs postdose
Day 15: Predose
Day 28 (D27-32): To be done predose 
on days the 3 PD (RHC, FRI and 
CPET) measures are performed.
Refer to operations manual for timing 
of additional RR measures during 
CPET.
Body Temperature 
X
X
X
12-lead ECG
X
X
X
X
X
X
X
Baseline Day: Prior to the first of the 3 
PD procedures (RHC, FRI and CPET).
Day 1: Predose and 3 hrs postdose
Day 15: Predose
Day 28: To be done predose on the day 
RHC is performed.
Echocardiogram (if needed)
X
High Resolution CT Scan (if 
needed)
X
Baseline CT scan for FRI may be used 
for assessment of exclusion criteria 
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
PFTs
X
X
X
Baseline and Day 28 PFTs are 
performed as part of CPET procedure.
Under special circumstances, if CPET 
is not performed, then Baseline and 
Day 28 PFTs will be done via 
spirometry.
See Section 8.7.4 for PFT details for 
screening and baseline /intervention 
periods.
Serum
(β-hCG; WOCBP only)
X
X
Urine Pregnancy Test 
(WOCBP only)
X
X
Serum FSH - (WONCBP only)
X
HIV, hepatitis B and C screen 
(per site SOP)
X
UDS or BDS (per site SOP)
X
X
Screening and baseline Day-1 UDS or 
BDS is mandatory, any additional UDS
or BDS are conducted per site SOP
ABGs
X
X
On room air as tolerated. 
Day 1 and 28 (at RHC day): Predose
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Oxygen Saturation (Pulse 
Oximetry)
X
X
X
X
X
X
On room, air as tolerated
Baseline and Day 28 at least every 5 
minutes while RHC is in progress.
During CPET assessment
Days 1, 15 and 28 (at RHC day): 
Predose and before and after 6MWT
Hematology
X
X
X
X
X
Days 15 and 28 (at RHC day): Predose
See Appendix 2 for laboratory test 
details.
At baseline (prior RHC) and Day 28 
(prior RHC), a local lab may also be 
used in addition to the central lab to 
assess certain parameters quickly at 
discretion of investigator. This does not 
replace the need to collect central lab 
safety.
Urinalysis
X
X
X
X
X
Chemistry
X
X
X
X
X
PT/ INR and aPTT
X
X
X
X
X
AE/SAE review
X
X
X
X
X
X
X
X
X
Days 2-14 and 16-27: AE/SAE review 
will occur at least 2x/week via phone 
call. May occur more often at 
investigator discretion
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Pharmacokinetics
Blood for Plasma MK-5475 
and or Metabolites Assay
X
X
X
Days 1: Predose, 0.5, 1, 2 and 3 hrs 
postdose
Day 15: 1 hr postdose
Day 28: Predose, 0.5, 1, 2 and 3 hrs 
postdose on the Day RHC is 
performed. PK sample is also to be 
drawn prior to start of RHC procedure.
If FRI is done on a different day from 
RHC, then additional PK samples will 
be drawn prior to start of FRI 
procedure
Pharmacodynamics
MMRC Breathlessness Scale
X
Borg Dyspnea Scale
X
X
X
Days 1, 15: Predose
Day 28 (at RHC day): 1hr postdose
To be done Pre and post 6MWT
Shortness of Breath 
Questionnaire (SOBQ)
X
X
X
Days 1, 15: Predose
Day 28 (at RHC day):  1 hr postdose
6MWT
X
X
X
Days 1, 15: Predose
Day 28 (at RHC day): 1hr postdose
Right Heart Catheterization 
(RHC) Measurements 
X
X
Day 28: 6 to 8 hrs post dose
See operations manual and Section 8. 
7.1 for details.
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Part 2
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Mixed Venous O2 Saturation
X
X
Day 28: 6 to 8 hrs post dose
Baseline and Day 28 measures are to 
be taken during RHC, at least 5
minutes apart.  See operations manual 
and Section 8. 7.1 for details.
CT Scan for Functional 
Respiratory Imaging (FRI)
X
X
Day 28: 6 to 8 hrs post dose
See Section 8.7.2
CPET
X
X
Day 28: 5.5 hrs post dose.
See Section 4.1 and 8.7.3
Biomarkers
Blood for Genetic Analysis 
X
Collect predose 
See sections 8.8 and 8.9
NTproBNP
X
X
Day 28 (at RHC day): Predose
See Appendix 2 for details
6MWT = 6 Minute Walk Test; ABG=Arterial Blood Gas; AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; CPET = Cardiopulmonary 
exercise testing; CT = computed tomography; CV = cardiovascular;  DPI = dry powder inhaler; ECG = electrocardiogram;  FBR = Future Biomedical Research;  FRI = 
Functional respiratory imaging;  FSH=follicle stimulating hormone; ID=identification;  MMRC= Modified Medical Research Council; NTproBNP= N-terminal pro-hormone b-
type natriuretic peptide; PE= physical exam; PFT=Pulmonary Function Test; PT = Prothrombin time; aPTT = activated partial thromboplastin time; RHC= Right heart 
catheterization; SAE=serious adverse event; SOBQ = Shortness of Breath Questionnaire; SOP=standard operating procedure; UDS=Urine Drug Screen; WOCBP = women of 
childbearing potential; WONCBP = women of non-childbearing potential
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
(optional)
X
Inclusion/Exclusion Criteria
X
X
X
X
Participant Identification Card
X
Medical History
X
X
X
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
Days 2-14 and 16-27: Conmed review 
will occur at least 2x/week via phone 
call. May occur more often at 
investigator discretion.
Assignment of Screening 
Number
X
Assignment of 
Treatment/Randomization 
Number
X
MK-5475/Placebo and Dose 
Diary Dispensing
X
DPI used for Day 1 witness dosing will 
be sent with participant for at home 
dosing
MK-5475/Placebo Witness 
Dosing
X
X
X
Participant is to bring DPI and dosing 
diary to CRU for witness dosing and 
diary review
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
MK-5475/pbo Drug 
Accountability
X
X
Cross check of dose counter to dose 
diary to be performed by site staff
Telephone/Virtual Technology 
Contact for at Home Dosing
X
X
To be performed each day +/- 2 hours
of the Day 1 dosing actual time
Inhaler Training/placebo 
administration
X
Preferably done at Screening 2 but, 
may be done at screening 1 if within 7 
days of Day 1. Retraining may occur 
during dosing period, at discretion of 
investigator
Inspiratory Flow Meter 
Assessment
X
X
X
X
Preferably done at Screening 2 but, 
may be done at screening 1 if within 7 
days of Day 1.
Days 1, 15 and 28: Predose
Safety Procedures
Full physical examination
X
X
See Section 8.3.1 for PE procedure
Targeted physical examination
X
X
Baseline: Prior to the first of 2 PD 
procedures (FRI or CPET) 
Day 28 : Predose
Targeted PE consists of CV and 
respiratory examination. 
Height
X
See Section 8.3.1 for height and weight 
procedures
Weight
X
X
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Heart Rate (HR), Blood 
Pressure (BP)
X
X
X
X
X
X
X
Baseline Day: Prior to each of the 2 PD 
procedures (FRI and CPET)
Day 1: Predose, 1 and 3 hrs postdose.
Day 15: Predose
Day 28 (D27-32): Predose, 1 and 3 hrs 
postdose    HR/BP will be performed 
prior to the FRI procedure. 
-Refer to operations manual for timing 
of HR/BP measures during CPET at 
baseline and on Day 28 (Day 27-32).
-Take before and after 6MWT on Days 
1, 15 and 28. (taken within 15 minutes 
of 6MWT).
See operations manual for 6MWT vital 
sign requirements.
See Section 8.3.2 for vital signs 
procedure.
See Section 8.11.5 for timing window
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Orthostatic Vital Signs
X
X
X
X
Days 1 and 15: Predose
Respiratory Rate (RR)
X
X
X
X
X
X
X
Baseline Day: Prior to the first of the 2
PD procedures (FRI and CPET).
Day 1: Predose and 3 hrs postdose
Day 15: Predose
Day 28 (D27-32): To be done predose 
on days the 2 PD (FRI and CPET) are 
performed
Refer to operations manual for timing 
of additional RR measures during 
CPET.
Body Temperature 
X
X
X
12-lead ECG
X
X
X
X
X
X
X
Baseline Day: Prior to the first of the 2 
PD procedures (FRI and CPET).
Day 1: Predose and 3 hrs postdose
Day 15: Predose
Day 28: Predose
High Resolution CT Scan (if 
needed)
X
Baseline CT scan for FRI may be used 
for assessment of exclusion criteria 
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
PFTs
X
X
X
Baseline and Day 28 PFTs are 
performed as part of CPET procedure. 
Under special circumstances, if CPET 
is not performed, then Baseline and 
Day 28 PFTs will be done via 
spirometry.
See Section 8.7.4 for PFT details for 
screening and baseline /intervention 
periods.
Serum
(β-hCG; WOCBP only)
X
X
Urine Pregnancy Test 
(WOCBP only)
X
X
Serum FSH - (WONCBP only)
X
HIV, hepatitis B and C screen 
(per site SOP)
X
UDS or BDS (per site SOP)
X
X
Screening and baseline Day-1 UDS or 
BDS is mandatory, any additional UDS
or BDS are conducted per site SOP
ABGs
X
X
On room air as tolerated. 
Day 1 and 28: Predose
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Oxygen Saturation (Pulse 
Oximetry)
X
X
X
X
X
X
On room, air as tolerated.
During CPET assessment on Days -1 
and 28.
Days 1, 15 and 28: Predose and also 
before and after 6MWT
Hematology
X
X
X
X
X
Days 15 and 28: Predose
See Appendix 2 for laboratory test 
details.
At baseline and Day 28, a local lab 
may also be used in addition to the 
central lab to assess certain parameters 
quickly at discretion of investigator. 
This does not replace the need to 
collect central lab safety.
Urinalysis
X
X
X
X
X
Chemistry
X
X
X
X
X
PT/ INR and aPTT
X
X
X
X
X
AE/SAE review
X
X
X
X
X
X
X
X
X
Days 2-14 and 16-27: AE/SAE review 
will occur at least 2x/week via phone 
call. May occur more often at 
investigator discretion
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
Pharmacokinetics
Blood for Plasma MK-5475 
and or Metabolites Assay
X
X
X
Days 1: Predose, 0.5, 1, 2 and 3 hrs 
postdose
Day 15: 1 hr postdose
Day 28: Predose, 0.5, 1, 2 and 3 hrs 
postdose and Pre- FRI (6-8 hours 
postdose).
  
If FRI and CPET are done on different 
days, then  PK samples will be drawn 
prior to the start of both the CPET and 
FRI.
Pharmacodynamics
MMRC Breathlessness Scale
X
Borg Dyspnea Scale
X
X
X
Days 1, 15: Predose
Day 28: 1hr postdose
To be done Pre and post 6MWT
Shortness of Breath 
Questionnaire (SOBQ)
X
X
X
Days 1, 15: Predose
Day 28:  1 hr postdose
6MWT
X
X
X
Days 1, 15: Predose
Day 28: 1hr postdose
CT Scan for Functional 
Respiratory Imaging (FRI)
X
X
Day 28: 6 to 8 hrs post dose
See Section 8.7.2
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Part 3
Study Period
Screening
Intervention
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening 1
     ≤35 days 
Screening 2 
     ≤7 days 
Baseline Day -1
(Day -5 to   -1)
Predose  on Day 1
D1
Days 2-14
D15
(+/- 1 day)
Days 16-27
D28
(D27 to D32)
Post-study
CPET 
X
X
Day 28: 5.5 hrs post dose.
See Section 4.1 and 8.7.3
Biomarkers
Blood for Genetic Analysis 
X
Collect predose 
See sections 8.8 and 8.9
NTproBNP
X
X
Day 28: Predose
See Appendix 2 for details
6MWT = 6 Minute Walk Test; ABG=Arterial Blood Gas; AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; CPET = Cardiopulmonary 
exercise testing; CT = computed tomography; CV = cardiovascular; DPI= dry powder inhaler;  ECG = electrocardiogram;  FBR = Future Biomedical Research;  FRI = 
Functional respiratory imaging;  FSH=follicle stimulating hormone; ID=identification;  MMRC= Modified Medical Research Council; NTproBNP= N-terminal pro-hormone b-
type natriuretic peptide; PE= physical exam; PFT=Pulmonary Function Test; PT = Prothrombin time; aPTT = activated partial thromboplastin time; SAE=serious adverse event; 
SOBQ = Shortness of Breath Questionnaire; SOP=standard operating procedure; UDS=Urine Drug Screen; WOCBP = women of childbearing potential; WONCBP = women of 
non-childbearing potential
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2
INTRODUCTION
2.1
Study Rationale
This is a 3-part, multi-site, multiple-dose trial of MK-5475 in participants with a diagnosis of 
pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD).
MK-5475 has been successfully administered to healthy participants and participants with 
PAH. The primary objective for this study is to assess MK-5475 in the PH- COPD 
population by evaluating the safety, pharmacokinetic and pharmacodynamics [including
changes in pulmonary vascular resistance (PVR), pulmonary blood volume (PBV) and
exercise tolerance].
Currently, there are no specific drug therapies for PH associated with lung diseases.
Localized/inhaled delivery of the sGC stimulator MK-5475 is anticipated to provide benefit 
in the PH-COPD patient population by selectively reducing pulmonary vascular resistance 
and pulmonary pressure via sGC/cGMP-mediated pulmonary vasodilation.
Data from the PAH study (PN002) has indicated that MK-5475 acutely reduces PVR by a 
threshold of at least 20% or more in up to 4.5 hours after administration. Since this 
pharmacodynamic effect is expected to be similar in patients with pulmonary hypertension 
from other causes, this study for PH-COPD will expand on these results by evaluating the 
change in PVR after 4 weeks of dosing.
Given patients with PH-COPD tend to be diagnosed in the middle to older adult age range,
participants to be enrolled in this study will range in age from 40 to 80 years for Parts 1 and 
2. The age range will be from 40 to 85 years for Part 3 given participants will not be 
required to undergo RHC.
Participants with BMI ≤40 kg/m2 may be included; the ongoing PAH (PN002) study permits 
the inclusion of participants with BMI ≤35 kg/m2. Given the lack of safety concerns, based 
on ECG, vital signs, or laboratory safety parameters in the ongoing PAH study (with dosing 
up to 480 µg), Bridging (PN008) as well as from the FIH and MAD studies, the Sponsor does 
not consider there to be an increased risk in PH-COPD participants with BMI up to 40 
kg/m2. Furthermore, participants with clinically significant co-morbidities will be excluded 
from participation per exclusion criterion #1 and #2.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-5475.
2.2.1
Pharmaceutical and Therapeutic Background
Pulmonary arterial hypertension (PAH) is a serious, often fatal condition that involves 
increased blood pressure (BP) in the pulmonary arterial circulation, eventually progressing to 
heart failure and death. A number of therapies for this disease have sought to achieve 
vasodilation of the pulmonary arterial circulation, thus, relieving the elevated pressure in 
these blood vessels and lessening the strain on the heart. One pathway that has been 
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successfully targeted for this purpose is the soluble guanylate cyclase (sGC) pathway. The 
sGC enzyme is physiologically activated by nitric oxide, which triggers intracellular 
messenger molecules that result in dilation of blood vessels. The medication riociguat, which 
is currently approved for treatment of PAH, activates sGC and causes vasodilation. However, 
this and other therapies for PAH are given systemically, which may result in vasodilation 
throughout the systemic circulation as well as the pulmonary circulation. This undesirable 
effect may cause hypotension, limiting the doses of medication that can be given. In addition, 
systemic administration of pulmonary arterial vasodilators to patients with chronic 
obstructive pulmonary disease (COPD) may dilate pulmonary blood vessels in diseased areas 
of lung, causing a mismatch between ventilation and perfusion (“V/Q mismatch”) which may 
cause arterial hypoxemia. This effect has limited the utility of existing medications for 
treatment of patients with pulmonary hypertension associated with COPD (PH-COPD). 
MK-5475 is a small-molecule stimulator of sGC which has been formulated as a dry powder 
for inhaled delivery with the Sponsor’s dry powder inhaler (DPI) device and is being 
developed for treatment of PAH as well as PH-COPD. By optimizing delivery to the lung, 
and hence directly to the pulmonary arterial circulation, preclinical models have shown that 
pulmonary arterial vasodilation can be achieved while limiting systemic exposure. It is also 
anticipated that MK-5475 will be preferentially deposited in areas of lung that are less 
damaged by COPD, thereby preserving the relationship between ventilation and perfusion 
and avoiding V/Q mismatch.
Rats with experimentally-induced pulmonary arterial hypertension were used as the primary 
pharmacodynamic (PD) model. These experiments showed that MK-5475 successfully 
reduced pulmonary arterial pressure in rats with minimal to no change in systemic blood 
pressure, and that inhaled delivery resulted in robust lung exposure to the compound with 
much lower systemic exposure. Based on the preclinical experiments, the clinical experience 
with riociguat, and the expectations for pharmacology of an inhaled compound, MK-5475 is
expected to achieve therapeutically significant reduction of pulmonary arterial pressure in 
patients with PAH, with little or no systemic hemodynamic effect.
As with the lead indication, the primary pharmacodynamic effect of MK-5475 in patients 
with PH-COPD is to induce vasodilation in the pulmonary arterial circulation.
2.2.2
Preclinical and Clinical Studies
Refer to the Investigator’s Brochure for detailed preclinical and clinical information on 
MK-5475. As noted, there were few findings noted in rat studies. In dogs, dose-dependent 
heart rate and blood pressure changes were noted during systemic intravenous delivery only. 
In two 1-month dog studies utilizing inhaled delivery, a dose-dependent slight thickening of 
the bronchial adventitia was noted, and this finding was used to establish the dog NOAEL.
The bronchial artery change seen in these dog inhalation toxicology studies at 0.2-0.4 
mg/kg/day was not observed in the 3-month dog study.
In the first in human study of 16 healthy male participants (PN001), single dose MK-5475 
ranging from 15 to 165 µg was generally well-tolerated. AEs reported were self-limiting and 
ranged from mild to moderate in intensity. No SAEs or events of clinical interest were 
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observed. Most frequently reported AEs were headache and oropharyngeal pain. No 
clinically important findings were observed in vital signs, ECGs, routine lab safety tests, 
pulmonary function tests and physical exams. Single-dose PK data in PN001 showed that 
MK-5475 has a median Tmax of 1 hour at doses ranging from 15-165 µg. The geometric 
mean terminal half-life (t ½) is approximately 2 hours across doses. Plasma exposures (AUC 
and Cmax) of MK-5475 appeared to show a linear upward trend in relationship to increasing 
doses. Maximum AUC0-24 observed was 1.47 nM*hr which is approximately three times 
below the dog NOAEL exposure (4.5 nM*hr). It is expected based on preclinical data and 
translational PK modeling that steady state will be achieved within 24 hours post the first 
dose.
PN002: Dosing of MK-5475 in Participants with Pulmonary Hypertension
This 2-part study evaluated the safety, PK and PD [right heart catheterization (RHC) and 
functional respiratory imaging (FRI)], single-dose MK-5475 ranging from 120 to 480 µg in 
participants with moderate to severe Group 1 PAH. and was generally well-tolerated.  No 
serious adverse events (SAEs) were reported and no participants discontinued due to an AE.  
Adverse events (AEs) were mild to moderate in intensity. A total of 52 AEs in 22 of 25
participants were reported. The most frequently reported AEs in 2 or more participants who 
received MK-5475 were bilirubin increased (1.02 and 2.13 x ULN )(n=2) and hyperkalemia
(1.03 to 1.07 x ULN) (n=2) .The most frequently reported nonintervention related AEs 
reported in 2 or more participants were back pain (n=11) and fatigue(n=2).  Refer to the 
Investigator’s Brochure for a full listing of AEs.
Following single inhaled MK-5475 administration, moderate to high inter- and intra-
individual variability in AUC and Cmax was observed in PAH participants compared to 
healthy participants.  Geometric mean AUC0-24 in PAH participants ranged from 0.259 to 
4.53 nM*hr for the 120 to 480 µg dose levels across study panels/periods. Geometric mean 
AUC0-24 in PAH participants at 240 μg ranged from 1.04 to 1.71 nM*hr. Geometric mean 
AUC0-24 in PAH participants at the 300 μg dose level ranged from 2.08 to 2.35 nM*hr 
across study panels, The geometric mean AUC0-24 at the 360 μg dose level in PAH 
participants ranged 1.21 to 3.82 nM*hr. Geometric mean AUC0-24 in all study populations 
thus far has remained below the AUC0-24 corresponding to NOAEL in 1 month tox study in 
dogs (4.5 nM*hr), except after a single 480 µg dose (AUC0-24=4.53 nM*hr). A total of four 
PAH participants reached an AUC0-24 higher than the dog NOAEL exposure in at least one 
of the periods in the study: one dosed at 300 µg (7.25 nM*hr) and three dosed at 360 µg 
(4.53 to 6.99 nM*hr). The highest individual AUC0-24 at the 360 μg dose level in PAH 
participants was 6.99 nM*hr which is about 1.6-fold above the NOAEL. Although this was 
above the 1-month dog NOAEL, the total dose delivered remained below the NOAEL dose 
of 500 μg. Safety and tolerability profile in participants in whom individual AUC0-24 levels 
exceeded the NOAEL AUC0-24 appears similar to other participants.
There was a mean percent reduction from baseline for the minimum result over the duration 
of the RHC procedure of at least 20% for each of the planned doses (120 µg, 240 µg and 360
µg).
The maximum peak effect for increase PBV was seen at 8 hours after dosing of MK-5475.
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PN003: MK-5475 MAD Study
This double-blind, randomized, placebo-controlled, multiple-ascending dose study to assess 
the safety, tolerability and PK of inhaled doses of MK-5475 in healthy male and female 
participants showed MK-5475 was generally well tolerated for 10 days of multiple dosing 
ranging from 30 to 165 µg and 5 days of dosing at 240 µg.  No SAEs or events of clinical 
interest were reported. No participants discontinued early from the study. Adverse events 
were rated mild to moderate by the investigator. All AEs deemed related by the investigator 
were resolved by discharge from the study.  Most frequently reported AEs by 2 or more 
participants who received MK-5475 were palpitations, abdominal discomfort, diarrhea, 
fatigue, oral herpes, musculoskeletal chest pain, headache, cough, oropharyngeal pain, throat 
irritation and contact dermatitis. Refer to the Investigator’s Brochure for a full listing of AEs. 
This study is clinically complete.
In healthy participants, the geometric mean of AUC0-24 were 0.129, 0.424, 0.975, 1.09 and 
1.71 nM*hr on Day 1 when the 30, 60, 120, 165 and 240 µg doses were administered. On 
Day 10 when the 30, 60, 120 and 165 µg doses were administered, the geometric mean of 
AUC0-24 were 0.218, 0.356, 0.883 and 0.915 nM*hr, respectively. On Day 5 at the 240µg
dose, the geometric mean of AUC0-24 was 2.0 nM*hr.  The terminal half-life on Day 5 and 
10 was approximately 2 hours and is similar to the terminal half-life achieved on Day 1 in the 
first in human study PN001 (1.88 hours). Cmax was 0.390 nM on Day 1 when the 240µg 
dose was administered. The Cmax value reached on Day 5 of dosing at 240 µg was 0.435
nM. Following administration of the 240µg dose for 5 consecutive days, the geometric mean 
AUC0-24 was 2.00 nM*hr which is roughly 2.25 times below the NOAEL (4.5 nM*hr).
PN004: MK5475 Sildenafil DDI Study
This is a randomized, placebo-controlled, crossover, balanced double-blind study of MK-
5475/pbo co-administered with open-label sildenafil to assess the safety tolerability and 
hemodynamic effects during co-administration.  This study was conducted in Belgium and is 
clinically complete. A total of 19 male and female participants were enrolled in the study. No 
SAEs or events of clinical interest were reported. One participant discontinued early from the 
study due to flu-like symptoms. Adverse events were rated mild to moderate by the 
investigator. All AEs deemed related by the investigator were resolved by discharge from the 
study.  Most frequently reported AEs by 2 or more participants which are deemed related to 
MK-5475 by the investigator include:  headache, dizziness, myalgia and hypoesthesia of the 
feet. A preliminary hemodynamic assessment showed that the effect on semi-recumbent SBP 
following the coadministration of MK-5475 and sildenafil is similar to that following 
administration of sildenafil alone
2.2.3
Ongoing Clinical Studies
PN006: MK-5475 PH COPD Study
A total of 9 male and female participants with PH-COPD received and completed 7 days of 
MK-5475 or placebo in Part 1. No SAEs or ECIs were reported and no participants 
discontinued due to an AE. A total of 4 AEs were reported in 4 of the 9 participants.  The 
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most common AE was headache (3). Preliminary blinded review of data showed that MK-
5475 360 μg or placebo was generally well tolerated based on review of safety assessments.
Following once daily inhaled administration of MK-5475 at 360 µg to participants with PH-
COPD for 7 days, median time to reach maximum systemic plasma concentrations was 
1 hour post dose on Day 1 and Day 7.  Geometric mean t1/2 was approximately 2 hours. 
Geometric mean Cmax and AUC0-24 at 360 µg on Day 1 were 0.830 nM and 3.31 nM*hr, 
respectively.  Geometric mean Cmax and AUC0-24 at 360 µg on Day 7 appeared to be 
higher than those on Day 1, with an accumulation ratio of approximately 1.2 for Cmax and 
approximately 1.3 for AUC0-24. AUC 0-24 was slightly less than the NOAEL on Day 7. It is 
noted that the mean concentrations at 1 hour post dose from Days 2 to 6 were comparable to 
that on Day 7, suggesting consistent exposures from Days 2 to 7. One participant had a much 
higher plasma exposure than other participants contributing PK data reported in this memo, 
with the AUC0-24 value of 10.7 nM*hr on Day 1 and 16.9 nM*hr on Day 7, compared to the 
projected NOAEL exposure of 4.5 nM*hr. The plasma Cmax and AUC0-24 data excluding 
results from the participant with very high exposure were generally comparable to that in 
healthy subjects receiving a single 360 µg and 380 µg MK-5475 dose in PN008.
It was determined that a second period in Part 1 was not needed based on safety and PK
from Part 1 of this study.
A total of 8 patients have enrolled in Part 2, to date. No SAEs or ECIs have been reported 
and no participants have discontinued due to an AE. One drug-related AE of watering eyes 
has been reported. There was one ECI of accidental overdose reported. One participant took 
1 additional dose of study drug on 2 different days.  No associated AEs occurred as a result 
of this ECI.  Preliminary blinded review of safety data showed that MK-5475 380 μg or 
placebo has been generally well tolerated.
PN007: Phase 2/3 Study of MK-5475 in Adults with Pulmonary Arterial Hypertension
This is a multicenter, randomized, placebo-controlled, parallel-group, double-blind Phase 2/3 
adaptive study to evaluate the efficacy, safety and tolerability of inhaled MK-5475 in adult 
participants with PAH. A total of 3 participants have enrolled, to date. One SAE of 
gastrointestinal bleed was reported in 1 participant. The participant was on warfarin therapy 
and thus, this AE was determined to be not related to study drug.
PN008: MK-5475 Formulation Bridging Study
This is a randomized, open-label, crossover, balanced study to compare the relative 
bioavailability of the MK-5475 Phase 1 formulation of 360, 120 μg and 240 μg to FMF of 
380, 100 and 195 μg, respectively. A total of 50 male and/or female participants have 
enrolled and received single-inhaled doses of MK-5475 ranging from 100 to 380 µg in this 
study. As the study is ongoing, the data presented is preliminary.  No SAEs or ECIs have 
been reported and no participants have discontinued due to an AE. A total of 10 non-serious 
AEs have been reported in 9 participants. All AEs were rated as mild in intensity. The most 
common AE reported is headache (3) and macular rash (2).  The 2 AEs of macular erythema 
rash were reported in 2 participants. The one participant developed a rash 24 hours postdose 
in Period 2. According to the investigator the rash appeared to look like insect bites. The 
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participant reported having been outdoors a few days prior to the dosing period. The second 
participant had a medical history of rash and it had worsened during the dosing period. The 
investigator deemed the AEs of rash as not related to study drug.
In healthy participants, median Tmax was 1-hour post dose following a single-dose 
inhalation at the 380 µg or 360 µg dose; geometric mean apparent terminal half-life was 
approximately 2 hours for either dose.  Variability in PK parameters for the 380 µg dose 
using the single-actuation FMF was similar to that for the 360 μg (6 x 60 µg) dose using the 
Phase 1 formulation. The geometric mean Cmax (0.56 hr*nmol/L) and AUC (2.02 
hr*nmol/L) following a single-dose inhalation at the 380 µg dose were lower than those at 
360 µg.  Cmax and AUC0-inf geometric mean ratio (90% confidence interval) (GMR [90% 
CI]) for the 380 µg to 360 µg comparison were 0.81 [0.69, 0.95] and 0.78 [0.66, 0.90], 
respectively.  Whereas the Cmax comparison met the predefined comparability bound of 
0.67-1.5, the lower 90% CI for AUC0-inf GMR was just below the predefined lower 
comparability bound.
2.2.4
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 medicine.
By delivering this compound via the inhaled route, 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.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
This study is to be conducted in male and female participants diagnosed with PH-COPD.
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Objectives
Endpoints
Primary
•
Objective: To assess the safety and 
tolerability of MK-5475 in participants 
with pulmonary hypertension associated 
with chronic obstructive pulmonary 
disease following 7 and 28 days of 
dosing. (Parts 1, 2 and 3)
•
Safety and tolerability will be 
evaluated during clinical assessments 
that include vital signs, safety 
laboratory testing, physical 
examinations, ECG readings, and 
review of adverse events (AEs). (Parts 
1, 2 and 3)
•
Objective: To assess the effect of MK-
5475 on pulmonary vascular resistance 
following 28 days of dosing in 
participants with pulmonary hypertension 
associated with chronic obstructive 
pulmonary disease. (Part 2)
•
Hypothesis: MK-5475 reduces mean 
pulmonary vascular resistance following 
28 days of dosing in participants with 
pulmonary hypertension associated with 
chronic obstructive pulmonary disease 
when compared to placebo. A true mean 
difference (MK-5475-placebo) of 15% is 
considered clinically meaningful. (Part 2)
•
Percent change from baseline for PVR 
of MK-5475/placebo on Day 28 in 
Part 2.
Secondary
•
To obtain preliminary plasma 
pharmacokinetic data of MK -5475 (e.g 
AUC0-24, AUC0-inf, Cmax, Tmax, 
terminal half-life, accumulation ratio) in 
participants with pulmonary hypertension 
associated with chronic obstructive 
pulmonary disease (Parts 1, 2 and 3)
•
AUC0-inf, AUC0-24, Cmax, C24, 
Tmax, apparent terminal half-life, 
accumulation ratio
•
To assess the effect of multiple inhaled 
doses of MK-5475 on pulmonary blood 
volume in participants with pulmonary 
hypertension associated with chronic 
obstructive pulmonary disease (Parts 2
and 3)
•
Percent change from baseline for PBV 
of MK-5475/placebo on Day 28 in 
Parts 2 and 3.
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Objectives
Endpoints
Tertiary/Exploratory
•
To assess the physiologic effects of 
multiple dose MK-5475 during 
cardiopulmonary exercise testing (Parts 2
and 3) in participants with pulmonary 
hypertension associated with chronic 
obstructive pulmonary disease
•
To explore the relationship of MK-5475  
concentration and summarize changes in 
pulmonary vascular resistance, 
pulmonary artery pressure, cardiac 
output/cardiac index, mixed venous 
oxygen saturation, arterial oxygenation 
and systemic vascular resistance in 
participants with pulmonary hypertension 
associated with chronic obstructive 
pulmonary disease (Part 2)
•
To explore the effects MK-5475 has on 
6MWD and level of dyspnea (Parts 1, 2
and 3)
•
To assess the effect of MK-5475 on 
NTproBNP relative to placebo following 
28 days of dosing in participants with 
pulmonary hypertension associated with 
chronic obstructive pulmonary disease 
(Parts 2 and 3)
•
To explore the relationship between 
genetic variation and response to the 
treatment(s) administered and 
mechanisms of disease. Variations across 
the human genome may be analyzed for 
association with clinical data collected in 
this study. (Parts 1, 2 and 3)
•
VO2max, exercise capacity, 
ventilatory efficiency, 
cardiopulmonary vs. pulmonary limit 
to exercise and ventilation/perfusion 
matching
•
Mean pulmonary artery pressure 
(mPAP), systemic vascular resistance 
(SVR), cardiac output (CO)/cardiac 
index (CI) and mixed venous and 
arterial oxygenation
•
6 MWD w/ Borg Dyspnea scale and 
SOBQ
•
Percent change from baseline in 
NTproBNP levels
•
Germline genetic variation and 
association to clinical data collected in 
this study
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4
STUDY DESIGN
4.1
Overall Design
This is a 3-part, randomized, multi-site study of MK-5475 in participants with PH-COPD. Up 
to approximately 48 participants will be enrolled. 
Part 1 of this study is a double-bind, randomized, placebo-controlled, multiple-dose 
assessment of safety, tolerability and PK of inhaled MK-5475 in male and female 
participants diagnosed with PH-COPD. Up to approximately 9 participants will be 
randomized in a ratio of 6 active (MK-5475 360 µg) and 3 placebo. A minimum of 3 of these 
participants will fall in the age range of 70 to 80 years. Participants will dose each morning 
for 7 consecutive days.  In Period 1, witness dosing of MK-5475/pbo and scheduled study 
procedures will occur on all days at the clinical research unit (CRU). Review of available 
safety and PK data will occur following the 7 days of dosing.
If the PK data from the first 24 hours after Day 1 dosing with 360 ug MK-5475 is 
substantially lower than observed with patients with PAH, then a second 7-day dosing period 
will be conducted at a higher dose. Review of a minimum of 4 participants Day 1 PK will be 
the basis for this decision because prior studies (PN003) demonstrated little to no 
accumulation with daily dosing. Witness or at home dosing for Period 2 will be dependent on 
the dosing regimen defined. If needed, in order to ensure 2nd daily dosing adherence and to 
assess for AEs, at home dosing in combination with telephone contact will occur on all days. 
If eligible, participants from Part 1 may continue into Part 2 upon confirmation by the 
SPONSOR.
Part 2 of this study is a double-bind, randomized, placebo-controlled, multiple-dose 
assessment of safety, tolerability, PK and PD of inhaled MK-5475 in male and female 
participants diagnosed with PH-COPD. Up to approximately 24 participants will be 
randomized with 2:1 ratio of 16 active (MK5475 380 µg) and 8 placebo. Participants will 
dose each morning for 28 consecutive days. The timing of dosing in Part 2 will be 
determined following review of PK data from Part 1. PD assessments include PVR by RHC, 
PBV by FRI with an IV iodinated contrast agent and exercise tolerance via CPET .  Baseline 
PD assessments for PVR, PBV and exercise tolerance will occur a minimum of 1 day but, no 
more than 5 days prior to dosing on Day 1. At the discretion of the investigator, PD 
procedures can be completed on the same day or across the 5-day window. Witness dosing of 
MK-5475/pbo and scheduled study procedures will occur on Days 1, 15 (+/- 1 day) and 28
(+4 days/-1 day) at the CRU. The Day 28 PD assessments for PVR and PBV will occur 6 to 
8 hours post dose. To allow flexibility in scheduling of RHC and FRI procedures, dosing 
may extend to a maximum of 32 days. If the RHC or FRI procedure is scheduled to extend 
beyond 30 days, participants may be required to return to the CRU to receive a new DPI
based on DPI time in use allowances as defined in the study operations manual.  Witnessed
dosing and the full complement of study procedures scheduled for Day 28 will occur on the 
day when RHC measures are performed. In order to ensure dosing adherence and to assess 
for AEs, at home dosing in combination with telephone/virtual technology contact will occur 
on all other days. 
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Pharmacodynamic Assessments
In Part 2, pulmonary hemodynamic measurements via RHC will be performed. A minimum 
of 2 pulmonary hemodynamic measurements taken a minimum of 5 minutes apart, including 
PVR calculated from data obtained by thermodilution (see manual of operations) will occur 
at least 1 but, no more than 5 days prior to dosing the first dose of study drug. Values from 
the 2 consecutive PVR measurements should be within 15% (highest PVR value will define 
the 15%) of each other to confirm a stable baseline. If the 2 PVR measurements deviate more 
than 15%, up to 2 additional PVR measurements may be obtained. If a stable baseline cannot 
be obtained after 4 measurements, the participant will not be eligible to participate in the 
study.  Along with confirming a stable PVR, the following parameters are to be met at 
baseline RHC in order to continue participation:
1. Mean Pulmonary Arterial Pressure (mPAP) ≥ 25 mmHg. The mean of the mPAP from 
the 2 individual measures that were used for PVR calculation taken at least 5 minutes 
apart will serve as the mPAP.
2. PVR ≥ 3.75 Woods units (or ≥ 300 dynes/sec/cm5) 
3. Pulmonary Artery Wedge Pressure (PAWP) ≤ 15 mmHg. The mean of the 2 values used 
to calculate PVR as described above may be used to define the baseline PAWP.
Details on RHC parameters to be performed are noted in the SOA and Section 8.7.1.
Computed tomography (CT) scans with an iodinated contrast agent to assess PBV at baseline 
and following 28 days of dosing will occur in Part 2 and Part 3. Details on FRI are noted in 
Section 8.7.2.
A novel CPET procedure to assess exercise tolerance/functional capacity at baseline and 
following approximately 28 days of dosing will occur in Part 2 and Part 3. Under special 
circumstances, omission of the CPET procedure will be permitted for the following reasons:

Technical reasons (e.g. CPET device malfunction)

Regulatory reasons (e.g. Trade Ministry or Customs denies or delays importation of 
device) 
All participants will be asked to perform the CPET procedure. If a participant is unable to 
complete the test for the scheduled 3 minutes, documentation of the stop time of the exercise 
portion of the procedure should be recorded. 
Part 3 of this study is a double-bind, randomized, placebo-controlled, multiple-dose 
assessment of safety, tolerability, PK and PD of inhaled MK-5475 in male and female 
participants diagnosed with PH-COPD. The timing as to the start of Part 3 will be determined 
by the Sponsor based on data from Part 2. Specifically, if analysis of incoming RHC, FRI 
and CPET data suggest that FRI is a reasonable surrogate for some RHC measurements, a 
larger sample size FRI and CPET will then be useful in order to further explore the 
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pharmacodynamic properties of this compound on pulmonary blood flow (FRI) and exercise 
physiology (CPET). Part 3 participants will not undergo RHC procedures as part of this 
study. Part 2 will continue to enroll participants who will undergo RHC. Up to 15 Part 3 
participants will be randomized with a 2:1 ratio active (MK-5475 up to 380 µg): placebo. 
Participants will dose each morning for 28 consecutive days.  PD assessments include PBV 
by FRI with an IV iodinated contrast agent and exercise tolerance via CPET.  Baseline PD 
assessments for PBV and exercise tolerance will occur a minimum of 1 day but, no more 
than 5 days prior to dosing on Day 1. At the discretion of the investigator, PD procedures can 
be completed on the same day or across the 5-day window. Witnessed dosing of MK-
5475/pbo and scheduled study procedures will occur on Days 1, 15 (+/- 1 day) and 28 (+4 
days/-1 day) at the CRU. The Day 28 PD assessments for PBV will occur 6 to 8 hours post 
dose. To allow flexibility in scheduling of FRI and CPET procedure, dosing may extend to a 
maximum of 32 days. If the FRI or CPET procedure is scheduled to extend beyond 30 days, 
participants may be required to return to the CRU to receive a new DPI based on DPI time in 
use allowances as defined in the study operations manual.  Witnessed dosing and the full 
complement of study procedures scheduled for Day 28 will occur on the day when the first 
PD measures (CPET or FRI) are performed. In order to ensure dosing adherence and to 
assess for AEs, at home dosing in combination with telephone/virtual technology contact will 
occur on all other days. 
Because this is a Phase 1 assessment of MK-5475 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is being conducted to evaluate safety, tolerability, pharmacokinetics, and 
pharmacodynamics of MK-5475 after administration of multiple doses to participants with 
PH-COPD. Preclinical and clinical studies in healthy and PAH participants with this 
compound support the conduct of this study, given the evidence that the compound appears 
to be safe, well-tolerated, and has suitable single-dose pharmacokinetics to support an 
evaluation of multiple dosing in this patient population.
Because this is the first introduction of this compound into participants with PH-COPD, Part 
1 of the study is designed to evaluate safety, tolerability, and pharmacokinetics in this 
population. A smaller group of participants will be administered the dose of 360 µg daily for 
seven days, with careful observation and monitoring of safety parameters. At the end of this 
period, safety and PK data will be reviewed to determine whether Part 2 will be triggered. In 
prior/ongoing studies with this compound, PAH patients have been found to experience 
lower systemic exposures than healthy participants, presumably based on respiratory 
impairment associated with their disease. As such, if the PK data from this initial dosing 
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period is lower than expected, an additional seven-day period of dosing may be repeated in 
Part 1 at a higher dose, after which the safety and PK data will be reviewed again to 
determine whether Part 2 should be triggered.
Once the safety, tolerability, and pharmacokinetics have been established in Part 1, 
pharmacodynamic assessments will be performed in a larger group of participants. The 
primary assessment for this study, right heart catheterization, is directly related to the 
ultimately desired clinical efficacy endpoint for this compound and is well-validated in the 
published literature. In addition, imaging and exercise testing will be used as exploratory 
measurements to evaluate various aspects of the physiological response to dosing. In Part 3, 
right heart catheterization will be omitted from the pharmacodynamic assessments, and only 
FRI and CPET assessments will be conducted. The purpose is to increase the sample size for 
FRI and CPET to make more robust evaluations of these pharmacodynamic effects. Other 
endpoints are as noted below.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The Borg Dyspnea Score, UCSD SOBQ and 6-Minute Walk Test (6MWT) are potential 
endpoints for later clinical studies and will be included to provide preliminary estimates of 
the impact MK-5475 may have on these parameters.
4.2.1.2
Safety Endpoints
Evaluation of clinically relevant safety parameters will include vital signs, 12-lead ECG, 
laboratory safety tests (blood and urine chemistry, hematology, anticoagulation tests) at pre-
specified timepoints and adverse events throughout the study. Oxygen saturation via pulse 
oximetry and arterial blood gases will be measured to evaluate the potential for V/Q 
mismatch. Given this is the first time MK-5475 is being given in the PH-COPD population,
these endpoints were chosen to provide a comprehensive evaluation of safety and tolerability 
of MK-5475.
4.2.1.3
Pharmacokinetic Endpoints
MK-5475 is an inhaled drug being developed for the management of PAH and PH -COPD. 
As with any inhaled compound, pharmacokinetic exposures are primarily determined by lung 
burden, which cannot be directly measured. Therefore, the pharmacokinetic end-points for 
this study will consist of systemic assessments of AUC0-24, AUC0-inf Cmax, C24, ,Tmax, 
apparent terminal half-life and accumulation ratio. Acknowledging the limitations of these 
data, they will be utilized for pharmacokinetic modeling and assessment of the safety margin 
with regard to systemic exposure.
4.2.1.4
Pharmacodynamic Endpoints
Reduction in PVR is being employed as the primary pharmacodynamic endpoint. This 
measurement directly reflects disease severity and response to therapy as it incorporates 
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measurements of pulmonary vasoconstriction (pulmonary artery pressure) and cardiac 
performance (cardiac output), and the relationship between PVR and the ultimate clinical 
endpoint of 6-minute walk distance (6MWD) is well established.
Broadly speaking, FRI imaging will be used because of its potential to inform multiple 
aspects of clinical development. The primary readout of PBV change will be compared with 
PVR and will enable estimates of the regional deposition of compound with comparison to 
regional pharmacodynamic effect within the lung. In COPD, this technique is of particular 
interest because it will provide data for the presence or magnitude of V/Q mismatch. 
Exercise testing (CPET) provides an extensive amount of information on both cardiac and 
pulmonary function during exercise. This will provide an estimate of whether cardiovascular 
performance improves relative to pulmonary performance. This will also allow an estimate of 
the improvement of exercise performance with treatment, which will supplement the other 
pharmacodynamic measures being performed. Finally, CPET will enable quantitation of the 
impact of MK-5475 on gas exchange, which will be used to evaluate the potential for V/Q 
mismatch after multiple dosing.
Assessment of NT pro BNP will be performed. This may provide additional information on
disease severity in this population at baseline and Day 28.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
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 absorption, distribution, metabolism, and excretion; 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 multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on DNA specimens for which consent 
was provided during this clinical study.
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research 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 future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
One of the primary objectives of this study is to evaluate the safety and tolerability of 
MK-5475 in this population. The inclusion of a placebo-control will facilitate an unbiased 
assessment of safety and tolerability. Because this is the first assessment in participants with 
PH-COPD, they may not receive clinical benefit from MK-5475 thus, an active comparator is 
not justified.
4.3
Justification for Dose
The methods used in calculating doses and estimated exposures are detailed in Sections 4.3.1 
and 4.3.2.
As this is a Phase 1 assessment of MK-5475 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
4.3.1
Starting Dose for This Study
Because MK-5475 is delivered via the inhaled route, calculations for the human equivalent
dose (HED) in the lung are used to set dosing guidelines. As noted in Section 2.2.2, the 
NOAEL was selected based on the 1-month dog inhaled toxicology study. At the NOAEL 
dose of 0.02 mg/kg/day, slight bronchial artery thickening was seen in the 1-month study, but 
was no longer observed in the 3-month study. The HED for the NOAEL dose of 0.02 mg/kg 
is adjusted for the dog weight of 10 kg and the lung deposition factor of 25% to yield a lung 
exposure of 50 µg (20 µg /kg * 10 kg *0.25 = 50 µg). This is adjusted for the presumed dog 
lung size of 100 g to yield an estimated lung burden of 0.5 µg /g. Adjusted for human lung 
size, with a presumed weight of 1000 g, and assuming 100% deposition in humans, the 
human delivered dose corresponding to the dog NOAEL would be 500 µg, and the 
corresponding systemic exposure level would be 4.5 nM*hr AUC 0-24h.
The starting dose for this study will be 360 µg inhaled, delivered once daily for seven days in 
Part 1. This dose has already been delivered to participants in PN002, and the observed 
systemic AUC 0-24h at that dose was 1.45 nM*hr. While multiple dosing has not been 
performed at this dose, in PN003 healthy participants were dosed with multiple doses of 240 
µg, with resulting systemic AUC 0-24h of 2.00 nM*hr, higher than that seen at 360 µg in 
PAH patients. As noted in section 2.2.3, systemic exposures have been consistently higher in 
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healthy participants compared with patients, likely due to their ability to generate a more 
robust inhalation. In addition, multiple dose PK has not demonstrated accumulation over 
time. Therefore, performing multiple dosing at 360 µg daily is justified by the fact that this 
dose has previously been given in single doses to patients, and that healthy participants have 
previously been observed to achieve and tolerate higher exposures when given multiple doses 
of 240 µg.
4.3.2
Maximum Dose/Exposure for This Study
The planned starting dose of 360 µg once daily in Part 1 will be transitioned to a maximum 
dose of 380 µg inhaled once daily for Part 2 and 3. The Part 2 and 3 dose will utilize a 
formulation which is intended to deliver the entire dry powder dose in one inhalation, as 
compared with the formulation used in Part 1 which requires 6 inhalations to deliver 360 µg. 
The formulation of 380 µg used for Parts 2 and 3 has been shown in a clinical study to have 
similar PK to the formulation of 360 µg used for Part 1. This dose of 380 µg will be the 
maximum dose for this study, except in the event that systemic PK in Part 1 is lower than 
AUC 0-24h of 1.4 nM*hr. In Part 1 of the currently ongoing PN002 in PAH patients, 
systemic PK levels at the 120 µg dose were found to be substantially lower than expected 
(based on prior data from healthy participants) and thus the clinical dose was increased. 
Although lung PK cannot be directly measured, systemic PK is assumed to be a surrogate for 
lung deposition of compound, and thus far clinical data have shown that systemic PK of 
MK-5475 is correlated with PVR reduction. Because COPD patients are predisposed to 
lower ability to generate adequate inspiratory flow, it is anticipated that their systemic PK 
may again be lower than anticipated due to lower deposition of compound in the deep lung. 
If this is the case, a second 7-day dosing period will be triggered using a higher dose of 
MK-5475, up to 380 µg inhaled twice daily. The expectation is that this higher dose will not 
approach or exceed the NOAEL AUC 0-24h exposure of 4.5 nM*hr. The timing of this 
divided dose will be determined based on the PK data from Part 1. See below Table 1 for 
GM exposures previously observed in PN 002 and PN003 as well as predicted exposures in 
the PH-COPD population.
Table 1
Geometric Mean AUC0-24 Actual and Predicted 
Actual: Following 
Multiple 240 µg 
Inhaled 
Administration in 
Healthy Subjects 
in PN003
Actual: Following 
Single 360 µg 
Inhaled 
Administration in 
PAH Participants 
in PN002
Predicted 
Following 
Multiple 360 µg 
Inhaled 
Administration in 
PH-COPD 
Patients
Predicted 
Following 
Multiple 380 µg 
Inhaled 
Administration in 
PH-COPD 
Patients
Geometric Mean
AUC0-24hr 
(nM*hr)
2.00
2.58
~2.58
~2.0
The estimated total radiation burden per participant after the completion of all CT scans will 
not exceed the maximum limit of 10 mSv [Directorate-General, Environment Nuclear Safety 
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and Civil Protec 1998]. If there is a need for fluoroscopy during RHC, the total radiation 
exposure during RHC will be equivalent to the amount of radiation the participant would 
receive if fluoroscopy was performed during RHC for initial diagnosis or follow-up. 
This study does take into account the desired yearly limit for study participants as per ICRP 
publication 62.
4.3.3
Rationale for Dose Interval and Study Design
In this study, participants will be dosed with 360 µg of MK-5475 in Part 1 and 380 µg in 
Parts 2 and 3 daily. As noted above, this dose has been previously administered to PAH 
patients in PN002, and a lower dose that resulted in higher systemic exposures has been 
previously administered to healthy participants in PN003. These studies were delivered with 
the following supportive data: MK-5475 acts via a well-established mechanism (sGC 
stimulator), for which a marketed agent acts similarly [riociguat]. Safety assessment toxicity 
trials and ancillary pharmacology trials with MK-5475 provide no contraindications to 
clinical trials in people with this compound via the inhaled route. No dose-limiting toxicities 
were observed in 1- or 3-month rat and dog toxicity trials, and substantial preclinical safety 
margins were obtained over initial human doses. As with the previous studies, safety will be 
ensured by the inclusion of extensive safety monitoring in the clinic, and the fact that 
MK-5475 is not considered a compound with a high degree of uncertainty, which is 
supported by both preclinical and clinical evidence. There will be frequent, careful 
assessments of adverse events throughout the postdose period. This recommendation is in 
keeping with the projected safety profile and the ability of the clinical site to monitor each 
participant closely.
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 from the study, or is lost to follow-up 
(ie, the participant is unable to be contacted by the investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
A primary objective of this early Phase 1 study is to identify the maximum safe and well-
tolerated dose and/or dosing regimen that achieve PK, pharmacodynamic, and/or biologic 
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targets in humans based on preclinical or early clinical data. Therefore, it is possible that 
study participants may not receive all doses specified in the protocol if this objective is 
achieved at lesser dose levels in this study. This would not be defined as early termination of 
the study, but rather an earlier than anticipated achievement of the study objective(s). If a 
finding (eg, PK, pharmacodynamic, efficacy, biologic targets, etc.) from another preclinical 
or clinical study using the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study results in the study(ies) or program being stopped for 
nonsafety reasons, this also does not meet the definition of early study termination.
Early study termination is defined as a permanent discontinuation of the study due to 
unanticipated concerns of safety to the study participants arising from clinical or preclinical
studies with the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study.
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/Female participants with PH-COPD between the ages of 40 and 80 years (inclusive)
(Parts 1and 2) or between the ages of 40 and 85 years (inclusive) (Part 3).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets the following 
criteria:
Type of Participant and Disease Characteristics
1. Be judged to have no untreated, clinically significant health issue from other co-
morbidities based on medical history, physical examination, vital signs and 
electrocardiograms performed at the screening visit(s). Health issues associated with 
severe obesity (BMI 35 to 40 kg/m2) and considered not clinically significant may be 
permissible at the discretion of the investigator and in consultation with the Sponsor.
2. Be judged to have no untreated, clinically significant health issue from other co-
morbidities based on laboratory safety tests performed at the screening visit(s). Appendix 
10.10 provides an algorithm for the assessment of out of range laboratory values. Health 
issues associated with severe obesity (BMI 35 to 40 kg/m2) and considered not clinically 
significant may be permissible at the discretion of the investigator and in consultation 
with the Sponsor.
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3. Have a body mass index (BMI) ≤ 40 kg/m2, inclusive at screening. Investigator site 
should verify CT scan equipment can accommodate participant size. See Section 8.3.1 for 
criteria on rounding to the nearest whole number. BMI= weight(kg)/height (m) 2. Body 
weight should not exceed 160 kg.
Demographics
4. Is male or female, from 40 years to 80 years of age inclusive (Parts 1 and 2) and from 40 
to 85 years of age inclusive (Part 3), at the time of signing the informed consent. For Part 
1, a minimum of 3 participants that will be randomized need to fall in the range of 70 to 
80 years of age.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
5. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 14 days, corresponding to time needed to eliminate 
study intervention(s) (eg, 5 terminal half-lives) plus an additional 90 days (a 
spermatogenesis cycle) after the last dose of study intervention.
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
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•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
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, corresponding to the time needed to eliminate any study intervention(s) (eg, 5 
terminal half-lives)  after the last dose of study intervention and agrees not to donate eggs 
(ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction 
during this period. The investigator should evaluate the potential for contraceptive 
method failure (ie, noncompliance, recently initiated) in relationship to the first dose of 
study intervention. 
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix [2].
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Additional Categories
8. Is willing to comply with the study restrictions (See Section 5.3 for a complete summary 
of study restrictions).
9. Have been diagnosed with mild to severe COPD according to GOLD diagnostic criteria 
(postbronchodilator FEV1/FVC ratio < 0.7)
10. Has MMRC Dyspnea Score in the range of 1 thru 3 at screening.
11. Be deemed clinically stable by the investigator.
12. Have a hemoglobin (Hgb) > 75% of the lower limit of the normal range (at screening).
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13. Be or have suspected Pulmonary Hypertension Group 3 in particular:
3.1 Chronic Obstructive Pulmonary Disease (COPD)
14. Have a history of RHC within 3 years of starting study medication demonstrating mPAP 
≥ 25mmHg and PVR ≥ 3.75 Woods units or 300 dynes/sec/cm5.
OR
Have an echocardiogram performed by the investigator (or appropriate designee) at screening 
or within 1 year of screening demonstrating pulmonary artery systolic pressure ≥ 38 mmHg ( 
Part 1 only) or  ≥ 50 mmHg (Part  2 only) in conjunction with one or more of the following: 
tricuspid regurgitation velocity >3 m/s or significant right heart enlargement and or reduced 
right heart function. In the event that echocardiography is technically challenged, the PI may 
elect to accept other echocardiographic evidence (i.e. morphologic or functional
measurements of the heart chambers, valves or great vessel) of good quality of pulmonary 
hypertension in consultation with the sponsor (Parts 1 and 2 only). 
NOTE: For Part 3, prior history of RHC is required for inclusion.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has pulmonary hypertension subtypes including the following according to Nice 2013
Group 1 Pulmonary arterial hypertension (PAH)

1.1. Idiopathic PAH

1.2. Heritable
a) BMPR2
b) ALK1, endoglin, SMAD9, CAV1, KCNK3
c) 1.2.3. Unknown

1.3. Drug and toxin-induced

1.4. Associated with
d) 1.4.1. Connective tissue disease
e) 1.4.2 HIV infection
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f)
1.4.3 Portal hypertension
g) 1.4.4. Congenital heart disease (unrepaired and not requiring repair or 
repaired simple cardiac defects at least 1year status post corrective 
surgery, with no clinically significant residual shunt)
h) 1.4.5 Schistosomiasis
i)
1.4.6 Chronic hemolytic anemia
1.5 Persistent pulmonary hypertension of the newborn (PPHN)
1’ Pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary
hemangiomatosis (PCH)
Group 2 Pulmonary hypertension owing to left heart diseases

2.1. Left ventricular Systolic dysfunction

2.2. Left ventricular Diastolic dysfunction

2.3. Valvular disease

2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital
cardiomyopathies
Group 3 pulmonary hypertension owing to lung diseases or hypoxia not associated with 
COPD
3.2. Interstitial lung disease
3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4. Sleep-disordered breathing. Participants with mild OSA may be permitted in 
consultation with the Sponsor provided OSA is not the cause of pulmonary 
hypertension.
3.5. Alveolar hypoventilation disorders
3.6. Chronic exposure to high altitude
3.7. Developmental abnormalities
Group 4 Pulmonary hypertension defined as Chronic thromboembolic pulmonary
hypertension [CTEPH])
Group 5 Pulmonary Hypertension with unclear multifactorial mechanisms
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5.1. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders,
splenectomy
5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis,
lymphangioleimyomatosis, neurofibromatosis, vasculitis
5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid 
disorders
5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, 
segmental pulmonary hypertension
2. Has a history of clinically significant endocrine , gastrointestinal, cardiovascular (e.g. 
HFpEF and HFrEF), hematological, hepatic (not including chronic stable Hep B and C), 
immunological, renal, respiratory (not including PH-COPD), genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases. 
3. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator.
4. 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 and with agreement of the SPONSOR (eg, malignancies 
which have been successfully treated ≥2 years prior to the prestudy [screening] visit).
5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or non-prescription drugs or food.
6. Is positive for hepatitis B surface antigen (acute infection) or HIV. Participants with 
positive hepatitis B surface antigen that demonstrate low viral load (chronic stable
infection) are permitted.
7. Has known sensitivity to iodine or iodine containing products (Parts 2 and 3 only).
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
9. Has persistent or permanent atrial fibrillation with an uncontrolled ventricular rate 
(i.e. ventricular rate > 90 bpm) (participants with paroxysmal atrial fibrillation or 
controlled atrial fibrillation with no clinically significant arrhythmia may be allowed per 
the judgement of the investigator).
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10. Has history of combined pulmonary fibrosis and emphysema (CPFE) or severe bullous 
emphysema. If no history, a confirmed negative high-resolution CT scan (HRCT) for 
these conditions needs to have been performed within last 2 years. In Parts 2 and 3, the 
baseline FRI scan may be used to aid in assessment of this criteria.
11. Has an active respiratory infection (common cold, influenza, pneumonia, acute 
bronchitis) with lung function values (FEV1 and/or FEV1/FVC ratio) that do not meet 
eligibility range (See INCL no. 9, EXCL no. 19) (May be rescreened upon resolution of 
the active infection).
12. Has a physical limitation that will inhibit the participant to effectively perform low-
intensity exercise testing (e.g. severe arthritis of the hip or knee).
Prior/Concomitant Therapy
13. Is unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 
half-lives) prior to administration of the initial dose of study drug, throughout the study 
(including washout intervals between treatment periods), until the poststudy visit. There 
may be certain medications that are permitted (see Section 6.5).
14. Is currently on monotherapy calcium channel blockers as a specific treatment for 
pulmonary hypertension.
15. Is currently taking nitrates, inhaled prostacyclin, immediate or extended release 
diltiazem, PDE5 inhibitors or sGC activators for the treatment of pulmonary 
hypertension. Participants previously using medications to treat PAH may be enrolled 
provided they have been off therapy for at least 2 weeks prior to the start of the screening 
period. 
NOTE: A medication should not be stopped for the purposes of meeting study criteria.  
However, the decision to stop/interrupt medication is based on the judgement of the 
investigator.
Prior/Concurrent Clinical Study Experience
16. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
17. Has a QTc interval ≥ 470 msec (for males) or ≥ 480 msec (for females) at screening and
Predose Day 1 (Part 1 Period 1) or Baseline Day -1 (Part 2 and 3).
18. Has a systolic BP < 100 mmHg, diastolic BP < 40 mmHg or HR > 100 bpm at screening 
and Predose Day 1 (Part 1 Period 1) or Baseline Day -1 (Part 2 and 3). The mean of these 
values will be used to determine eligibility.
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19. Has FEV1 < 30% predicted based on PFTs at screening. This is indicative of very severe 
COPD.
20. Does not meet the RHC criteria defined in Section 4.1 at baseline (Part 2 only).
21. Participant has an estimated creatinine clearance of ≤30 mL/min based on the Cockcroft 
Gault equation at screening:  
ClCr = (140-age[yr])(body wt [kg])
72)(serum creat [mg/dL])   
When creatinine is measured in micromole/litre, use the following formula: (for 
females multiply result by 0.85)
                           ClCr = (140-age[yr])(body wt[kg])
(72)(serum creatinine [micromol/L] x 0.0113)
An actual creatinine clearance, as determined by a 24-hour urine collection, may be 
used in place of, or in conjunction with, the Cockcroft-Gault equation.
NOTE:  Investigator is to use clinical judgement to determine appropriate degree of 
renal impairment and use of contrast agent for CT scans.
Other Exclusions
22. Suffers from claustrophobia and is unable to undergo a CT scan.
23. Has participated in a PET research study or other research study involving administration 
of a radioactive substance or ionizing radiation within 12 months prior to the screening 
visit or has undergone or plans to have extensive radiological examination within the 
period with a radiation burden over 10 mSv (such as CT scan or nuclear medicine exam)
(HRCT to rule out CPFE or severe bullous emphysema in the last 2 years or any 
radiological examination as part of the study does not fall under plans for extensive 
radiological examination).
24. Is under the age of legal consent.
25. Does not agree to follow the smoking restrictions as defined by the CRU.
26. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
27. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
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28. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 12 months. Participants must have a negative UDS prior to 
randomization.
29. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
30. Has been committed to an institution by way of official or judicial order.
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
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Appendix 2.
On full PK sampling days (ie, Days 1 and 7 in Part 1) participants will fast from all food 
and drinks, except water, for at least 8 hours prior to the first dose of study drug 
administration on these days. Participants will fast from all food and drinks except water 
between study drug administration and the first scheduled meal. Meals and snack(s) will be 
provided by the investigator at time points indicated in the Schedule of Activities. 
Participants will fast from all food and drinks except water between meals and snacks. The 
caloric content and composition of meals per individual CRU will be the same on each full 
PK sampling day. Upon discharge from the CRU for at home dosing (if applicable), meals 
and snacks will be unrestricted in caloric content, composition and timing.
On intermediate days (Days 2-6) in Part 1 participants will fast from all food and drink, 
except water, for 8 hours prior to first dosing on each of these days. There are no fasting 
requirements post dose. Meals and snacks will be unrestricted in caloric content, composition 
and timing.
In Parts 2 and 3 Days 1, 15 and 28, participants will fast from all food and drinks, except 
water, for at least 8 hours prior to first dose of study drug administration on these days. There 
are no fasting/meal requirements post dose and at other intermediate dosing days.
Fasting/ meal requirements prior to initiation of exercise testing, FRI and RHC (Part 2 only)
will be determined by the investigator as per local SOP.
Up to 240 mL of water may be provided following the last inhalation of study drug 
administration. Additional water will be restricted 1 hour prior to and 1 hour after study drug 
administration on full PK sampling days. There are no water restrictions on intermediate 
days.
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5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study and until the poststudy visit.
On full PK sampling days (ie, Days 1 and 7 in Part 1; Days 1 and 28 in Parts 2 and 3), 
participants will refrain from the consumption of all fruit juices 24 hours prior to study drug 
administration. 
On all other days during the study, the consumption of all fruits and fruit juices (except for 
grapefruit, grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy and poststudy visits. On full PK sampling days 
(ie, Days 1 and 7 in Part 1; Days 1 and 28 in Parts 2 and 3), participants will refrain from 
consumption of caffeinated beverages or xanthine-containing products from 12 hours prior to 
study drug administration. In Part 1, caffeine restrictions will continue for 12 hours post 
study drug administration and in Parts 2 and 3 caffeine restrictions post dose will continue 
until the completion of the 3 hour post dose procedures on Day 1 and the 6 to 8 hour post 
dose procedures on Day 28. 
At all other times, caffeinated beverages or xanthine-containing products will be limited to 
no more than 6 units per day (1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy and 
poststudy visits. On full PK sampling days (ie, Days 1 and 7 in Part 1; Days 1 and 28 in 
Parts 2 and 3) participants will refrain from consumption of alcohol 24 hours prior to and 
after study drug administration.  
At all other times, alcohol consumption is limited to no more than approximately 3 alcoholic 
beverages or equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], 
wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the CRU.
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5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running,
bicycling, etc.) from the prestudy (screening) visit until administration of the initial dose of 
study drug, throughout the study (including washout intervals between treatment periods) and 
until the poststudy visit.
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 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention OR withdraws from the study a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number. The study site should 
contact the Sponsor for the replacement participant’s treatment/randomization number.
The replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
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 and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period 
Use
IMP/
NIMP
Sourcing
Part 1
Placebo 
Com-
parator
Pbo
Drug
Dry Powder
0 µg
0 µg
Oral
Oral 
inhalation 
once daily for 
7 days
Placebo
IMP
Sponsor
Part 1
Experi-
mental
MK-5475
Drug
Dry Powder
60 µg
360 µg
Oral
Oral 
inhalation 
once daily for 
7 days
Experi-
mental
IMP
Sponsor
Parts 2 
and 3
Placebo 
Com-
parator
Pbo
Drug
Dry Powder
0 µg
0 µg
Oral
Oral 
inhalation 
once daily for 
28 days
Placebo
IMP
Sponsor
Part 2
Experi-
mental
MK-5475
Drug
Dry Powder
60 µg
360 µg
Oral
Oral 
inhalation 
once daily for 
28 days
Experi-
mental
IMP
Sponsor
Parts 2 
and 3
Experi-
mental
MK-5475
Drug
Dry Powder
380 µg 
380 µg
Oral
Oral 
inhalation 
once daily for 
28 days
Experi-
mental
IMP
Sponsor
Parts 2 
and 3
Experi-
mental
MK-5475
Drug
Dry Powder
100 µg
100 µg
Oral
Oral 
inhalation 
once daily for 
28 days
Experi-
mental
IMP
Sponsor
Parts 2 
and 3
Experi-
mental
MK-5475
Drug
Dry Powder
195 µg
195 µg
Oral
Oral 
inhalation 
once daily for 
28 days
Experi-
mental
IMP
Sponsor
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Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period 
Use
IMP/
NIMP
Sourcing
Parts 2 
and 3
Experi-
mental
MK-5475
Drug
Dry Powder
32 µg
32 µg
Oral
Oral 
inhalation 
once daily for 
28 days
Experi-
mental
IMP
Sponsor
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
Abbreviations: µg = micrograms; Pbo=placebo
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
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
Specific calculations or evaluations required to be performed in order to administer the 
proper dose to each participant are outlined in a separate document provided by the Sponsor.
The rationale for selection of doses to be used in this study is provided in Section 4.3.
MK-5475 and placebo for inhalation will be dosed per the instructions outlined in the Study 
Operations Manual.
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.
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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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
See Table 3 and Table 4 for sample allocation schedule.
Table 3
Sample Allocation schedule (Parts 1 and 2)
Sample Size (N)
Part 1 Period 1
Part 1 Period 2 *
Part 2
16
MK-5475 dose 1
MK-5475 dose 2
MK-5475
8
Placebo
Placebo
Placebo
*if applicable 
9 subjects will participate in Part 1. 24 subjects will participate in Part 2. Participants from Part 1 may participate in Part 
2 upon agreement with Sponsor and if deemed eligible.
The first 9 allocation numbers on the schedule will be used for Part 1.  Replacement numbers in the 100s will be used to 
replace subjects that don’t complete Part 1 as well as any subject that completes Part 1 but either doesn’t participate in 
Part 2 or discontinues during Part 2. This is to ensure that the treatment that the Part 1 subject would have received in 
Part 2 is given to the Part 2 “replacement” subject in order to maintain the desired 2:1 randomization. 
Replacement numbers in the 200s will be used to replace those subjects that discontinue who were assigned a 
replacement number in the 100s. 
Replacement numbers in the 300s will be used as rescue numbers, as needed
Table 4
Sample Allocation schedule (Part 3)
Sample Size (N)
Part 3
10
MK-5475
5
Placebo
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique will be used. MK-5475 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study site personnel. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
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6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant to ensure that proper 
technique was performed during inhalation of the study intervention.
When participants self-administer study intervention(s) at home, adherence with study 
intervention will be assessed. Adherence will be assessed via telephone or virtual technology 
contact [direct questioning, verbal or visual verification of dosing, proper inhalation 
technique] and documented in the source documents and CRF. In case virtual technology is 
used in Parts 2 and 3, a smartphone application will be used to video record dosing with the 
aid of facial recognition and artificial intelligence technology to ensure study medication is 
correct and properly dosed.  The application’s interactive software sends information to a 
secure server and the CRU will be able to access the information via a secure web portal to 
monitor participant adherence.
Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.
A record of the DPI device dispensed and taken by each participant must be maintained and 
reconciled with study intervention and compliance records. Intervention start and stop dates, 
including dates for intervention delays and/or dose reductions will also be recorded in the 
CRF.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study OR during time periods specified by this protocol for that 
medication or vaccination. If there is a clinical indication for any medications or vaccinations
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Listed below are specific examples of permitted (but are not limited to) concomitant therapy 
or vaccination:
1.
Paracetamol/acetaminophen for minor ailments without sponsor consultation.
2.
Angiotensin converting enzyme inhibitors (e.g., enalapril)
3.
Angiotensin receptor blockers (e.g., losartan)
4.
Medications for the treatment of COPD (e.g. LABA, SABA, LAMA, mucolytics and 
ICS).
NOTE: There should be a minimum of 3 minutes elapsed between dosing of any 
inhaled COPD medication and dosing of MK-5475/pbo.
5.
Certain calcium channel blockers (e.g. amlodipine) not being used for the treatment 
of PAH based on vasoreactivity testing.
6.
Trimetazidine
7.
Mineral corticoid receptor antagonists (e.g. spironolactone, eplerenone)
8.
Hypoglycemic agents
9.
Diuretics
10.
Beta-blockers.
11.
Aspirin, warfarin, low-molecular weight heparin. Anticoagulation management and 
risks with regard to performance of the RHC will be managed according to the 
investigator’s clinical judgment.
12.
HRT
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13.
Local anesthetic (e.g. lidocaine) when performing RHC insertion procedure per site 
SOPs.
14.
If needed for the RHC period, intravenous sedatives (e.g., midazolam) or analgesics 
(e.g., fentanyl) may be given preferably before the procedure and may be used 
judiciously during the procedure per standard of care.
Listed below are specific examples of prohibited concomitant therapy or vaccination:
1.
PDE5 inhibitors 
2.
sGC activators   
3.
Nitrates
4.
Inhaled prostacyclin
5.
Dual endothelin receptor antagonists
6.
Immediate release or extended release diltiazem
Note: A medication should not be stopped for the purposes of meeting study 
inclusion criteria. However, the decision to stop/interrupt medication is 
based on the investigator’s judgment.
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 (Escalation/Titration/Other)
Following the completion of 7 days of dosing in Part 1 in at least 4 participants, the decision
to proceed to BID or increased dosing for an additional 7 days will be based on key 
preliminary data of safety variables (including, vital signs, 12-lead ECG, laboratory safety 
tests, AEs and assessment for V/Q mismatch (Oxygen saturation via pulse oximetry and 
arterial blood gases) from the previous dose levels up to at least 24 hours from the last dose 
of study drug and preliminary pharmacokinetic data (based on PK data up to at least 24 hours 
after Day 1 dosing). Pharmacodynamic data may be included in the dose escalation decisions 
(Section 8. 6). Part 2 may begin following review of safety and PK of at least 7 participants
in Part 1, if needed. The timing of the start of Part 3 will be based on review of preliminary 
PD data from Part 2 and will be triggered at the discretion of the Sponsor.  Upon the 
triggering of Part 3, Part 2 may continue to run in parallel at the Sponsor’s discretion.
If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose escalation, the dose will not be increased as planned. Instead, participants may:
•
Receive the same dose level to further explore safety and tolerability at that level,
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•
Receive a lower dose of the study intervention,
•
Receive the same or lower dose as a divided dose,
•
Receive a lower dose with or without food, or
•
Dosing may be stopped.
Participant discontinuation criteria are outlined in Section 7.
6.6.1
Stopping Rules
The following stopping rules will be employed during the conduct of this study.
If any of the below stopping rules are met, the study will be paused and no further dosing 
will occur until the Sponsor has reviewed the totality of data available. In order to continue 
the study (upon joint agreement with the Sponsor and investigator), a substantial amendment 
will be submitted for approval.
1. An individual participant reports an SAE considered related to the study drug by the 
investigator.
2. Three (3) or more participants report severe non-serious AEs (ex. hypoxia AEs) 
considered related to study drug by the investigator.
If any of the below stopping rules are met, subsequent doses may be lowered based upon 
joint agreement of the Sponsor and investigator in order for the study to continue.
1. Should the emerging PK (mean) data indicate that the maximum clinical exposure (Cmax 
or AUC), as defined in Section 4.3 will be exceeded, subsequent higher doses will be 
adjusted based upon joint agreement of the Sponsor and investigator.
2. Individual stopping criteria:  Hemodynamic changes that exceed the pre-specified
parameters (See Appendix 10.11)
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity for 
this study]. The emergency unblinding call center should only be used in cases of emergency 
(see Section 8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists 
with the clinical supplies.
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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 prior to completion of the protocol-specified treatment 
period/vaccination regimen will still continue to participate in the study as specified in 
Section 1.3 and Section 8.1.9, or if available, a protocol clarification letter.
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. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9.
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 interrupts study intervention administration for more than 2 consecutive 
days or has 3 cumulative missed doses.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant has a positive urine drug screen (confirmed by recheck) at any time 
during the course of the study.
•
Part 1 participant does not meet the echocardiogram or baseline RHC or exercise criteria 
for Part 2 (See Sections 4.1 and 5.2).
For participants who are discontinued from study intervention all applicable discontinuation 
activities will be performed according to Section 8.1.9, or if available, a protocol clarification 
letter.
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Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
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 future biomedical research, 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.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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).
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•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 500mL (See operations/laboratory manual).
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.
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 
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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 of 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 inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 5 weeks before screening.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization OR intervention
allocation. Each participant will be assigned only 1 screening number. Screening numbers 
must not be re-used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
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 identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
On clinic visit days in Parts 1, 2 and 3, administration of study intervention(s) will be 
monitored by the investigator and/or study staff.
During at home dosing, telephone contact or virtual technology use will occur to ensure 
study intervention adherence (Section 6. 4).
8.1.8.1
Timing of Dose Administration
After it is confirmed that the participant meets eligibility, the first dose of study intervention 
will occur after the completion of predose study procedures. The time of the dose will be 
designated as time “0” and the exact time of administration will be recorded. Dosing will 
continue once daily in the morning. In Part 1 dosing will occur at or near the same time 
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everyday within the allowable window noted in Section 8.11.5. In Parts 2 and 3, a window of 
+/- 2 hours from the time of Day 1 dosing will be permitted on remaining dosing days. 
Following review of PK in Part 1, Period 1, if it is determined that subsequent dosing (Part 1, 
Period 2 and Part 2) is split into 2 administrations each day, the first dose will be designated 
as time “0” and all postdose procedures will be anchored off this dose. For any participants 
from Part 1 that may go into Part 2, a minimum 14-day washout will occur prior to dosing.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.11  to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a follow-
up telephone call at the end of the follow-up period ( Section 8.4.1) to confirm if any AEs 
have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main 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.
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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 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the intensity
of the AEs observed, the relation to study drug, the reason thereof, etc., in the medical chart. 
If it is not possible to record this assessment in the chart prior to the unblinding, the 
unblinding should not be delayed.
In the event that 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.
8.1.11
Domiciling
In Part 1, participants may report to the CRU the evening prior to the scheduled day of 
administration of the study intervention at the discretion of the investigator on Days 1 and 7. 
Participants will remain in the unit until the Day 2, 1-hour postdose and Day 7, 24-hour
postdose procedures have been performed. At the discretion of the investigator, participants 
may be requested to remain in the CRU longer. The decision how to monitor the participant 
will be at the discretion of the investigator after discussion with the Sponsor.
In Parts 2 and 3, participants will report to the CRU for Day -1(up to Day -5) for baseline PD
procedures RHC (done in Part 2 only), FRI and CPET and will remain in the CRU post 
procedure as determined by the investigator.  Participants may report to the CRU the evening 
prior (or sooner at a date specified for some of the baseline activities) to the scheduled day of 
administration of the study intervention, at the discretion of the investigator on Day 1.
Participants will remain in the unit until the 3-hour, postdose procedures have been 
performed. At the discretion of the investigator, participants may be requested to remain in 
the CRU longer. Participants will report to the CRU for study intervention and study 
procedures on Day 15. On Day 28 (+4/-1 days) participants may report to the CRU the 
evening prior to the scheduled day of administration of the study intervention and will remain 
in the CRU post PD procedures as determined by the investigator.  If the CRU is unable to 
domicile the participant overnight the evening prior to Day 28 (+4/-1 days), (in Part 2 or  
Part 3), the participant will be domiciled at a facility (e.g. hotel) in close proximity to the 
CRU in order to ensure timely reporting for dosing and study procedures. 
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8.1.12
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.
8.2
Efficacy Assessments
The 6MWT, as an assessment of functional capacity will be performed in accordance with 
“Guidelines of the Six-minute Walk Test” [American Thoracic Society 2002] by the
American Thoracic Society (ATS).” This assessment requires the participant to walk as far as 
possible on a flat surface (e.g. hallway) over a period of 6 minutes. Participants will be asked 
to rate their level of dyspnea and fatigue at baseline and following completion of the 6MWT 
with the use of the Borg Dyspnea Clinical Rating Scale.  Details of the 6MWT can be found 
in the study operations manual.
The SOBQ asks participants to rate their level of breathlessness on a 6-point scale when they 
perform or if they were to perform certain tasks associated with daily living. Questions about 
limitations due to breathlessness are also asked.
Refer to SOA for planned timepoints of these assessments.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood/tissue volumes drawn/collected by 
visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.  The screening physical examination should include an 
assessment of arterial blood flow to the hands by Allen Test to determine suitability of radial 
artery for ABG collection.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
In Parts 2 and 3, targeted physical examination will consist of assessment of cardiovascular 
and respiratory systems.
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BMI
Body Mass Index equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Oral, Tympanic or Temporal temperature, pulse rate, respiratory rate, and blood pressure 
will be assessed. The same method should be used for all measurements.
•
Blood pressure and pulse measurements will be assessed in a supine or semi-recumbent 
position with a completely automated device. Manual techniques will be used only if an 
automated device is not available.
•
Blood pressure and pulse measurements should be preceded by at least 10 minutes of rest 
for the participant in a quiet setting without distractions.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semi-recumbent OR 
supine position for at least 10 minutes prior to having VS measurements obtained. Semi-
recumbent OR Supine VS will include HR, systolic and diastolic BP, respiratory rate and 
body temperature at timepoints indicated in the SoA. The correct size of the BP cuff and the 
correct positioning on the participants' arm is essential to increase the accuracy of BP 
measurements. Position used for participants should be consistent during the study. 
The screening and Day 1 predose (baseline) HR and BP will be triplicate measurements, 
obtained approximately 1-2 minutes apart. Day 1 Predose measurements will occur within 3 
hours of dosing MK-5475/placebo. The median of these measurements will be used as the 
baseline to calculate change from baseline for safety evaluations (and for rechecks, if 
needed).   Post-dose and poststudy VS measurements will be single measurements.
On Day 1 and Day 7 or 28, as applicable, participants will continue to rest semi-
recumbent/sitting from dosing until 3 hours postdose except to stand for the measurement of 
orthostatic VS (if needed) or other study-related procedure.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
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8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained. Participants should 
be semi-recumbent for at least 10 minutes and then stand upright for 2 minutes prior to 
measurement of orthostatic VS.
8.3.2.3
Oxygen Saturation
Indirect measurements of O2 saturation will be obtained using pulse oximetry on each 
participant at the times noted in the SOA (See Section 1.3)
Direct measurements of O2 saturation will be obtained via ABGs on each participant at the 
times noted in the SOA (See Section 1.3)
Indirect and direct measurements of O2 saturation will be performed on room air, so long as 
it is tolerated by the participant.
8.3.3
Electrocardiograms
12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals
will be performed. 
In all parts, triplicate ECGs are required at predose on Day 1.  The 3 individual ECG tracings 
should be obtained approximately 1 to 2 minutes apart. The full set of triplicates should be 
completed in less than 6 minutes. The mean of the measurements will be used as the baseline 
to calculate change from baseline for safety evaluations and rechecks, if needed. Screening, 
post-dose and poststudy ECG measurements will be single assessments.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semirecumbent OR supine for at least 10 minutes prior 
to each ECG measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin marker pen to ensure reproducible electrode placement.
During each treatment period, if a participant demonstrates an increase in QTc interval ≥60 
msec compared with mean predose baseline measurement, the ECG will be repeated twice 
within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent the 
value at that time point. If the mean QTc interval increase from baseline for any postdose 
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time point is ≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs 
every 15 minutes for at least 1 hour or until the QTc is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study cardiologist 
may be appropriate and the Sponsor should be notified.
If the QTc interval is ≥500 msec on any postdose ECG, the Sponsor should be notified and 
the ECGs should be reviewed by a cardiologist. The participant should be telemetry-
monitored (until the QTc is <500 msec) or should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a cardiac or intensive care unit) is available.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 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.
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.
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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 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
AEs, SAEs, and other reportable safety events that occur after the provides documented 
informed consent, but before intervention allocation/randomization, must be reported by the 
investigator for randomized participants only if the event is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo, or a procedure.
From the time of intervention allocation/randomization through 14 days following cessation 
of 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 any time outside of the time 
period specified in the previous paragraph also 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 he/she 
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 5.
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Table 5
Reporting Time 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
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning 
of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 24 hours 
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 towards 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 SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of 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.
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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: 

An overdose of Sponsor's product, as defined in Section 8.5.

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 must trigger 
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).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of 
PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, samples at 
lower doses may not be assayed if samples at higher doses reveal undetectable drug 
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concentrations). 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.
Additional PK samples may be drawn, if RHC (Part 2 only) , FRI and exercise testing are not 
performed on the same day (Day 28).
8.7
Pharmacodynamics
Pharmacodynamic assessments that are part of the RHC (Part 2 only) and FRI procedures 
will be performed according to the study operations and procedures manuals.
8.7.1
Right Heart Catheterization Procedure (Part 2)
Before beginning the RHC procedure, monitoring equipment should be calibrated and 
zeroed. 
Because all of these subjects have substantial lung disease, it is recommended that pressure 
measurements are taken averaged over the respiratory cycle (i.e. computer-generated mean) 
rather than at end-expiration [Nathan, S. D., et al 2019]. At least 3 complete respiratory 
cycles should be included in the screen shot from which the mean value is derived. Pressures 
measured at each study time point will include right atrium pressure (RAP), right ventricular 
systolic and end diastolic pressure (RVSP, RVEDP), pulmonary artery wedge pressure 
(PAWP), and pulmonary artery pressure (PAP) (systolic, diastolic and mean). Cardiac output 
(CO), oxygen saturation and MVO2 will also be collected. 
The baseline portion of RHC will occur on Day -1 but no earlier than 5 days before (Day -5)
the first dose of study intervention. In the case where the baseline RHC was performed and 
the participant was not randomized within 35 days from Day 1, if the participant is 
rescreened, the initial baseline RHC will be considered the Baseline (Day -1) measurement 
provided the RHC was performed within 10 weeks of randomization Day 1.
The study-related portion of the RHC will occur on Day 28 (+4/-1 days) at the 6 to 8 hour
postdose timepoint.  All PAP (systolic, diastolic and mean) PAWP, right atrium pressure
(RAP), right ventricular systolic and end diastolic pressure (RVSP, RVEDP), will be single 
measurements. All measurements will be performed twice no less than 5 minutes apart after 
which the RHC may be removed unless clinically indicated to do earlier. The number of CO 
measurements at each timepoint are described in the study operations manual. Participants 
will undergo monitoring of systemic hemodynamics and adverse events throughout the RHC.  
Up to 4 measurements may be performed at baseline, if needed, as per Section 4.1.
Waveform analysis will be performed through the use of a blinded central reader. 
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Standard operating procedures for RHC will be developed with the site. All specifications 
and details will be provided in the Study Operational Manual.
8.7.2
CT Scan for Functional Respiratory Imaging (Parts 2 and 3)
The CT scans will be performed at the local imaging center according to clinical site standard 
operating procedures in conjunction with instructions provided in the study operations 
manual. 
For each scanning session (Day -1 Baseline and Day 28 at 6 to 8 hours post-dose), 
participants will be prepped and placed in a supine position on the scanner bed. The Day -1 
scan may be performed no earlier than 5 days before (up to Day -5) the first dose of study 
intervention.  In the case where the baseline FRI was performed and the participant was not 
randomized within 35 days from Day 1, if the participant is rescreened, the initial baseline 
FRI will be considered the Baseline (Day -1) measurement provided the FRI was performed 
within 10 weeks of randomization Day 1.
The Day 28 scan will have a window of +4/-1 days.
An iodinated contrast agent will then be administered by IV bolus prior to each CT scan to 
allow for acquisition of images.
Time in the scanner for each scheduled acquisition will last under 15 minutes (window +15 
minutes).
Additional details regarding imaging procedure and contrast agent are outlined in the vendor 
imaging manual and/or study operations manual. 
8.7.3
Cardiopulmonary Exercise Testing (CPET)
In Parts 2 and 3 of the study, a novel technique for cardiopulmonary exercise testing will be 
performed at baseline Day -1 (Up to Day -5) and on Day 28 (+4/-1day) at 5.5 hours post
dose.  Participants will be asked to perform a low-intensity exercise test for a minimum of 2
minutes to a maximum of 3 minutes. Cardiopulmonary parameters including but not limited 
to VO2 max, exercise capacity, ventilatory efficiency, cardiopulmonary vs. pulmonary limit 
to exercise and ventilation/perfusion matching will be obtained.
In the case where the baseline CPET was performed and the participant was not randomized 
within 35 days from Day 1 (e.g. rescreening, RHC/FRI delayed), the initial baseline CPET 
will be considered the Baseline (Day -1) measurement provided the CPET was performed 
within 10 weeks of randomization Day 1.
Under special circumstances, the CPET procedure may be omitted for the reasons outlined in 
Section 4.1.
Additional details regarding CPET are outlined in the study operations manual. 
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8.7.4
Pulmonary Function Tests (PFTs- Spirometry)
PFTs should be performed as per the SoA.  
Spirometry should be performed in accordance with guidelines established by the American 
Thoracic Society/European Respiratory Society (ATS/ERS) Standardization of Lung 
Function Testing: Standardization of Spirometry; 2005 [American Thoracic Society 2005]. 
Additional details regarding spirometry procedures will follow manufacturer’s instructions 
and site SOPs. Every attempt must be made to use one spirometer consistently on each 
participant. The spirometry should be performed with the participant sitting in a chair with 
arms and no wheels; however, if it is necessary to test the participant standing or in another 
position, this should be noted on the spirometry report. The participant position should be 
consistent throughout the study.
In Part 1, at least three measurements (to obtain 2 reproducible) for FEV1 and FVC will be 
performed at each scheduled time point. The largest FEV1 and the largest FVC should be 
recorded after the data are examined from all the acceptable measurements, even if they do 
not come from the same measurement.
The site normal ranges are to be used to determine percent predicted.
The spirometer is to be calibrated following the principles of the ATS/ERS Guidelines and 
the device manual on the days when spirometry is performed. The calibration records should 
be kept in a reviewable log.
It is preferred that the calibration equipment that is used to calibrate the spirometer be 
subjected to a validated calibration according to the manufacturer’s specifications.
In all parts: The following pulmonary function tests: (FEV1, FVC, FEV1/FVC ratio and PEF), 
DLCO (DLCO, DLCO adjusted for Hgb and DLCO/VA) and lung volume (TLC, VC, IC, 
FRC and RV) will be captured by the pulmonary function lab as per their standard 
procedures at the screening visit.
PFTS performed as part of standard of care may be used for the screening visit PFTs 
provided these assessments were performed within 35 days of Day 1(randomization).
Part 1, Day 1 and 7 PFTs will be performed via spirometer at the CRU.
In Parts 2 and 3, the following pulmonary function parameters will be captured during the 
CPET procedure: FVC actual and percent predicted; FEV1 actual and percent predicted and
FEV1/FVC ratio; IC actual.
In special cases where the CPET is not performed, assessment for FVC actual and percent 
predicted; FEV1 actual and percent predicted and FEV1/FVC ratio will be performed by
spirometry.
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8.7.5
Inspiratory Flow Meter Assessment
Measurements (at least 3-5 minutes apart) for inspiratory flow rate will be performed at 
timepoints as per the study flowchart. 
The meter is to be reset following each measurement as per the instructions in the device 
manual. All measurements obtained will be recorded
Additional details regarding Inspiratory Flow Meter Assessment are outlined in the study 
operations manual. 
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and 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 drawn 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.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided 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 
8.10
Health Economics Medical Resource Utilization and Health Economics
Health Economics OR Medical Resource Utilization and Health Economics are not evaluated 
in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.11.1
Screening
Approximately up to 5 weeks prior to intervention allocation/randomization, potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation/randomization if 
there are Day -1 procedures planned per protocol.
8.11.2
Treatment Period
Part 1
After pre-dose procedures have been completed and it is confirmed that the participant meets 
eligibility, the participant will be assigned a unique randomization number.   The participant 
will be administered MK-5475 or placebo as an inhalation. The time of the dose will be 
designated as time “0” and the exact time of administration will be recorded. Post-dose study 
procedures will be performed according to the SoA.  At the discretion of the investigator, 
participants will be discharged from the CRU after completion of the final post dose 
procedure on Day 2. Participants will return daily on Days 3 thru 6 for witness dosing and 
any scheduled study procedures as defined in the study flowchart. Participants will be 
readmitted in preparation for Day 7 study procedures (can be admitted on site the evening 
before) and will remain in the CRU until 24-hour postdose procedures are complete.
If a second dosing period is needed, participants will do the same as described above. If a 
second daily dose is required and it is determined the dose will occur at home, the CRU will
contact the participant via phone to ensure dosing adherence and proper dosing technique.
Participants from Part 1 may continue into Part 2, if agreed upon by the SPONSOR.  If it is 
determined that a participant can continue into Part 2, an assessment of AEs/SAEs will occur 
via a phone call about 14 days after the last dose of study intervention in Part 1.
Part 2
Participants will report to the CRU on Day -1 for baseline PD measurements (RHC, FRI and 
exercise testing). Performance of these procedures may occur on the same day or can span 
across several days but, not to exceed 5 days prior to first dosing on Day 1. On Day 1, after 
all pre-dose procedures are complete and it is confirmed that the participant meets eligibility, 
the participant will be assigned a unique randomization number (participants coming over 
from Part 1 and eligible for Part 2 will keep the same randomization number as in part 1).  
The participant will be administered MK-5475 as an inhalation. The time of the dose will be 
designated as time “0” and the exact time of administration will be recorded. Post-dose study 
procedures will be performed according to the SoA. Participants will be dispensed study 
intervention and a dosing diary for at home dosing and will be discharged from the CRU 
after completion of the final scheduled study procedure on Day 1. Participants are to bring 
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their study intervention and dosing diary back with them on clinic visit days (Days 15 and 
28).
On at home dosing days (Days 2-14, 16-27) participants will be contacted by site personnel 
via telephone or virtual technology will be used to ensure dosing adherence and proper 
dosing technique.
Participants will return to the CRU for witness dosing and scheduled study procedures as per 
the SOA on Day 15 (+/-1 day).
On Day 28 (+4/-1 days), participants will have witnessed dosing, PD measurements and 
other study procedures as per the SOA. The Day 28 Part 2 PD assessments will occur 5.5 to 8 
hours post dose. To allow flexibility in scheduling of the PD procedures, dosing may extend 
to a maximum of 32 days and can be performed on the same day or across a 6-day window. 
Additional witnessed dosing may occur if PD measurements span across several days.
Additional PK measurements may be obtained and will be dependent on the timing of the 
PVR, PBV and the CPET assessments. 
Following completion of CPET, PVR and PBV assessments, participants may be discharged 
from the CRU at the discretion of the investigator per local SOPs.
Part 3  
Participants will report to the CRU on Day -1 for baseline PD measurements (FRI and 
exercise testing). Performance of these procedures may occur on the same day or can span 
several days but, not to exceed 5 days prior to first dosing on Day 1. On Day 1, after all pre-
dose procedures are complete and it is confirmed that the participant meets eligibility, the 
participant will be assigned a unique randomization number.  The participant will be 
administered MK-5475 as an inhalation. The time of the dose will be designated as time “0” 
and the exact time of administration will be recorded. Post-dose study procedures will be 
performed according to the SoA. Participants will be dispensed study intervention and a 
dosing diary for at home dosing and will be discharged from the CRU after completion of the 
final scheduled study procedure on Day 1. Participants are to bring their study intervention 
and dosing diary back with them on clinic visit days (Days 15 and 28).
On at home dosing days (Days 2-14, 16-27) participants will be contacted by site personnel 
via telephone or virtual technology will be used to ensure dosing adherence and proper 
dosing technique.
Participants will return to the CRU for witness dosing and scheduled study procedures as per 
the SOA on Day 15 (+/-1 day). 
On Day 28 (+4/-1 days), participants will have witnessed dosing, PD measurements and 
other study procedures as per the SOA. The Day 28 Part 3 PD assessments will occur 5.5 to 8 
hours post dose. To allow flexibility in scheduling of the PD procedures, dosing may extend 
to a maximum of 32 days and can be performed on the same day or across a 6-day window. 
Additional witnessed dosing may occur if PD measurements span across several days. 
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Additional PK measurements may be obtained and will be dependent on the timing of the 
PBV and the CPET assessments. 
Following completion of CPET and PBV assessments, participants may be discharged from 
the CRU at the discretion of the investigator per local SOPs.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all OR a subset of study procedures specified in the SoA may be completed at the 
discretion of the investigator and with Sponsor agreement. The subset of study procedures 
completed will be communicated in a PCL.
8.11.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If Part 1 Period 2 is not needed, the poststudy visit 
after Period 1 will occur within approximately 14 days after the decision being 
communicated. If the poststudy visit occurs less than 14 days after the last dose of study 
intervention, a subsequent follow-up telephone call should be made at 14 days post the last 
dose of study intervention to determine if any AEs have occurred since the poststudy clinic 
visit.
Part 1 participants should complete their 14-day post -study visit. Upon SPONSOR 
agreement, if they enroll in Part 2 within 30 days of completing the Part 1 post-study visit, 
Screening 1 assessments will not be required, and the participant can move forward to 
baseline Day -1.
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
In Part 1 of the study, the blood sample for MK-5475 is the critical procedure.
At any postdose time point, the blood sample for MK-5475 needs to be collected as close to 
the exact time point as possible. All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Study procedures can be performed prior or after the 
prescribed/scheduled time.
In Part 2 of the study, RHC measurements and, in particular, PVR, are the critical procedure. 
RHC measurements should be collected as close to the scheduled timepoint as possible. All 
other procedures should be completed as close to the prescribed/scheduled time as possible. 
Study procedures can be performed prior or after the prescribed/scheduled time.
In Part 3, FRI measurement is the critical procedure. FRI measurements should be collected 
as close to the scheduled timepoint as possible. All other procedures should be completed as 
close to the prescribed/scheduled time as possible. Study procedures can be performed prior 
or after the prescribed/scheduled time.
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The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
PK Collection as outlined in Table 6.
Table 6
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window a
0 - < 6 min
2 min
≥ 6 min
5 min
≥ 1 hr in Part 1
≥ 1 hr in Part 2 and 3
15 min
20 min
≥ 24 hr
30 min
a Window is +/- from collection time on each dosing day versus the first dose given
•
Predose Day 1 safety evaluations: vital signs, indirect oxygen saturation (pulse oximetry)
and ECG up to 3 hrs; laboratory safety tests, direct oxygen saturation (ABGs) and 
physical exam up to 24 hrs
•
Baseline RHC (Part 2 only) related procedures, FRI and CPET:  Day -1(up to 5 days 
prior to Day 1)
•
Predose Day 1 6MWT w/ Borg Dyspnea Score and SOBQ:  up to 3 hrs
•
Day 1, 15 and 28 Postdose evaluations: vital signs, ECG, laboratory safety tests, direct 
and indirect oxygen saturation, PFTs (Part 1); 6MWT w/ Borg Dyspnea Score and SOBQ
and physical exam
-
0 to <1 hr postdose may be obtained within 10 min of the theoretical sampling time
-
≥ 1 hr to < 24 hr postdose may be obtained within 15 min of the theoretical sampling 
time
-
≥ 24 hr postdose within 1 hr of the theoretical sampling time
•
In Part 1, study intervention within 30 minutes of Day 1 dosing time on Days 2-7
•
In Parts 2 and 3, study intervention administration (each subsequent dosing day): within -
2 hrs of Day 1 actual dosing time
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•
Day 28 (+4/-1 Days) CPET within 30 minutes of theoretical scheduled time of 5.5 hours 
post dose
•
Day 28 (+4/-1 Days) FRI and RHC (Part 2 only) related procedures within 30 minutes of 
theoretical scheduled time of 6 to 8 hours post dose
•
In Part 2, It is preferred that FRI procedure occurs prior to RHC and is as close to 6 hours 
post dose as possible to allow RHC to be complete by 8 hours post dose.
•
In Part 2, It is preferred that FRI and RHC occur on the same day, however, If FRI is 
scheduled on a different day from RHC, dosing of study drug may occur at home and the 
participant will report to the CRU at the time of scheduled CT Scan for FRI.
•
In Part 3, it is preferred that FRI and CPET occur on the same day, however if  CPET is 
scheduled on a different day from FRI, dosing of study drug may occur at home and the 
participant will report to the CRU at the time of scheduled CPET procedure.
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-5475 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Repeat of or decrease in the dose of the study intervention administered in any given 
period/part.
•
Entire parts may be omitted
•
Decrease in the duration of study intervention administration (eg, number of days)
•
Adjustment of the dosing interval (eg, divided doses [bid to qd, qd to bid, tid, or vice 
versa])
•
Lengthening of the wash-out period between doses
•
Remove a planned PK pause if agreed by Sponsor and investigator if no further increases 
in total daily dose
•
Addition of PK pause
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•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
•
Modification of the PK/pharmacodynamic sample processing and shipping details based 
on newly available data
•
Changes to the time intervals between dosing and FRI scans, RHC and CPET.
The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (eg, to 
obtain data closer to the time of peak plasma concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a summary of the statistical analyses for this trial. Full detail is in the 
Statistical Analysis Plan (SAP) (Section 9.2-9.9). 
Pharmacodynamics/Efficacy: Individual Day 28 PVR percent change from baseline values 
from Part 2 will be analyzed in an ANCOVA model with a categorical effect for treatment 
group and a continuous covariate for baseline MPAP.  To test the primary hypothesis, the 
posterior probability that the true mean treatment difference (MK-5475 – Placebo) in PVR 
percent change from baseline is less than -15% will be calculated using a non-informative 
prior. If this posterior probability exceeds 60%, then the primary research hypothesis will be 
supported.Percent changes from baseline on Day 28 for secondary (PBV from FRI) and 
exploratory (Exercise Test, 6 MWT, NTproBNP) endpoints from Part 2 and Part 3 will be 
analyzed in a similar model as described above, with summary statistics provided for the 
treatment comparisons. A subset of exploratory endpoints (Mean pulmonary artery pressure 
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(mPAP), systemic vascular resistance (SVR), cardiac output (CO)/cardiac index (CI) and 
mixed venous and arterial oxygenation) will be analyzed in a similar fashion only for Part 2. 
Descriptive statistics will be provided by study part for all other pharmacodynamic/efficacy
endpoints.
Safety: Summary statistics and plots will be generated for the change from baseline values, as 
deemed clinically appropriate by study part and treatment. Depending on the safety 
parameter, the difference from baseline will either be computed on the original scale (raw 
change from baseline) or on the log scale and back-transformed for reporting (percent change 
from baseline). Summary statistics for the raw laboratory safety tests, vital signs, ECG, labs 
and AEs may also be computed, as deemed clinically appropriate.
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Pharmacology Statistics Department of Merck Research Laboratories in
collaboration with the Pharmacokinetics and Pharmacodynamic Drug Metabolism (PPDM) 
and Clinical Pharmacology Departments. 
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
9.3
Hypotheses/Estimation
Primary: MK-5475 reduces mean pulmonary vascular resistance following 28 days of dosing 
in participants with pulmonary hypertension associated with chronic obstructive pulmonary 
disease when compared to placebo. A true mean difference (MK-5475-placebo) of 15% is 
considered clinically meaningful (Part 2).
9.4
Analysis Endpoints
Primary
Pharmacodynamics: The primary pharmacodynamic endpoint will be the % change from 
baseline for PVR on Day 28 in Part 2, which will be calculated from variables obtained by 
RHC.  Baseline is the Day -1 measurement.  
Safety: Safety and tolerability will be evaluated during clinical assessments that include vital 
signs, safety laboratory testing, physical examinations, ECG readings, and review of adverse 
events (All Study Parts).
Secondary
Pharmacodynamics: The secondary pharmacodynamic endpoint will be the % change from 
baseline for PBV on Day 28 in Part 2 and Part 3, obtained via FRI.  Baseline is the Day -1 
measurement.   
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Pharmacokinetics:  AUC0-24, AUC0-inf, Cmax, C24, Tmax, apparent terminal half-life, and 
the accumulation ratio of MK-5475 from all study parts.
Exploratory
Pharmacodynamics: The exploratory pharmacodynamic endpoint will be the % change from 
baseline for results from the Exercise Test (VO2max, exercise capacity, ventilatory 
efficiency, cardiopulmonary vs. pulmonary limit to exercise and ventilation/perfusion 
matching) , and NTproBNP on Day 28 in Part 2 and Part 3.  Baseline is the Day -1 
measurement. Mean pulmonary artery pressure (mPAP), systemic vascular resistance (SVR), 
cardiac output (CO)/cardiac index (CI) and mixed venous and arterial oxygenation will also 
be measured and analyzed for Part 2. 
Efficacy: The Borg Dyspnea Score, UCSD SOBQ and 6-minute walk Test (6MWT) are 
potential endpoints for later clinical studies and will be included as additional exploratory 
endpoints from all study parts.
9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the treatment(s) they actually received. 
All Participants as Treated (ASaT) –This population includes all participants who received at 
least one dose of the investigational drug. This population will be used for assessments of 
safety and tolerability. 
Per-Protocol (PP) –The population includes the subset of participants who comply with the 
protocol sufficiently to ensure that generated data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Compliance covers such 
considerations as exposure to treatment, availability of measurements and absence of 
important protocol deviations. Important protocol deviations will be identified to the extent 
possible prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data from at least one treatment will be included in the primary analysis dataset. 
This population will be used for the PD, PK and efficacy analyses.
9.6
Statistical Methods
Primary
Pharmacodynamics
Individual Day 28 PVR percent change from baseline values from Part 2 will be analyzed in 
an ANCOVA model with a categorical effect for treatment group, and a continuous covariate 
for baseline MPAP.  To test the primary hypothesis, the posterior probability that the true 
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mean treatment difference (MK-5475 – Placebo) in PVR percent change from baseline is less 
than -15% will be calculated using a non-informative prior. If this posterior probability 
exceeds 60%, then the primary research hypothesis will be supported.
Plots of % change from baseline for PVR will be plotted by site to assess site variability.
Safety 
Summary statistics and plots will be generated for the change from baseline values, as 
deemed clinically appropriate by study part and treatment. Depending on the safety 
parameter, the difference from baseline will either be computed on the original scale (raw 
change from baseline) or on the log scale and back-transformed for reporting (percent change 
from baseline). Summary statistics for the raw laboratory safety tests, vital signs, ECG, labs 
and AEs may also be computed, as deemed clinically appropriate.
Secondary
Pharmacodynamics
Percent change from baseline for PBV from Part 2 and Part 3 will be analyzed in a similar 
model as described above for PVR, with summary statistics provided for the treatment 
comparisons.
Pharmacokinetics
Individual values will be listed for each PK parameter by study part treatment, and the 
following (non - model-based) descriptive statistics will be provided: N (number of subjects 
with non-missing data), arithmetic mean, standard deviation, arithmetic percent CV 
(calculated as 100 x standard deviation/arithmetic mean), median, minimum, maximum, 
geometric mean, and geometric percent CV (calculated as 100 x sqrt( exp(s2) - 1), where s2 
is the observed variance on the natural log-scale).
Exploratory
Pharmacodynamics
Percent change from baseline for Exercise Test results, and NTproBNP from Part 2 and Part 
3 will be analyzed in a similar model as described above for PVR, with summary statistics 
provided for the treatment comparisons.
Efficacy
Descriptive statistics will be provided for results from the Borg Dyspnea Score, UCSD 
SOBQ and 6-minute walk Test (6 MWT) by study part and treatment.
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9.7
Interim Analyses
Following the completion of Part 1 Period 1, pharmacokinetic data will be reviewed to 
determine if Part 1 Period 2 is necessary before starting Part 2. The data from Part 2 will be 
analyzed, specifically the incoming FRI and CPET data, to decide if a larger sample size is 
necessary for these measurements. This will govern the timing of the start of Part 3. 
9.8
Multiplicity
Since there is only one testable hypothesis, no multiplicity adjustment is required.
9.9
Sample Size and Power Calculations
The operating characteristics calculations for percent change from baseline for PVR are 
based on an assumed true between subject standard deviation of 19.2%.  The variance 
estimate is based on currently available data from MK-5475 P002, using PVR values 
calculated based on Fick-derived cardiac output.  
With 24 subjects completing the study (16 on MK-5475 and 8 on placebo) and a posterior 
probability threshold of 60%, there is 83% probability of supporting the primary hypothesis 
if the true difference in PVR reduction between MK-5475 and placebo is -25%.
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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 Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, 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 local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 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. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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.
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 fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees 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.
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. 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. 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.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. 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.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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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 chart 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 
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, commonly 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.
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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 prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
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 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, 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 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 trial directive 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 directive, 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.
10.1.6
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, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 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.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
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 
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Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
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.
10.1.9
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 7 will be performed by the local laboratory for Part 1 and
central laboratory for Parts 2 and 3.
•
Local laboratory results are only required in the event that 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 CRF.
•
Protocol-specific requirements for inclusion or exclusion 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.
•
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 monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted 14 days after the last dose of study intervention.
-
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 subject's participation in the study.
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Table 7
Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
fasting
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Tests
•
PT/INR and aPTT
•
Mixed Venous oxygen saturation (MV02) (Part 2 only)
•
Arterial blood gas (ABG) 
•
NTproBNP
•
Follicle-stimulating hormone (FSH) (as needed in women of nonchildbearing 
potential only)
•
Serum or urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) if applicable
•
Serum/ urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)
•
[Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)
In Parts 2 and 3, all study-required laboratory assessments will be performed at least by a 
central laboratory, with the exception of the following tests (some tests may also be done 
in extra using the local lab at the discretion of the investigator at baseline and day 28):
•
MVO2 (Part 2 only), ABG, FSH, βhCG, Serum/urine drug screen, HIV, HBsAg, HeP 
C virus antibody
NOTES: Urea is acceptable of BUN if not available as per institutional standard; WBC differential = 
absolute
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
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 (also referred to as Sponsor’s 
product) 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
    New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE.
    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.”
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•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
    Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
    Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
    Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
    Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
    Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
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 pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.   Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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•
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.
10.3.3
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
10.3.4
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/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product 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 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
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count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? 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 Sponsor’s product 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 Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product 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, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(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 SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT 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 Sponsor’s product or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her 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 Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
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 his/her 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.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
    The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
    The site will enter the SAE data into the electronic system as soon as it becomes 
available.
    After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
    If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
    Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
    If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
    In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
    Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
    Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
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 two 
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
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c Male condoms must be used in addition to hormonal contraception.
d IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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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.
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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.
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 are 
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 which 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.
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5.  Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing 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 future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main 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 main 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 utilized 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 
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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.
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@merck.com.
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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
N/A
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10.8
Appendix 8: Blood Volume Table
Part 1
Pre-study
Treatment 
Period
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Tests
1
2 to 4
1
4 to 6
13
52 to 78
HIV/Hepatitis Screen 
(at the discretion of the 
investigator)
1
1
5
5
Blood for Planned 
Genetic Analysis 
1
1
8.5
8.5
Serum βHcg (if 
applicable)
1
1
2
5
10
FSH (if applicable)
1
3.5
3.5
PT/aPTT
1
2 to 4
1
4 to 6
5
20 to 30
ABGs
2 to 4
2 to 4
1
2 to 4
Blood for MK-5475
24 to 48
24 to 48
6
144 to 288
Total Blood Volume per Participant
245 mL or 
427b
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) may 
be obtained. Note: not to exceed 50 mL
b. Additional blood samples will only apply if a second dosing period is performed
Part 2 
Pre-study 
(Screening)
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Tests
1
3
1
5
5.5
27.5
HIV/Hepatitis Screen 
(at the discretion of the 
investigator)
Hepatitis B DNA (if 
applicable)
1
1
1
1
5
5
5
5
Blood for Planned 
Genetic Analysis 
1
1
8.5
8.5
Serum βHcg (if 
applicable)
1
1
2
5
10
FSH (if applicable)
1
3.5
3.5
PT/aPTT
1
3
1
5
5
25
NTproBNP
2
2
2.5
5
Local lab safety test (at 
discretion of 
investigator)
2 (baseline and 
day 28)
13
26
ABGs
2
2
1
2
MV02
5
5
15
75
Blood for MK-5475
12b
12
6
72 b
Total Blood Volume per Participanta                                                                           Up to 264.5b or 254.5 b mL
a If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) may 
be obtained. Note: not to exceed 50 mL.
b  Up to 1 additional  PK samples may be drawn if  RHC, FRI  are performed on separate days Day 28 (+4/-1 days) (up to 
6mL).
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Part 3
Pre-study 
(Screening)
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/ 
Test
Laboratory Safety Tests
1
3
1
5
5.5
27.5
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
Hepatitis B DNA (if 
applicable)
1
1
1
1
5
5
5
5
Blood for Planned 
Genetic Analysis 
1
1
8.5
8.5
Serum βHcg (if 
applicable)
1
1
2
5
10
FSH (if applicable)
1
1
3.5
3.5
PT/aPTT
1
3
1
5
5
25
NTproBNP
2
2
2.5
5
Local lab safety test (at 
discretion of 
investigator)
2 (baseline and 
day 28)
2
13
26
ABGs
2
2
1
2
Blood for MK-5475
12b
12
6
72 b
Total Blood Volume per Participant a                                                                           Up to 184.5 or 178.5 mL
a If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) may 
be obtained. Note: not to exceed 50 mL.
b Up to 1 additional PK samples may be drawn if  CPET and FRI  are performed on separate days Day 28 (+4/-1 days) (up 
to 6mL).
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10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The participant may be excluded from the study;
2. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety 
test source document).
3. The participant may be included in the study if the abnormality is consistent with 
a pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical
condition should be annotated on the laboratory report.
OR
4. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.   If the repeat test value is within the normal range, the participant may enter 
the study.
b.   If the repeat test value is still abnormal, the study investigator will evaluate 
the potential participant with a complete history and physical examination, 
looking especially for diseases that could result in the abnormal laboratory 
value in question. If such diseases can be ruled out, and if the abnormal 
laboratory value is not clinically relevant, then the participant may enter the 
study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.10 Appendix 10: Hemodynamic Stopping Criteria
Hemodynamic stopping criteria
Individual stopping criteria
During the treatment period, if a particular participant demonstrates a sustained change
(defined below) in any one of the following parameters, that participant will not participate in 
additional dosing. For assessing change from baseline, post-dose values will be compared to 
the Day 1 predose baseline of each Part/Period established by 3 semi-recumbent/supine
measurements of heart rate and blood pressure obtained ~1-2 minutes apart within 3 hours 
prior to dosing.
Participants meeting individual hemodynamic stopping criteria may be re-challenged in this 
study only after consultation or discussion between the primary investigator and the sponsor.
During the treatment period if a particular participant demonstrates change in any one of the 
following parameters lasting ≥ 90 minutes, dosing in that participant will be halted and the 
participant may be withdrawn from the study or re-challenged at the same dose or at a lower 
dose. Participants that meet criteria listed below will be followed up until parameters no 
longer meet stopping rule criteria. Each participant will individually define his limit for 
continuation. Stopping rules will apply for a particular participant when he demonstrates a 
sustained change (at least 4 triplicate measurements or at least 1 triplicate measurement 
every 30 min of which the median result of each triplicate measurement will account for 
checking the stopping criteria) of ≥90 minutes in any one of the following criteria during the 
postdose period:
Heart rate:
1) Resting HR increase over the predose baseline of ≥ 25 bpm.
2) Resting HR > 120 bpm
Blood pressure:
1) Resting SBP reduction > 25 mmHg over the predose baseline.
2) Resting SBP < 90 mmHg or participant placed in the Trendelenburg position.
3) Resting SBP ≥ 180 mmHg
4) Resting DBP < 50 mmHg or DBP ≥ 110 mmHg
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Blood pressure and heart rate:
1) For any participants: > 20 mmHg drop in resting SBP and > 20 bpm rise in resting HR
2) For any participants: > 30 mmHg drop in orthostatic SBP and > 30 bpm rise in orthostatic 
HR
On intermediate dosing days (Part 1, Days 2-6, Parts 2 and 3, Day 15) and Day 28, if the 
predose HR or BP measurements meet one of the criteria listed above the site will perform an 
immediate recheck in triplicate of the vital sign parameter out of range.
If the median of the triplicate recheck value is normal, the dose of study drug can be 
given.
If the median recheck value remains abnormal, the vital sign parameter is to be 
rechecked in triplicate every 30 minutes until it returns to near baseline.
If the median recheck vital sign parameter returns to normal in less than 90 minutes, 
this is not considered sustained (stopping criteria not met) and the participant can be 
dosed.
Definitions for HR and BP
Participants must be resting and semirecumbent/supine for at least 10 minutes prior to 
obtaining any measurements (except for changes noted while obtaining orthostatic signs).
Baseline HR and BP: Predose baseline values will be determined for each specific 
participant. For the investigator, the baseline will be calculated using the median from the 
triplicate measurements obtained approximately 1-2 minutes apart within approximately 
3 hours prior to dosing on Day 1 to determine that change from baseline. For all formal 
statistical testing, the mean baseline will be used to calculate the change from baseline. 
Sustained changes are defined as lasting greater than or equal to 90 minutes. If any of the 
resting, semi-recumbent or orthostatic parameters defined above are exceeded, that 
participant must remain resting and semi-recumbent/supine for at least the next 90 minutes. 
During that time, BP (systolic and diastolic) and HR will be obtained every 30 minutes 
(i.e., at 30, 60, and 90 minutes following). If a participant’s BP (systolic or diastolic), or
heart rate exceeds the parameters for the median of all three of the following three 30-minute 
periods, this is defined as a sustained finding, and dosing will end for that particular 
participant. Following 90 minutes, if, in the opinion of the investigator, the participant 
requires further observation, the participant will remain resting and semi-recumbent/supine
until HR and/or BP return to baseline. For HR and BP that are out of range, if the recheck is 
within normal range this is not considered a sustained change.
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10.11 Appendix 11: Guidelines for the Treatment of Hypo/Hypertension
The following is guidance for the investigator with the understanding that the investigator 
must always use his/her own clinical judgment in carrying out this guidance and/or deviating 
from them, with a principle focus on ensuring the safety of study participants.
Severe Hypotension
In the event that a participant develops severe hypotension (systolic blood pressure <80 with 
or without symptoms or <90 accompanied by symptoms) the following is suggested:

Participant may be placed in the Trendelenburg position (supine with head 
downward/feet elevated above the heart).

Intravenous access should already be in place.  

Bolus intravenous normal saline as appropriate until SBP is >100 mmHg or until 
symptoms resolve.   

The participant should be frequently monitored for HR and BP.

The participant should be rapidly evaluated. Evaluations will include a physical 
examination. 12-lead ECG and laboratory safety panel may be performed at the 
discretion of the investigator.

If/when appropriate, efforts should be made to ensure the participant has two functioning 
and open intravenous access sites.

If participant remains hypotensive and/or there has been no resolution of any associated 
symptoms despite the above, the participant should be rapidly transferred to a location 
where definitive care (i.e., an Emergency or Intensive Care Unit) is available.
Severe Hypertension
If a participant develops severe hypertension (systolic blood pressure >170 mmHg and/or 
diastolic blood pressure >105 mmHg) the following is suggested:

Participant should be placed in a semi-recumbent position.

Intravenous access should already be in place in the participant.

The participant should be frequently monitored for HR and BP until BP returns to 
baseline.

The participant should be rapidly evaluated. Evaluations will include a physical 
examination. 12-lead ECG and laboratory safety panel may be performed at the 
discretion of the investigator.
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
Treatment should be considered per local standards, based upon the degree of 
hypertension and/or presence/absence of symptoms (e.g., headache, evidence of heart 
failure or coronary insufficiency).

Blood pressure should be reduced within a few hours.
Participants who are symptomatic or with evidence of end-organ damage should be rapidly 
transferred to a location where definitive care (i.e., Emergency Room or Intensive Care Unit) 
is available.
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
6MWD
6-minute Walk Distance
6MWT
6-minute Walk Test
ABG
arterial blood gas
AE
adverse event 
APaT
All-Participants-as-Treated
AR
adverse reaction
AUC
area under the curve
BDS
blood drug screen
β-hCG
β-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
CI
cardiac index
CG
Cockcroft-Gault
CO
Cardiac output
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CL
clearance
CMAX
maximum concentration
CPET
cardiopulmonary exercise test
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CV
cardiovascular
DC
discharge
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DPI
dry powder inhaler
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FAS
Full Analysis Set
FMF
final market formulation
FRC
functional respiratory capacity
FRI
functional respiratory imaging
FVC
forced vital capacity
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
Hgb
hemoglobin
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
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Abbreviation
Expanded Term
HIV
human immunodeficiency virus
HR
heart rate
hr
hour
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC
Inspiratory capacity
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICS
Inhaled corticosteroid
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LABA
Long-acting beta agonist
LAMA
Long-acting muscarinic antagonist
MedDRA
Medical Dictionary for Regulatory Activities
min
minutes
MMRC
Modified Medical Research Council
MTD
maximum tolerated dose
MVO2
mixed venous oxygen saturation
NCS
not clinically significant
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
NTpro BNP
N-terminal pro-hormone b-type natriuretic peptide
OSA
Obstructive sleep apnea
PAH
pulmonary arterial hypertension
PAP
pulmonary artery pressure
PAWP
Pulmonary artery wedge pressure
PBO
placebo
PBV
pulmonary blood volume
PD
pharmacodynamic
PE
physical exam
PEF
peak expiratory flow
PET
positron emission tomography 
PFT
pulmonary function tests
PH
pulmonary hypertension
PK
pharmacokinetic
PT
prothrombin time
aPTT
activated partial thromboplastin time
PVR
Pulmonary vascular resistance
PP
per-protocol
QP2
department of quantitative pharmacology and pharmacometrics
RAP
right atrium pressure
RHC
right heart catheterization
RNA
ribonucleic acid
RR
respiratory rate
RV
residual volume
RVSP
right ventricular systolic pressure
RVEDP
right ventricular end diastolic pressure
SABA
Short-acting beta agonist
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Abbreviation
Expanded Term
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
sGC
Soluble guanylate cyclase
SoA
schedule of activities
SOBQ
Shortness of Breath Questionnaire
SOP 
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
SVR
systemic vascular resistance
TLC
total lung capacity
Tmax
Time to maximum concentration
UCSD SOBQ
University of California San Diego Shortness of Breath Questionnaire
V 
volume of distribution
VO2max
maximal oxygen uptake
VS
vital sign
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential 
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11
REFERENCES
[Directorate-General, 
Environment Nuclear 
Safety and Civil Protec 
1998]
Directorate-General ENSaCP.  European 
Commission - radiation protection 99:  Guidance 
on medical exposures in medical and biomedical 
research.
[03R6BL]
[American Thoracic 
Society 2002]
American Thoracic Society. ATS statement: 
Guidelines for the six-minute walk test. Am J 
Respir Crit Care Med 2002;166:111-7.
[00QTB2]
[Nathan, S. D., et al 
2019]
Nathan SD, Barbera JA, Gaine SP, Harari S, 
Martinez FJ, Olschewski H, et al. Pulmonary 
hypertension in chronic lung disease and 
hypoxia. Eur Respir J. 2019;53:1801914.
[05FW3V]
[American Thoracic 
Society 2005]
American Thoracic Society. ATS Documents: 
Statements, Guidelines & Reports: ATS/ERS 
standardisation of lung functioning testing: 
Standardisation of spirometry. 
http://www.thoracic.org/statements/
[00V3HY]
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