Conditions: Pulmonary Arterial Hypertension
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This study of frespaciguat in participants with Group 1 pulmonary arterial hypertension (PAH) will assess the safety, tolerability and pharmacokinetics (PK) of inhaled frespaciguat. There is no formal hypothesis to be tested.

Detailed description:
In Part 1, one panel (Panel A) of up to 8 participants will dose in up to 3 dosing periods, with a minimum washout of 7 days between dosing periods. In each dosing period, 6 participants will receive frespaciguat and 2 will receive placebo, with 2 different participants receiving placebo in each of the dosing periods. Review of available safety data will occur prior to escalating to the next dose level.

Participants from Part 1 may continue into Part 2, which will assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose inhaled frespaciguat. Three additional panels of participants (Panels B, C and D) will be enrolled into Part 2. Participants in Panel A will participate in 2 open-label dosing periods to assess PD measures associated with right heart catherization (RHC) \[Period 2\] and functional respiratory imaging (FRI) \[Period 3\]. Participants in Panels B, C, and D will participate in 3 dosing periods: Period 1 (open-label assessment of safety/tolerability and PK), Period 2 (FRI period) and Period 3 (RHC period).

Arms:
arm 1: Participants in Panel A will receive a single inhaled dose of frespaciguat 120 ug in Period 1 of Part 1, followed by frespaciguat 165 ug in Period 2, followed by frespaciguat 240 ug in Period 3. Each dose will be separated by at least a 7-day washout. In Part 2 Period 2, participants will receive a single inhaled dose of frespaciguat 240 ug and undergo a right heart catheterization (RHC). In Part 2 Period 3, participants will receive a single inhaled dose of frespaciguat 240 ug and undergo a functional respiratory imaging (FRI). arm 2: Participants in Panel B will receive a single inhaled dose of frespaciguat 300 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of frespaciguat 360 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of frespaciguat 360 ug and undergo RHC. Each dose will be separated by at least a 7-day washout. arm 3: Participants in Panel C will receive a single inhaled dose of frespaciguat 300 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of frespaciguat 360 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of frespaciguat 360 ug and undergo RHC. Each dose will be separated by at least a 7-day washout. arm 4: Participants in Panel D will receive a single inhaled dose of frespaciguat 480 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of frespaciguat 120 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of frespaciguat 120 ug and undergo RHC. Each dose will be separated by at least a 7-day washout. arm 5: Participants will receive a single inhaled dose of matching placebo in Part 1.

Interventions: intervention 1: Frespaciguat intervention 2: Placebo
Intervention descriptions: intervention 1: Single inhaled dose of frespaciguat 120, 165, 240, 300, 360, or 480 ug depending upon randomization intervention 2: Single inhaled dose of placebo to match frespaciguat

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03744637 
Document Date: 
16-JUN-2020
A Study to Assess the Effect of Single Doses of MK -5475 on 
Pulmonary Vascular Resistance in Patients with Moderate to Severe 
Pulmonary Arterial Hypertension


PRODUCT:  MK-5475  
1
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
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 Effect of Single Doses of MK -5475 on Pulmonary 
Vascular Resistance in Patients with Moderate to Severe Pulmonary Arterial Hypertension
Protocol Number: 002-03
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):
Approval Date: 16 June 2020
 
 
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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-5475-002-03
16-JUN-2020
A panel of up to 8 subjects added (Panel D) to evaluate PD effects (PVR and PBV) at 120 
mcg and safety at 480 mcg.  The data will inform the range of potential efficacious doses 
for later studies.
MK-5475-002-02
29-MAY-2019
Panel C added to Part 2 and doses change for Panel B to evaluate higher doses based on 
PK results seen at 120, 165 and 240 µg doses in Part 1.
Incorporated ERAs into list of exclusionary criteria /prohibited medications.
MK-5475-002-01
31-OCT-2018
Incorporate flexible language for protocol modifications related to timing of safety and 
PK procedures based on newly learned data
MK-5475-002-00
22-OCT-2018
Original Version
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
A panel of up to 8 subjects added (Panel D) to evaluate PD effects (PVR and PBV) at 120 mcg and safety at 480 mcg.  The data will 
inform the range of potential safe and efficacious doses for later studies.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
Sample size, intervention, duration in 
study for Panel D added
To expand the range of potential safe and efficacious 
doses
1.2 Scheme
Panel D added
To expand the range of potential safe and efficacious 
doses
1.3 SOA
Panel D added. Adjusted PK sample 
timepoints for Panel D, Period 2 (FRI 
period).
To expand the range of potential safe and efficacious 
doses
2
Changed to 4 panels
To expand the range of potential safe and efficacious 
doses
2.2.2 Pre-Clinical and 
Clinical Studies
Moved summary of PN003 to completed 
clinical studies section.  Removed AE and 
PK table for PN 001
AE and PK tables for PN 001 are available in edition 3 of 
the IB.
2.2.3 Ongoing Clinical 
Studies
Updated safety and PK data of PN002 to 
date. Added summary for PN004
New data available
 
 
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Section # and Name
Description of Change 
Brief Rationale 
3.0  Hypotheses,Objectives 
and Endpoints
Panel D added 
To expand the range of potential safe and efficacious 
doses
4.1 Overall Design
Description of Panel D added to study 
design.
To expand the range of potential safe and efficacious 
doses
4.2 Scientific Rationale for 
Study Design
Rationale to explore 120 µg and 480 µg 
doses added
To expand the range of potential safe and efficacious 
doses
4.3,2 Maximum 
Dose/Exposure for this 
Study
Rationale for the highest dose 480 µg and 
estimated exposure of this dose added
To expand the range of potential safe and efficacious 
doses
5.1 Inclusion Criteria
Panel D added
To expand the range of potential safe and efficacious 
doses
5.2 Exclusion Criteria
Updated a- fib exclusion criteria. Removed 
Hep B exclusion criteria
To enhance recruitment for Panel D
6.1 Study Interventions 
Administered
Study interventions of 120µg and 480 µg 
for Panel D added.  Device language 
removed
To expand the range of potential safe and efficacious 
doses.
Device language is not applicable as it applies to 
marketed drug/device combination products.
6.3.1 Intervention 
Assignment
Sample allocation schedule for Panel D 
added
To expand the range of potential safe and efficacious 
doses
8.4.8 Device Events, 
Adverse Device Events 
Device language removed
Device language is not applicable as it applies to 
marketed drug/device combination products
 
 
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Section # and Name
Description of Change 
Brief Rationale 
8.7.1 Right Heart 
Catheterization Procedures
Language added if RHC procedure needs 
to stop earlier
RHC procedure may need to stop earlier at the discretion 
of the investigator. 
8.11.2 Treatment Visit 
Period
Panel D added
To expand the range of potential safe and efficacious 
doses
8.11.5 Critical Procedures 
Based on Study Objectives: 
Timing of Procedures
Panel D added
To expand the range of potential safe and efficacious 
doses
9.1 Statistical Analysis Plan 
Summary
Panel D added
To expand the range of potential safe and efficacious 
doses
9.4 Analysis Endpoints
Panel D added
To expand the range of potential safe and efficacious 
doses
9.6 Statistical Methods
Panel D added
To expand the range of potential safe and efficacious 
doses
10.4 device Events, Adverse 
Device Events and Medical 
Device Incidents: 
Definitions, Collection and 
Documentation
Removed  
This is not applicable due to drug/device combination is  
considered investigational
10.8 Blood Volume Table
Blood Volume Table Added for Panel D
To expand the range of potential safe and efficacious 
doses
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................20
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................30
2.2.1
Pharmaceutical and Therapeutic Background .............................................30
2.2.2
Preclinical and Clinical Studies ...................................................................31
2.2.3
Ongoing Clinical Studies.............................................................................32
2.2.4
Information on Other Study-related Therapy ..............................................33
2.3
Benefit/Risk Assessment......................................................................................33
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................33
4
STUDY DESIGN............................................................................................................36
4.1
Overall Design......................................................................................................36
4.2
Scientific Rationale for Study Design.................................................................37
4.2.1
Rationale for Endpoints ...............................................................................38
4.2.1.1
Efficacy Endpoints.............................................................................38
4.2.1.2
Safety Endpoints................................................................................38
4.2.1.3
Pharmacokinetic Endpoints ...............................................................38
4.2.1.4
Pharmacodynamic Endpoints.............................................................38
4.2.1.5
Planned Exploratory Biomarker Research.........................................38
4.2.1.5.1
Planned Genetic Analysis ........................................................39
4.2.1.6
Future Biomedical Research..............................................................39
4.2.2
Rationale for the Use of Comparator/Placebo .............................................39
4.3
Justification for Dose...........................................................................................39
4.3.1
Starting Dose for This Study........................................................................40
4.3.2
Maximum Dose/Exposure for This Study ...................................................40
4.3.3
Rationale for Dose Interval and Study Design ............................................42
4.4
Beginning and End of Study Definition .............................................................42
4.4.1
Clinical Criteria for Early Study Termination .............................................43
5
STUDY POPULATION ................................................................................................43
5.1
Inclusion Criteria.................................................................................................43
 
 
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5.2
Exclusion Criteria................................................................................................47
5.3
Lifestyle Considerations......................................................................................51
5.3.1
Meals and Dietary Restrictions....................................................................51
5.3.1.1
Diet Restrictions.................................................................................51
5.3.1.2
Fruit Juice Restrictions ......................................................................52
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................52
5.3.2.1
Caffeine Restrictions..........................................................................52
5.3.2.2
Alcohol Restrictions...........................................................................52
5.3.2.3
Tobacco Restrictions..........................................................................53
5.3.3
Activity Restrictions ....................................................................................53
5.4
Screen Failures.....................................................................................................53
5.5
Participant Replacement Strategy......................................................................53
6
STUDY INTERVENTION............................................................................................53
6.1
Study Intervention(s) Administered...................................................................54
6.2
Preparation/Handling/Storage/Accountability .................................................56
6.2.1
Dose Preparation..........................................................................................56
6.2.2
Handling, Storage, and Accountability........................................................56
6.3
Measures to Minimize Bias: Randomization and Blinding..............................57
6.3.1
Intervention Assignment..............................................................................57
6.3.2
Stratification.................................................................................................57
6.3.3
Blinding........................................................................................................58
6.4
Study Intervention Compliance..........................................................................58
6.5
Concomitant Therapy..........................................................................................58
6.5.1
Rescue Medications and Supportive Care ...................................................60
6.6
Dose Modification (Escalation/Titration/Other)...............................................60
6.6.1
Stopping Rules.............................................................................................60
6.7
Intervention After the End of the Study............................................................61
6.8
Clinical Supplies Disclosure................................................................................61
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................61
7.1
Discontinuation of Study Intervention...............................................................61
7.2
Participant Withdrawal From the Study...........................................................62
7.3
Lost to Follow-up .................................................................................................63
8
STUDY ASSESSMENTS AND PROCEDURES........................................................63
8.1
Administrative and General Procedures ...........................................................64
8.1.1
Informed Consent.........................................................................................64
8.1.1.1
General Informed Consent.................................................................64
 
 
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................64
8.1.2
Inclusion/Exclusion Criteria ........................................................................65
8.1.3
Participant Identification Card.....................................................................65
8.1.4
Medical History ...........................................................................................65
8.1.5
Prior and Concomitant Medications Review...............................................65
8.1.5.1
Prior Medications...............................................................................65
8.1.5.2
Concomitant Medications..................................................................65
8.1.6
Assignment of Screening Number...............................................................65
8.1.7
Assignment of Treatment/Randomization Number.....................................66
8.1.8
Study Intervention Administration ..............................................................66
8.1.8.1
Timing of Dose Administration.........................................................66
8.1.9
Discontinuation and Withdrawal .................................................................66
8.1.9.1
Withdrawal From Future Biomedical Research ................................66
8.1.10
Participant Blinding/Unblinding..................................................................67
8.1.11
Domiciling ...................................................................................................68
8.1.12
Calibration of Equipment.............................................................................68
8.2
Efficacy/Immunogenicity Assessments ..............................................................69
8.3
Safety Assessments...............................................................................................69
8.3.1
Physical Examinations.................................................................................69
8.3.2
Vital Signs....................................................................................................69
8.3.2.1
Resting Vital Signs ............................................................................70
8.3.2.2
Oxygen Saturation .............................................................................70
8.3.2.3
Orthostatic Vital Signs.......................................................................70
8.3.3
Electrocardiograms ......................................................................................70
8.3.4
Clinical Safety Laboratory Assessments .....................................................71
8.3.5
Pulmonary Function Tests (PFTs (Spirometry)...........................................71
8.3.6
Inhalation Airflow Meter Assessment .........................................................72
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................72
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................73
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......75
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...75
8.4.4
Regulatory Reporting Requirements for SAE .............................................75
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................75
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................76
8.4.7
Events of Clinical Interest (ECIs)................................................................76
 
 
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8.5
Treatment of Overdose........................................................................................76
8.6
Pharmacokinetics.................................................................................................76
8.6.1
Blood Collection for Plasma MK-5475 .......................................................77
8.7
Pharmacodynamics..............................................................................................77
8.7.1
Right Heart Catheterization Procedures.......................................................77
8.7.2
CT Scan for Functional Respiratory Imaging..............................................77
8.8
Biomarkers ...........................................................................................................78
8.8.1
Planned Genetic Analysis Sample Collection..............................................78
8.9
Future Biomedical Research Sample Collection...............................................78
8.10
Health Economics Medical Resource Utilization and Health Economics.......78
8.11
Visit Requirements...............................................................................................79
8.11.1
Screening......................................................................................................79
8.11.2
Treatment Period Visit.................................................................................79
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........80
8.11.4
Poststudy......................................................................................................80
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......80
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................82
9
STATISTICAL ANALYSIS PLAN .............................................................................84
9.1
Statistical Analysis Plan Summary.....................................................................84
9.2
Responsibility for Analyses.................................................................................84
9.3
Hypotheses/Estimation ........................................................................................85
9.4
Analysis Endpoints...............................................................................................86
9.5
Analysis Populations............................................................................................86
9.6
Statistical Methods...............................................................................................87
9.7
Interim Analyses ..................................................................................................88
9.8
Multiplicity ...........................................................................................................88
9.9
Sample Size and Power Calculations .................................................................88
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................89
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........89
10.1.1
Code of Conduct for Clinical Trials.............................................................89
10.1.2
Financial Disclosure.....................................................................................91
10.1.3
Data Protection.............................................................................................91
10.1.3.1
Confidentiality of Data ......................................................................92
10.1.3.2
Confidentiality of Participant Records...............................................92
10.1.3.3
Confidentiality of IRB/IEC Information............................................92
10.1.4
Publication Policy........................................................................................92
 
 
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10.1.5
Compliance with Study Registration and Results Posting Requirements ...93
10.1.6
Compliance with Law, Audit, and Debarment ............................................93
10.1.7
Data Quality Assurance ...............................................................................94
10.1.8
Source Documents .......................................................................................94
10.1.9
Study and Site Closure.................................................................................95
10.2
Appendix 2: Clinical Laboratory Tests..............................................................95
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................97
10.3.1
Definition of AE ..........................................................................................97
10.3.2
Definition of SAE ........................................................................................98
10.3.3
Additional Events Reported.........................................................................99
10.3.4
Recording AE and SAE ...............................................................................99
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................103
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................104
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................105
10.5.1
Definitions..................................................................................................105
10.5.2
Contraception Requirements......................................................................106
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................107
10.7
Appendix 7: Country-specific Requirements..................................................112
10.8
Appendix 8: Blood Volume Table ....................................................................113
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....115
10.10 Appendix 10: Hemodynamic Stopping Criteria..............................................116
10.11 Appendix 11: Guidelines for the Treatment of Hypo/Hypertension.............118
10.12 Appendix 12: Abbreviations .............................................................................120
11
REFERENCES.............................................................................................................122
 
 
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LIST OF TABLES
Table 1
Overall Study Design.......................................................................................18
Table 2
Study Interventions..........................................................................................55
Table 3
Sample Allocation Schedule............................................................................57
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................74
Table 5
Pharmacokinetic Blood Collection Windows..................................................81
Table 6
Protocol-required Safety Laboratory Assessments..........................................96
 
 
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LIST OF FIGURES
Figure 1
Part 2 Panel A Study Design (Periods 2 and 3) .........................................19
Figure 2
Part 2 Panel B, C and D Study Design (Periods 2 and 3)..........................19
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Study to Assess the Effect of Single Doses of MK -5475 on Pulmonary 
Vascular Resistance in Patients with Moderate to Severe Pulmonary Arterial Hypertension
Short Title: Dosing of MK-5475 in Participants with Pulmonary Hypertension
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study is to be conducted in male and female participants with group 1 pulmonary 
arterial hypertension (PAH).
Primary Objectives
Primary Endpoints
- To evaluate the safety and tolerability of 
MK-5475 in participants with pulmonary 
arterial hypertension (PAH). (All parts)
Safety and tolerability will be evaluated 
during clinical assessments that include 
vital signs, safety laboratory testing, 
physical examinations, ECG readings, 
PFTs and review of adverse events.
- To assess the duration and effect following 
a single inhaled dose of MK-5475 on 
pulmonary vascular resistance (PVR) in 
participants with pulmonary arterial 
hypertension (PAH). (Part 2, Period 2 (Panel 
A) and Period 3 (Panels B, C and D))
Peak reduction from baseline in PVR after 
a single inhaled dose of MK-5475 
Secondary Objectives
Secondary Endpoints
- To estimate the effect of MK-5475 given as 
single inhaled doses on systemic 
hemodynamic parameters (heart rate (HR), 
systolic and diastolic blood pressure (BP)) in 
participants with pulmonary arterial 
hypertension. (Part 2 Period 2 (Panel A) and 
Period 3 (Panels B, C and D))
- HR and BP change from baseline at 0.5, 
4.5, and 24 (or prior to discharge) hours 
post-dose. 
- To assess the effect following a single 
inhaled dose of MK-5475 on pulmonary 
blood volume (PBV) in participants with 
pulmonary arterial hypertension. (Part 2, 
Period 3 (Panel A) and Period 2 (Panels B, C 
and D))
- Increases from baseline PBV at 1, 3, 8 
and 24 hours postdose.
 
 
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Pulmonary Arterial Hypertension (PAH)
Population
Participants with moderate to severe Group 1 PAH
Study Type
Interventional
Intervention Model
Sequential
This is a single-site study.
Type of Control
Not applicable
Study Blinding
Double-blind
Masking
Data Analyst
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 22 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Part 1 
(Panel A)
MK-5475
120, 165, 
240 µg
Single 
dose
Inhalation
Once/Periods 
1-3
Experi-
mental
Pbo
0µg
Single 
dose
Inhalation
Once/ Periods 
1-3
Pbo control
Placebo
0µg
Single 
dose
Inhalation
Once/ 
Screening 2
Training
Part 2 
(Panel A)
MK-5475
240 µg
Single 
dose
Inhalation
Once/Periods 
2-3
Experi-
mental
Part 2 
(Panel B)
MK-5475
300, 
360 µg
Single 
dose
Inhalation
Once/Periods 
1-3a
Experi-
mental
Pbo
0 µg
Single 
dose
Inhalation
Once/Screeni
ng 2
Training
Part 2 
(Panel C)
Pbo
0 µg
Single 
dose
Inhalation
Once/Screeni
ng 2
Training
MK-5475
300,       
360 µg
Single 
dose
Inhalation
Once/Periods 
1-3a,b
Experi-
mental
Part 2 
(Panel D)
Pbo
0 µg
Single 
dose
Inhalation
Once/
Screening 2
Training
Part 2 
(Panel D)
MK-5475
480, 120 
µg
Single 
dose
Inhalation
Once/Periods 
1 - 3
Experi-
mental
Abbreviations: µg=micrograms; pbo=placebo
a
Panel B and C: The dose of Part 2, Periods 2 and 3 (360 µg) will depend on the 
observance of adequate safety and tolerability in Part 2, Period 1
b
Panel C dose will not exceed the maximum dose administered in Panel B.
Total 
Number
4
Duration of 
Participation
Each participant will participate in the study for approximately 15- 25
weeks for Panel A, 13 – 19 weeks for Panels B – C and 10 to 12 weeks for 
Panel D from the time the participant signs the Informed Consent Form 
through the final contact. After a screening phase of 5 weeks, each 
participant in Part 1 will receive 3 single doses of MK-5475/placebo over 
approximately 5 to 7 weeks. Participants in Part 2 will receive up to 2-3
single doses over approximately 3 to 8 weeks. Participants in Part 1 may 
participate in Part 2. After the end of treatment, each participant will be 
followed for 14 days.
 
 
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PRODUCT:  MK-5475  
17
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Number of Participants:
Approximately 8 participants in Part 1 and 24 participants in Part 2 will be 
allocated/randomized such that 8 evaluable participants in Part 1 and 24 evaluable 
participants in Part 2 complete the study as described in Section 9.5. Participants from Part 1 
can participate in Part 2.
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.
 
 
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PRODUCT:  MK-5475  
18
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
1.2
Schema
The study design is depicted in Table 1. Detailed depiction of Part 2, Periods 2 and 3 are in 
Figure 1 and Figure 2.
Table 1
Overall Study Design
Panel
Part 1
Period 1
Part 1 
Period 2
PK 
Break 
Part 1
Period 3
Part 2 Period 
1c
Part 2 Period 
2c
Part 2 Period 3
A (N=8)b
120µg/ 
Pboa
165µg/ 
Pboa
240µg/ Pboa
240 µg w/ 
Right Heart 
Catheterizati
on (RHC)a, d
240 w/ 
Functional 
Respiratory 
Imaging 
(FRI)a, d
B (N=4)d
300 µga,d
360 µg w/
Functional 
Respiratory 
Imaging 
(FRI)a
360 µg w/ 
Right Heart 
Catheterizatio
n (RHC)a
C (N= up to 
8)b
300 µga
360 µg w/ 
Functional 
Respiratory 
Imaging 
(FRI)a
360 µg w/ 
Right Heart 
Catheterizatio
n (RHC)a
D
(N= up to 7)
b
480 µg e
120 µg w/ 
Functional 
Respiratory 
Imaging 
(FRI)a
120 µg w/ 
Right Heart 
Catheterizatio
n (RHC)a
a.
The suggested doses may be adjusted downward based on evaluation of safety, tolerability, pharmacokinetic 
and/or pharmacodynamic data observed in previous intervention periods. Refer to Section 6.6 (Dose 
Modification) for the safety, pharmacokinetic, and pharmacodynamic data that will be reviewed prior to dose 
escalation.  
b.
Participants in Part 1 may continue to participate in Part 2 provided they meet RHC criteria at baseline Part 2 
Period 2.  The minimum sample size for Panel C = 6 but, may increase based on the number of participants 
from Panel A who do not move forward to Part 2 or fail to meet the baseline RHC criteria in Period 2. The 
maximum sample size for Panel D = 7 but, will depend upon the total number of participants enrolled in Panel 
C at the time Panel D begins. Total sample size in Part 2 equals 24.
c.
Participants in Panel A that continue into Part 2 will not have a Period 1 but, will go directly to Period 2 where 
RHC is performed. This period can occur in parallel with Panel B, Period 1. Panel C, Period 1 may begin 
following review of PK from Panel B Period 1 (Parallel with Periods 2 or 3 of Panel B).
d.
A rolling evaluation of PK may occur for participants in Panel B and C, Period 1. Review of Panel B PK for 
Period 1 will occur before dosing of Panel B, Period 2 and Panel C, Period 1. Panel C, Period 2 may begin 
following review of PK for the first 4 participants of Panel C.
e.
Panel D, may occur in parallel with participants already actively enrolled in Panel C.
 
 
05J3S0
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PRODUCT:  MK-5475  
19
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Figure 1
Part 2 Panel A Study Design (Periods 2 and 3)
Figure 2
Part 2 Panel B, C and D Study Design (Periods 2 and 3)
 
 
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PRODUCT:  MK-5475  
20
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
1.3
Schedule of Activities (SoA)
Intervention 
(Panel A: Part 1, Periods 1-3)
(Panel B, C and D: Part 2, Period 1)
Study Period
Screening
Notes
≤35 days pre-
randomization
≤7 days pre-
randomization
Day 
1
Hours
Scheduled Hour, Day
Screening 1
Screening 2
Pre-
dose
0
~0.1 
(5min)
0.25  
(15min)
0.5
(30min)
1
2
3
4
8
24
Post 
Study
~14 
days
All post study 
procedures to be 
performed for 
participants in
Panel A. that do not 
go onto Part 2.
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Inclusion/Exclusion Criteria
X
X
X
Pre-dose 
assessment applies 
to Period 1 only
Participant Identification Card
X
Medical History
X
Prior/Concomitant Medication Review
X
X
X----------------------------------------------------------------X
X
Assignment of Screening Number
X
Assignment of Allocation Number
(Randomization)
X
Period 1 only.
All participants 
receive an 
allocation number.
MK-5475/pbo Administration
X
Placebo applies to 
Part 1 – Panel A
Standard Meals
X-------X
See section 5.3.1 
for timing of meals 
and snacks
 
 
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PRODUCT:  MK-5475  
21
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Intervention 
(Panel A: Part 1, Periods 1-3)
(Panel B, C and D: Part 2, Period 1)
Study Period
Screening
Notes
≤35 days pre-
randomization
≤7 days pre-
randomization
Day 
1
Hours
Scheduled Hour, Day
Screening 1
Screening 2
Pre-
dose
0
~0.1 
(5min)
0.25  
(15min)
0.5
(30min)
1
2
3
4
8
24
Post 
Study
~14 
days
All post study 
procedures to be 
performed for 
participants in
Panel A. that do not 
go onto Part 2.
Domiciling
X--------------------------------------------------------------X
See Section 8.1.11 
for domiciling 
details
Training with Spirometer Device 
(PFTs)
X
Training will be 
done for each 
participant at one 
occasion for site 
spirometry 
measures. 
Inhaler Training/Placebo 
Administration
X
Preferably done at 
Screening 2 but, 
may be done at 
Screening 1 if  
within 7 days of 
pre-randomization.
Inspiratory Flow Meter Assessment
X
X
Panels B, C and D
only. Day 1 
procedure can be 
done within 3 hours 
at predose.
Safety Procedures
Full physical examination (PE)
X
X
X
X
Pre-dose measure is 
prior to each 
Height
X
 
 
05J3S0
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PRODUCT:  MK-5475  
22
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Intervention 
(Panel A: Part 1, Periods 1-3)
(Panel B, C and D: Part 2, Period 1)
Study Period
Screening
Notes
≤35 days pre-
randomization
≤7 days pre-
randomization
Day 
1
Hours
Scheduled Hour, Day
Screening 1
Screening 2
Pre-
dose
0
~0.1 
(5min)
0.25  
(15min)
0.5
(30min)
1
2
3
4
8
24
Post 
Study
~14 
days
All post study 
procedures to be 
performed for 
participants in
Panel A. that do not 
go onto Part 2.
Weight
X
X
period. See section 
8.3.1 for PE, height 
and weight 
procedures and 
8.11.5 for timing 
window.
Heart Rate(HR) & Blood Pressure(BP)
X
X
X
X X
X X
X
X
Pre-dose measure is 
prior to each 
period. See section 
8.3.2 for all 
appropriate vital 
sign procedures and 
8.11.5 for timing 
window.
Orthostatic Vital Signs (HR & BP)
X
X
X
X
X
X
Body Temperature(Temp)
X
X
X
X
X
Respiratory Rate (RR)
X
X
X
X X
X X
X
X
12-lead ECG
X
X
X
X X
X X
X
X
Pre-dose measure is 
prior to each 
period. See section 
8.3.3 for ECG 
procedure details 
and 8.11.5 for 
timing window.
 
 
05J3S0
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PRODUCT:  MK-5475  
23
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Intervention 
(Panel A: Part 1, Periods 1-3)
(Panel B, C and D: Part 2, Period 1)
Study Period
Screening
Notes
≤35 days pre-
randomization
≤7 days pre-
randomization
Day 
1
Hours
Scheduled Hour, Day
Screening 1
Screening 2
Pre-
dose
0
~0.1 
(5min)
0.25  
(15min)
0.5
(30min)
1
2
3
4
8
24
Post 
Study
~14 
days
All post study 
procedures to be 
performed for 
participants in
Panel A. that do not 
go onto Part 2.
Pulmonary Function Tests (PFTs)
X
X
X
X
X
Pre-dose measure is 
prior to each 
period. See section 
8.3.5 for specific 
parameters to be 
performed at 
screening and pre / 
post-dose and 
8.11.5 for timing 
window.  
Serum β-Human Chorionic 
Gonadotropin
(β-hCG; WOCBP only)
X
X
Urine Pregnancy Test (WOCBP only)
X
Pre-dose measure is 
prior to each period
Serum Follicle Stimulating Hormone 
(FSH) - (WONCBP only)
X
Echocardiogram (if needed, for Panel B
or C participants only)
X
Follow site SOP for 
assessment of PAH 
in newly diagnosed 
participants in 
Panel B, C or D
only
HIV, hepatitis B and C screen (per site 
SOP)
X
 
 
05J3S0
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PRODUCT:  MK-5475  
24
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Intervention 
(Panel A: Part 1, Periods 1-3)
(Panel B, C and D: Part 2, Period 1)
Study Period
Screening
Notes
≤35 days pre-
randomization
≤7 days pre-
randomization
Day 
1
Hours
Scheduled Hour, Day
Screening 1
Screening 2
Pre-
dose
0
~0.1 
(5min)
0.25  
(15min)
0.5
(30min)
1
2
3
4
8
24
Post 
Study
~14 
days
All post study 
procedures to be 
performed for 
participants in
Panel A. that do not 
go onto Part 2.
Urine/Blood Drug Screen (UDS/BDS) 
(per site SOP)
X
X
Screening and 
Period 1 UDB/BDS 
is mandatory, any 
additional 
UDS/BDS are 
conducted per site 
SOP
Hematology/Chemistry
X
X
X
X
See Appendix 2 for 
laboratory tests
Urinalysis
X
X
X
X
PT/aPTT
X
X
X
X
AE/SAE review
X
X
X---------------------------------------------------------------X
X
See all sections 
under 8.4  
Phone Call for AE/SAE review
X
Panel A 
participants that go 
into Part 2 will 
have a phone call 
only 14 days after 
last dosing period.
Pharmacokinetics
Blood for Plasma MK-5475 parent 
and/or metabolites
X
X
X
X
X X X X X X
Pre-dose measure is 
prior to each 
period. See 
operations manual 
for sample 
processing details.
 
 
05J3S0
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PRODUCT:  MK-5475  
25
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Intervention 
(Panel A: Part 1, Periods 1-3)
(Panel B, C and D: Part 2, Period 1)
Study Period
Screening
Notes
≤35 days pre-
randomization
≤7 days pre-
randomization
Day 
1
Hours
Scheduled Hour, Day
Screening 1
Screening 2
Pre-
dose
0
~0.1 
(5min)
0.25  
(15min)
0.5
(30min)
1
2
3
4
8
24
Post 
Study
~14 
days
All post study 
procedures to be 
performed for 
participants in
Panel A. that do not 
go onto Part 2.
Biomarkers
Blood for Genetic Analysis 
X
Pre-dose Period 1 
only – See Section 
8.8 and 8.9
 
 
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PRODUCT:  MK-5475  
26
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Part 2
Study Period
Intervention (FRI Period)
Panel A = Period 3
Panel B, C and D = Period 2
Notes
Day 1
Hour
Scheduled Time  
Predose and 
Pre Baseline 
Scan
Baseline 
Scan
0
1
3
8
Prior to 
Discharge 
post 8 hr 
scan (if 
needed)
24
Prior to 
Discharge 
post 24 hr 
scan
Post 
Study
Post Study procedures are 
performed following the 
completion of Period 3 (All 
Panels)
Administrative Procedures
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
MK-5475 Administration
X
Inspiratory Flow Meter Assessment
X
X
Assessment to be done within 3 
hours at predose (Panels B, C
and D only). Post Study 
assessment (Panel A only) An 
optional predose assessment may 
be done for Panel A.
Standard Meals
X------X
A standard snack may be given 
between the 1 and 3 hour CT 
scans. Meal will be given about 1 
hour after 3 hour postdose scan. 
See 5.3.1
Safety Procedures
Full physical examination (PE)
X
X
Pre-dose PE may occur w/in 24 
hrs of baseline scan
Weight
X
Heart Rate(HR) & Blood Pressure(BP)
X
X
X
X
See section 8.3.2 for all 
appropriate vital sign procedures.
Body Temperature(Temp)
X
X
X
X
Respiratory Rate (RR)
X
X
X
X
12-lead ECG
X
X
X
X
Serum β-Human Chorionic 
Gonadotropin
(β-hCG; WOCBP only)
X
 
 
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PRODUCT:  MK-5475  
27
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Part 2
Study Period
Intervention (FRI Period)
Panel A = Period 3
Panel B, C and D = Period 2
Notes
Day 1
Hour
Scheduled Time  
Predose and 
Pre Baseline 
Scan
Baseline 
Scan
0
1
3
8
Prior to 
Discharge 
post 8 hr 
scan (if 
needed)
24
Prior to 
Discharge 
post 24 hr 
scan
Post 
Study
Post Study procedures are 
performed following the 
completion of Period 3 (All 
Panels)
Urine Pregnancy Test (WOCBP only)
X
See Appendix 10.2 for details 
regarding laboratory tests. Pre-
dose lab tests may occur w/in 24 
hrs of baseline scan
Hematology/Chemistry
X
X
Urinalysis
X
X
PT/aPTT
X
X
PFTs
X
AE/SAE review
X
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
Panels A, B and C: Predose, 1, 3, 
8 and 24 hours postdose.
Panel D: Predose, 15 min, 30 
min, 1, 2, 3, 4, 8 and 24 hours 
postdose
See operations manual for 
sample processing details
Pharmacodynamics
CT Scan for Functional Respiratory 
Imaging (FRI)
X
X
X
X
X
Baseline scan to occur w/in 30 
minutes of dosing
 
 
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PRODUCT:  MK-5475  
28
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Part 2
Study Period
Intervention (RHC Period)
Panel A = Period 2
Panel B, C and D = Period 3
Notes
Day 1
Day 1 
Hour
Scheduled Hour, Day
Pre RHC
Pre dose
0
0.25
0.5 
1
2
3
4
4.5
24h or 
prior to 
D/C
See FRI flowchart for Poststudy 
procedures to be completed 
following Period 3.
Administrative Procedures
RHC Inclusion/Exclusion Criteria
X
Pre-dose assessment applies to 
Period 2 if Panel A and Period 3, 
if Panel B, C or D
Prior/Concomitant Medication Review
X------------------------------------------------------------------------------X
MK-5475 Administration
X
Inspiratory Flow Meter Assessment
X
Assessment to be done within 3 
hours at predose (Panels B, C
and D). An optional predose 
assessment may be done for 
Panel A.
Standard Meals
X
X
See section 5.3.1 for timing of 
meals and snacks
Domiciling
X-------------------------------------------------------------------------------X
See Section 8.1.11
Pharmacodynamic Procedures
Right Heart Catheterization (RHC) Measurements
X
X
X
X
X
X
X
See section 8.7.1 and operations 
manual for RHC details
Pulmonary Arterial Pressure (PAP)
X
X -----------------------------X
q 30 minutes
Arterial O2 Saturation (pulse oximetry)
X
X
X
X
X
X
X
On room air
Mixed Venous O2 Saturation (MVO2)
X
X
X
X
X
X
X
On room air
Safety Procedures
Full physical examination
X
X
Pre RHC PE may occur w/in 24 
hours of dosing
Heart Rate (HR) & Blood Pressure (BP)
X
X
X-----------------------------X
X
HR/BP q 30 minutes
See section 8.3.2 for all 
appropriate vital sign 
procedures.
Body Temperature (Temp)
X
X
Respiratory Rate (RR)
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
See section 8.3.3 for ECG 
procedure details
 
 
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PRODUCT:  MK-5475  
29
PROTOCOL/AMENDMENT NO.:  002-03 
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Part 2
Study Period
Intervention (RHC Period)
Panel A = Period 2
Panel B, C and D = Period 3
Notes
Day 1
Day 1 
Hour
Scheduled Hour, Day
Pre RHC
Pre dose
0
0.25
0.5 
1
2
3
4
4.5
24h or 
prior to 
D/C
See FRI flowchart for Poststudy 
procedures to be completed 
following Period 3.
Urine Pregnancy Test (WOCBP only)
X
Hematology/Chemistry
X
X
See Appendix 10.2 for details 
regarding laboratory tests. Pre 
RHC labs may occur w/in 24 hrs
Urinalysis
X
X
PT/aPTT
X
X
AE/SAE review
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
See operations manual for 
sample processing details
 
 
05J3S0
06DQP7


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PRODUCT:  MK-5475  
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oropharyngeal pain (N=2), nausea (N=2), catheter site pain (N=2), back pain (N=2), 
musculoskeletal chest pain (N=2), and dizziness postural (N=2).
Multiple-dose PK data in PN003 showed that the geometric mean t1/2 on Day 5 and 10 was 
approximately 2 hours and is similar to the geometric mean t1/2 achieved on Day 1 in the 
first in human study PN001 (1.88 hours). The geometric mean AUC0-24 ranged from 0.129 
to 1.71 nM·hr on the first day for the 30 to 240 µg dose levels. On the last day the geometric 
mean AUC0-24 ranged from 0.218 to 2.00 nM·hr. Following administration of the 240µg 
dose for 5 days, the GM AUC0-24 was 2.00 nM·hr, which is approximately 2.25 times below 
the AUC0-24 (4.5 nM·hr) corresponding to the NOAEL in the dog.
2.2.3
Ongoing Clinical Studies
PN002: Dosing of MK-5475 in Participants with Pulmonary Hypertension (Current 
Study)
In this 2-part study evaluating the safety, PK and PD [right heart catheterization (RHC) and 
functional respiratory imaging (FRI)], single-dose MK-5475 ranging from 120 to 360 µg in 
participants with moderate to severe group 1 PAH is generally well-tolerated. To date, 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 45 AEs in 15 of 18
participants were reported. Of these, 9 AEs were considered related to study drug by the 
investigator. AEs deemed related were rhinitis (1), dizziness (1), ALT increased (2.94 x 
ULN) (1) bilirubin increased (1.18 and 2.13 x ULN)(2) hyperkalemia (1.02 to 1.07 xULN)
(3) and platelet count decreased (0.33 below LLN) (1).  Refer to the Investigator’s Brochure 
for a full listing of AEs to date.
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 4.28 
nM*hr for the 120 to 360 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 4.28 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). 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.
 
 
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PN004: MK5475 Sildenafil DDI Study
This is a randomized, placebo-controlled, 2-period, 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 and 
randomized 1:1 to 2 treatment sequences. Sildenafil was administered TID for 3 days in each 
period.  Participants were randomized to the sequence to which they would receive single-
dose of MK-5475 240 µg and placebo on Day 3 of sildenafil dosing. 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. 
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. Thus, MK-5475 does not add to the BP lowering effects of sildenafil.
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.
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
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study is to be conducted in male and female participants with group 1 pulmonary 
arterial hypertension (PAH).
 
 
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Objectives
Endpoints
Primary
•
To evaluate the safety and tolerability 
of MK-5475 in participants with 
pulmonary arterial hypertension 
(PAH). (All parts)
Safety and tolerability will be evaluated 
during clinical assessments that include 
vital signs, safety laboratory testing, 
physical examinations, ECG readings, 
PFTs and review of adverse events.
•
To assess the duration and effect 
following a single inhaled dose of MK-
5475 on pulmonary vascular resistance 
(PVR) in participants with pulmonary 
arterial hypertension (PAH). (Part 2, 
Period 2 (Panel A) and Period 3 (Panels 
B, C and D))
Peak reduction from baseline in PVR 
after a single inhaled dose of MK-5475 
Secondary
•
To estimate the effect of MK-5475 
given as single inhaled doses on 
systemic hemodynamic parameters 
(heart rate (HR), systolic and diastolic 
blood pressure (BP)) in participants 
with pulmonary arterial hypertension. 
(Part 2 Period 2 (Panel A) and Period 3 
(Panels B, C and D))
•
HR and BP change from baseline at 0.5, 
4.5, and 24 (or prior to discharge) hours 
post-dose. 
•
To obtain preliminary plasma 
pharmacokinetic (PK) data of MK-
5475 (e.g. area under the curve (AUC) 
0-24, AUC 0-∞, Cmax, C24, Tmax, 
t1/2) in participants with pulmonary 
arterial hypertension. (Part 1 and 2)
•
AUC 0-∞, AUC 0-24, Cmax, C24, 
Tmax, apparent terminal half-life
•
To assess the effect following a single 
inhaled dose of MK-5475 on 
pulmonary blood volume (PBV) in 
participants with pulmonary arterial 
hypertension. (Part 2, Period 3 (Panel 
A) and Period 2 (Panels B, C and D))
•
Increases from baseline PBV at 1, 3, 8
and 24 hours postdose.
 
 
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PRODUCT:  MK-5475  
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PROTOCOL/AMENDMENT NO.:  002-03 
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4
STUDY DESIGN
4.1
Overall Design
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.
This is a 2-part, 4-panel, single-site, study of MK-5475 in participants with group 1 PAH.
Up to 25 participants will be enrolled. Clinical indication for right heart catheterization 
(RHC) is needed in order to participate in the study.  
Part 1 of this study is a double-blind, randomized, single-ascending dose assessment of 
safety, tolerability and pharmacokinetics (PK) of inhaled MK-5475 in participants with group 
1 PAH. One panel (Panel A) of up to 8 participants will dose in up to 3 dosing periods. In 
each dosing period, 6 participants will receive MK-5475 and 2 will receive placebo (Pbo). 
Two (2) different participants will receive placebo in each of the dosing periods. There will 
be a minimum washout of 7 days between dosing periods. Review of available safety data 
(e.g. vital signs, ECG, labs, PFTs and AEs) up to 24 hours post dose of at least the first 4
participants must occur prior to escalating to the next dose level. A break to review PK data 
from Periods 1 and 2 will occur after completion of Period 2.  Review of safety will occur 
after completion of Period 3 in all participants from Panel A, prior to initiation of Part 2. An 
optional break to review rolling PK data from Panel A Period 3 will be dependent upon 
exposures observed in Periods 1 and 2. Participants from Part 1 may continue into Part 2.
Part 2 of this study will assess the safety, tolerability, PK and pharmacodynamics of inhaled 
MK-5475. Three additional panels of participants (Panels B, C and D) will be enrolled into 
Part 2. Participants in Panel B (N=4), C (N= up to 8) and D (N= up to 7) will participate in 
up to 3 dosing periods. Period 1 of Panel B will be an open label assessment of, 
safety/tolerability and PK. where participants will receive MK-5475. A review of available 
safety data up to 24 hours post dose and a rolling PK assessment will occur following 
completion of Panel B, Period 1, prior to going to the FRI period. Panel C, Period 1 will be 
an open label assessment of MK-5475. Panel C may begin once PK and safety data are
reviewed from Panel B, Period 1. A rolling PK and safety data review of the first 4 
participants of Panel C will occur prior to moving to the FRI period. The remaining 
participants in Panel C may enter Period 1 while this review is in progress.  Following a 
review of individual safety along with a review of PK from first four participants in Panel C, 
the remaining participants will proceed to Period 2 (FRI period). The sample size of Panel C 
may increase based on number of participants from Panel A who do not continue into Part 2.  
Further enrollment of Panel C may end once screening of Panel D has begun. Panel D, Period 
1 will be an open label safety/ tolerability and PK assessment of MK-5475.  Following a
review of individual safety of Period 1, participants will then proceed to Periods 2 (FRI 
period) and 3 (RHC period). The maximum sample size of Panel D is 7 but, may be less 
based on the final number of participants enrolled in Panel C and review of data from 
previous participants in Panel D. The total number of participants enrolled in Part 2 will be 
up to 24.
 
 
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FRI Period
In Part 2, Period 2 for Panels B, C and D and Period 3 for Panel A, participants will undergo 
FRI. Participants will undergo a series of computed tomography (CT) scans to assess 
baseline and changes after dosing in pulmonary blood volume (PBV) through functional 
respiratory imaging (FRI) with an intravenous (IV) iodinated contrast agent. 
RHC Period
In Part 2, Period 2 for Panel A and Period 3 for Panels B, C and D, assessment of safety and 
up to 4 baseline pulmonary hemodynamic measurements taken about 10 minutes apart, 
including pulmonary vascular resistance (PVR) calculated from data obtained by 
thermodilution (see Manual of Operations) will occur prior to dosing of MK-5475. Values 
from two consecutive PVR measurements should be within 15% of each other (highest PVR 
value will define the 15%) to confirm stable baseline. If the PVR data from the first two 
measurements deviates by more than 15%, up to 2 additional PVR measurements may be 
obtained.  If a stable baseline PVR cannot be obtained after 4 measurements, the subject will 
not be eligible to continue dosing and will be discontinued from the study.
1.
Pulmonary Arterial Pressure (mPAP) ≥ 25mmHg. Predose mPAP obtained from 3 
individual measurements taken about 10 minutes apart. The mean value from the 2 last 
measurements will serve as the PVR baseline value. 
2. Pulmonary Vascular Resistance (PVR) ≥ 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.
Following dosing of MK-5475 in Part 2, Period 2 (Panel A) and 3 (Panels B, C and D),
assessment of safety as well as systemic (HR and BP) and pulmonary [cardiac output (CO), 
cardiac index (CI), pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure 
(PAWP), systemic vascular resistance (SVR) and PVR] hemodynamic changes will be 
performed as outlined in the SoA.
Because this is a Phase 1 assessment of MK-5475 in humans, the pharmacokinetic (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 8.12 for examples of modifications permitted within 
the protocol parameters.
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 a single dose to participants with 
PAH. Preclinical studies as well as the first-in-human study with this compound support the 
conduct of this study, given the evidence that the compound appears to be safe, well-
tolerated, and has suitable pharmacokinetics to support a pharmacodynamic evaluation.
 
 
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Because this is the first introduction of this compound into participants with PAH, Part 1 of 
the study was designed to evaluate safety, tolerability, and pharmacokinetics in this 
population. As a conservative measure to ensure participant safety, dosing began at 120 μg, a 
level below the maximum dose of 165 μg that was given to healthy participants in PN001. 
The dose was gradually escalated first to 165 μg and then to the maximum dose of 240 μg in 
Part 1. In Part 2 Panels B and C, the dose will begin at 300 μg and escalate to 360 μg (See 
Section 4.3.2). Given the favorable safety profile observed in the preclinical 3-month 
toxicology studies and in clinical studies at doses up to 360 μg and to further explore the 
range of possible safe and effective doses of MK-5475, a dose of 480 μg of MK-5475 will be 
given in the first period of Panel D. In periods 2 and 3 of Panel D, a dose of 120 μg will be 
given in order to explore the PK/PD relationship at a lower dose. 
Once the safety, tolerability, and pharmacokinetics have been established in Part 1 and Part 
2, Period 1, pharmacodynamic assessments will be performed in a larger group of 
participants. These assessments (right heart catheterization and functional respiratory 
imaging) are directly related to the ultimately desired clinical efficacy endpoints for this 
compound and are well-validated in the published literature [Grimminger, F., et al 2009]. 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are no efficacy endpoints for this study.
4.2.1.2
Safety Endpoints
This will be the second introduction of MK-5475 into humans (See Section 2.2.3). The first 
introduction was supported by preclinical safety and toxicological testing in rats and dogs
(See Investigator’s Brochure).
Safety and tolerability will be monitored through clinical assessments of AEs, repeat physical 
exams, vital sign measurements, standard lab safety tests, ECGs and spirometry tests.
4.2.1.3
Pharmacokinetic Endpoints
MK-5475 is an inhaled drug being developed for the management of PAH. Pharmacokinetic
end-points including systemic assessments of AUC0-24hr, AUC0-∞Cmax, C24, ,Tmax, apparent 
terminal half-life will be assessed through the duration of this study.
4.2.1.4
Pharmacodynamic Endpoints
The primary pharmacodynamic endpoint will be PVR, which is calculated from variables 
obtained by RHC. Secondary pharmacodynamic endpoints include the systemic 
hemodynamic parameters of HR and BP as well as PBV using FRI.
4.2.1.5
Planned Exploratory Biomarker Research
There are no exploratory biomarkers planned.
 
 
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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.
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 Part 1 (Panel A), a placebo-controlled study will facilitate an unbiased assessment of 
safety and tolerability. Because this is the first assessment in PAH participants, and they will 
not receive clinical benefit from MK-5475, 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 example in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
 
 
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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. For dogs, 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. 
The starting dose for this study will be 120 μg inhaled in a single dose, allowing 
approximately a 4-fold safety margin below the NOAEL. In terms of systemic exposure, at 
this dose, the observed systemic AUC 0-24h was 0.663 nM*hr, which is approximately 1/7th
of the systemic NOAEL of 1-month dog toxicology exposure level of 4.5 nM*hr AUC 0-24h. 
Because the 1-month dog NOAEL was set according to a local finding rather than a systemic 
finding, and no systemic effects of this compound have been observed except for 
hemodynamic changes at much higher exposures in preclinical species, this would provide an 
adequate safety margin. Higher doses have already been administered to humans in the other
studies for this compound, with acceptable safety, tolerability, and pharmacokinetic data.
4.3.2
Maximum Dose/Exposure for This Study
As above, because of the inhaled route of delivery, estimated lung burden was used to 
determine the maximum allowable exposure based on the lung burden at the dog NOAEL 
dose. As demonstrated, the dog NOAEL dose corresponds to a delivered human dose of 500 
μg. However, in general there were few preclinical findings in either rat or dog safety 
studies. The NOAEL dose in dogs was 0.02 mg/kg/day; at the three-fold higher dose of 0.06 
mg/kg/day, only mild focal bronchial artery thickening was observed, that occurred in one 
animal in the study.
For the studies in healthy volunteers, the maximum human dose was 240 μg, which provided 
a ~2-fold safety margin below the NOAEL. In accordance with EMA guidance for first-in-
human studies (Guideline on Strategies to Identify and Mitigate Risks for First in Human and 
Early Clinical Trials with Investigational Medicinal Products), this conservative safety 
margin was applied because the study involved healthy participants. At this dose level, the 
compound was well tolerated and all safety data was within normal parameters. In addition, 
the observed pharmacokinetic data established that systemic exposures to the compound 
were well below the systemic NOAEL level established in dogs. 
Having established the tolerability of 240 μg in normal healthy participants, the present study 
will involve participants in the target population for this therapy. The maximum dose will be 
advanced to a maximum of 480 μg, which is below the NOAEL dose. The preclinical finding 
that was noted in dogs appears to be due to a vasoactive pharmacological effect within the 
 
 
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lung, presumably vasodilation induced by MK-5475. Since pulmonary hypertension patients 
suffer from chronic vasoconstriction, it is likely that they would be better able to tolerate 
acute vasodilation of blood vessels in the lung without harmful sequelae than healthy
participants. In addition, we note that although 100% deposition in humans is assumed in 
these calculations, the true deposition based on the fine particle fraction is lower (~30-60%), 
affording an additional safety margin. Therefore, the true lung exposure will be lower than 
projected above. Thus, a less conservative safety margin is appropriate in patients than in 
healthy participants, as these participants may potentially benefit directly from development 
of an additional therapy for their disease. 
Finally, although systemic exposure is considered less relevant for inhaled compounds, based 
on the observed PK data from the prior study, it was initially projected that systemic 
exposure will also be approximately 2-fold below the observed AUC 0-24h of 4.5 nM*hr 
from the dog NOAEL dose at the 240 μg dose. Based on the initial PK data observed in this 
study for participants in Panel A, the observed systemic PK at a dose of 240 μg was 
substantially lower than projected, with AUC 0-24h of 1.42 nM*hr. Given the low 
gastrointestinal bioavailability of this compound, and the observed direct proportionality 
between delivered dose and systemically measured PK, this reduced exposure was thought to 
be related to the decreased ability of diseased patients to generate adequate inhaled exposure 
compared with healthy subjects (as the lung deposition of inhaled DPI compounds is directly 
affected by the inspiratory flow generated by the subject). As the dose in this study was 
increased to 300 and then 360 μg, subsequent participants have exhibited higher exposures.
In order to further explore the relationship between systemic exposure and delivered dose at 
higher doses, the maximum dose will be increased in this study to 480 μg. At this dose, the 
resulting systemic exposure is projected to be approximately 3.5nM*hr AUC 0-24h. While 
participants may exceed the NOAEL systemic exposure, this exposure was set on the basis of 
a local finding in the lung in a 30-day toxicology study. In contrast, the finding which was 
used to set the NOAEL is expected to be driven by lung burden, which at this dose remains 
below the NOAEL dose of 500 μg. While higher systemic exposures from a single dose may 
lead to hemodynamic changes, such changes were only observed in preclinical species at 
systemic exposures far above the NOAEL exposure in pharmacology studies. No evidence of 
any impact on systemic hemodynamics including heart rate or blood pressure has been 
observed thus far in any clinical study of MK-5475, and given the short systemic half-life of 
this compound, it is expected that any such change after a single dose of compound would be 
self-limited. Finally, a subsequent 3-month GLP toxicology study showed that the finding 
used to establish the NOAEL was no longer present in a longer duration study.
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 
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.
 
 
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4.3.3
Rationale for Dose Interval and Study Design
In this study, Panel A participants were dosed with single doses of 120 μg, 165 μg, and 240 
μg in successive dosing periods. In Panels B and C doses up to 360 μg were given. In the 
initial clinical studies in healthy volunteers with this compound, 120 μg, 165 μg and 240 μg 
doses were delivered with acceptable safety, tolerability, and pharmacokinetic data. These 
doses were delivered with the following supportive data: MK-5475, a sGC stimulator, is not 
considered a compound with a high degree of uncertainty related to the potential risk of harm 
to participants, according to the publication "Guideline on Strategies to Identify and Mitigate 
Risks for First-in-Human and Early Clinical Trials with Investigational Medicinal Products" 
(European Medicine Agency [EMA]) released July 2017. The degree of uncertainty was 
determined by careful evaluation of the following: mode of action of MK-5475, presence or 
absence of biomarkers, the nature of the target, the relevance of available animal models 
and/or findings in non-clinical safety studies, and the study population. 
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 the initiation of clinical trials in people 
with this compound via the inhaled route. No dose-limiting toxicities were observed in 1 
month rat and dog toxicity trials, and substantial preclinical safety margins were obtained 
over initial human doses. As with the previous study, 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 potential for risk of harm, 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. There will be at least a 7-
day washout period between doses for any given participant, which is supported by the half -
life of MK-5475 observed in humans (approximately 2 hours).
In Part 2 of the study, participants will receive single doses of 240 μg (Panel A) or 300 μg to 
360 μg (Panels B and C) in each of two or three successive periods. Single doses will be 
given in Panel D (480 μg and 120 μg) in three successive periods. For all panels extensive 
safety monitoring, and with at least a 7-day washout period will occur between doses for any 
given participant.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, 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 
 
 
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appropriate communication(s) will be generated. The overall study end will then not be 
identified until the Sponsor has made the decision to end the study following this review 
period. The Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics 
Committee(s) [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. 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
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 
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.
5
STUDY POPULATION
Male/Female participants with group 1 PAH between the ages of 18 and 70 years  
(inclusive).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Be judged to have no untreated, clinically significant health issues from other co-
morbidities (e.g. uncontrolled diabetes) based on medical history, physical examination, 
vital sign (VS) measurements and electrocardiograms (ECGs) performed at screening 
visit.
 
 
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2. Be judged to have no untreated, clinically significant health issues from other co-
morbidities (e.g. uncontrolled diabetes) based on laboratory safety tests obtained at the 
screening visit(s). Appendix 2 provides a table of laboratory safety tests to be performed. 
Appendix 9 provides an algorithm for the assessment of out of range laboratory values.
3. Have a Body Mass Index (BMI) ≤35 kg/m2, inclusive at screening. See Section 8.3 for 
criteria on rounding to the nearest whole number. BMI = weight (kg)/height (m)2. Weight 
should not exceed 160 kg.
Demographics
4. Participant is male or female.
(Panel A)
5. Participant is from 18 years to 70 years of age inclusive, at the time of signing the 
informed consent.
(Panel B, C and D)
6. Participant is from 18-70 years of age inclusive, at the time of signing the informed 
consent.
Female Participants

A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
o
She is a woman of nonchildbearing potential (WONCBP), as defined in Appendix 
[5]
OR
o
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) 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.
 
 
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o
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.
o
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.
Male Participants
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) 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
Informed Consent
7. The participant provides written informed consent for the study. The participant may also 
provide consent for future biomedical research. However, the participant may participate 
in the main study without participating in future biomedical research.
Additional Categories
8.
Is willing to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
 
 
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9.
Be or have suspected Group 1 pulmonary hypertension as defined by the Nice 2013 
Clinical Classification, including:
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)
1.4.4. Congenital heart disease (unrepaired and not requiring repair or 
repaired simple cardiac defects at least 1-year status post corrective 
surgery, with no clinically significant residual shunt)
10.
Be deemed clinically stable by the investigator.
11.
Have a hemoglobin (Hgb) of > 75% of the lower limit of the normal range (at 
screening visit).
12.
Have a clinical indication for RHC as part of initial work-up or ongoing medical 
management.
a.
(Panel A) Inclusion Criteria Have history of right heart catheterization within three
years of starting study medication demonstrating mean pulmonary artery pressure of 
≥ 27 mmHg and PVR of ≥ 300 dynes/sec/cm5 (RHC may have been performed prior 
to initiation of participant’s prescribed background therapy); if subject is status post-
surgical repair of congenital heart defect, these criteria must be met at least one year 
after surgery.
(Panel B, C and D) Inclusion Criteria
b.
Have history of right heart catheterization within three years of starting study 
medication demonstrating mean pulmonary artery pressure of ≥ 27 mmHg and PVR 
of ≥ 300 dynes/sec/cm5 (RHC may have been performed prior to initiation of 
participant’s prescribed background therapy); if subject is status post-surgical repair 
of congenital heart defect, these criteria must be met at least one year after surgery. 
 
 
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OR
Have an echocardiogram performed by the investigator (or appropriate designee) at 
screening or within 1 year of screening demonstrating pulmonary artery systolic 
pressure ≥50 mmHg in conjunction with one or more of the following: tricuspid 
regurgitation velocity > 3.0 m/s and or significant right heart enlargement and or 
reduced right heart function.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has pulmonary hypertension subtypes including the following according to Nice 2013
Clinical Classification:
1.4.2. HIV infection
1.4.3. Portal hypertension
1.4.5. Schistosomiasis
1.4.6. Chronic hemolytic anemia
1’. Pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary
hemangiomatosis (PCH) 1”. Persistent pulmonary hypertension of the newborn 
(PPHN)
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
3. Pulmonary hypertension owing to lung diseases and/or hypoxia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern
 
 
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3.4. Sleep-disordered breathing
3.5. Alveolar hypoventilation disorders
3.6. Chronic exposure to high altitude
3.7. Developmental abnormalities
4. Pulmonary hypertension defined as Chronic thromboembolic pulmonary
hypertension [CTEPH])
5. Pulmonary Hypertension with unclear multifactorial mechanisms
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 (not including stable diabetes 
mellitus), gastrointestinal, cardiovascular, hematological, hepatic (not including 
chronic stable Hep B and C), immunological, renal, respiratory, genitourinary, or 
major neurological (including stroke and chronic seizures) abnormalities or 
diseases. Participants with a remote history of uncomplicated medical events (eg, 
uncomplicated kidney stones, as defined as spontaneous passage and no 
recurrence in the last 5 years, or childhood asthma) may be enrolled in the study 
at the discretion of the investigator. Participants with controlled hypertension are 
allowed to be enrolled.
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 that the investigator 
feels poses a risk to the participant if they participate in the study. 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 
 
 
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the Sponsor (eg, malignancies which have been successfully treated ≥10 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. This 
includes milk or lactose allergy/intolerance.
6. Has known hypersensitivity to iodine or iodine containing products.
7. Is positive for HIV.
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 or controlled atrial 
fibrillation with no clinically significant arrhythmia may be allowed per the 
judgment of the investigator).
10. Has significantly impaired gas exchange.
11. Has an active respiratory infection (e.g. common cold, bronchitis, influenza, 
pneumonia) with lung function values (FEV1 and/or FVC) outside of the normal 
range at pre-dose Period 1 (May be rescreened upon resolution of the active 
respiratory infection).
Prior/Concomitant Therapy
12. Is currently on monotherapy calcium channel blockers as a specific treatment for
pulmonary hypertension based on a history of positive vasoreactivity testing.
13. Has taken nitrates within 24 hours of anticipated dosing.
14. Has taken inhaled prostacyclin within 24 hours of anticipated dosing (iloprost or 
treprostinil).
15. Has taken diltiazem immediate release taken within 24 hours or extended release 
taken within 48 hours of anticipated dosing. 
16. Has taken sildenafil or valdenafil within 24 hours or tadalafil within 7 days of 
anticipated dosing.  Participants in whom sildenafil, valdenafil or tadalafil has 
been stopped prior to these respective time points are eligible.
17. Has taken sGC activator for PAH within 24 hours of anticipated dosing.       
18. Has taken endothelin receptor antagonists (ERAs) (e.g. bosentan, ambrisentan, 
macitentan) within 24 hours of anticipated dosing.
 
 
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19. 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).
Prior/Concurrent Clinical Study Experience
20. 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
21. Has a QTc interval ≥470 msec (for males) or ≥480 msec (for females) at 
screening and Predose Period 1
22. Has a systolic BP <100 mmHg, Diastolic BP < 40 mmHg or HR >100/min at 
baseline. Mean of these values will be used at screening and Predose Period 1.
(See exclusion criteria #9 for HR associated with uncontrolled a-fib).
23. Participant has an estimated creatinine clearance of < 60 mL/min based on the 
Cockcroft-Gault equation; the Cockcroft-Gault equation is 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.
Other Exclusions
24. Is unable to correctly use the TWISTHALER® device (after instruction by the 
study staff) at a visit prior to randomization.
25. Is under the age of legal consent.
26. Does not agree to follow the smoking restrictions as defined by the CRU.
27. Part 2 only: Suffers from claustrophobia and would be unable to undergo CT 
scan.
 
 
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28. Part 2 only: Has participated in a PET research study or other 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 this period with a radiation burden over 10 mSv 
(such as a CT scan exam or nuclear medical exam).
29. 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.
30. 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.
31. 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 
urine drug screen (UDS) prior to randomization or assignment of allocation 
number.
32. 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.
5.3
Lifestyle Considerations
Women of childbearing potential (WOCBP) can be enrolled. 
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Part 1 Periods 1-3, Part 2 Period 1
In each treatment period, participants will fast from all food and drinks, except water, for at 
least 8 hours prior to study drug administration and lab safety tests. Participants will fast 
from all food and drinks except water between study drug administration and the first 
scheduled meal. Standardized meals will be provided by the investigator at about 4 and 10 
hours post-dose.  A snack will be offered at about 7 and 13 hours post dose. Participants will 
fast from all food and drinks except water between meals and snacks. The caloric content and 
composition of meals will be the same in each treatment period. After the 24-hour postdose 
procedures have been completed, subsequent meals and snacks will be unrestricted in caloric 
content, composition and timing.
 
 
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Part 2 Periods 2-3 (RHC and FRI Periods)
Participants will fast from all food and drink except water for at least 4 hours prior to lab 
safety tests, study drug administration or insertion of the RHC or the start of the baseline CT 
scan.  In the RHC Period, participants may be permitted a snack at approximately 2 hours 
post dose and a standard meal at the completion of the RHC procedure, after which they may 
be given a meal at the investigator’s discretion. After completion of dosing in the FRI Period, 
snacks may be provided by the investigator between the 1 and 3 hour post dose scans and a 
standard meal will be provided about 1 hour after the 3 hour post dose scan. At the 
investigator’s discretion, subsequent meals and snacks will be unrestricted in caloric content, 
composition and timing.
In both parts, up to 240 mL of water may be provided after the last inhalation of study drug. 
Water will be restricted 1 hour prior to initial inhalation and 1 hour after the last inhalation of 
study drug in each period.
Instructions on whether to take MK-5475 with or without food and/or drink may be modified 
during the study based on newly available data.
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 including the washout intervals between treatment periods and 
until the poststudy visit.
Participants also will refrain from the consumption of all fruit juices 24 hours prior to and 
after study drug administration. On all other days during the study, consumption of 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 and from 12 hours prior to 
and after study drug administration in each treatment period. At all other times, caffeinated 
beverages or xanthine-containing products will be limited to no more than 6 units per day 
amounts (>6 units: 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 and from 24 hours prior to and after study drug administration in each 
treatment period. At all other times, alcohol consumption is limited to no more than 
approximately 3 alcoholic beverages or equivalent (1 glass is approximately equivalent to: 
 
 
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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 not be permitted to smoke 24 hours prior to and on the day of dosing. At all 
other times, participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the Clinical Research Unit (CRU).
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 or assigned an allocation number in the study. A minimal 
set of screen failure information may be included, as outlined in the electronic case report 
forms (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 
supplies. Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
 
 
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6.1
Study Intervention(s) Administered
The study intervention to be used in this study is 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 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Part 1
Placebo 
Compar
ator
Placebo
Drug
Dry Powder
0 µg
0 µg
Inhalation
One time in 
each period
Placebo
IMP
Sponsor
Part 1 
Periods 
1-3
Experi
mental
MK-5475
Drug
Dry Powder
15 µg, 
60 µg
120 µg, 
165 µg, 
240 µg
Inhalation
Each dose 
will be given 
only 1 time
Experi-
mental
IMP
Sponsor
Part 2 
Periods 
1-3
Experi
mental
MK-5475
Drug
Dry Powder
15 µg, 
60 µg
240 µg, 
300 µg, 
360 µg
Inhalation
One time in 
each period
Experi-
mental
IMP
Sponsor
Part 2 
Periods 
1-3 Panel 
D
Experi
mental
MK-5475
Drug
Dry Powder
60 µg
120 µg, 
480 µg
Inhalation
One single 
dose in a 
period
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.
 
 
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These supplies are being provided as open label bulk supplies and will be assigned and 
dispensed by the unblinded pharmacist at the site.
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.
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 inSection 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. A sample allocation schedule is provided in Table 3 below.
Table 3
Sample Allocation Schedule
Panel A a
Participant
(N) 
Part 1 Period 1
Part 1 Period 2
Part 1 Period 3
Part 2 Period 2
Part 2 Period 3
N=2
120µg
Placebo
240 µg
240µg
240µg
N=2
120µg
165µg
Placebo
240µg
240µg
N=2
120µg
165µg
240µg
240µg
240µg
N=2
Placebo
165µg
240µg
240µg
240µg
a The participants in Panel A will be randomly assigned.
A total of 20 participants will participate in Part 2 (Panels A+B+C)
Panel B
Participant
(N) 
Part 2 a Period 1
Part 2 a, Period 2
Part 2 a, Period 3
N= 4
300 µg
  360 µg
360 µg
Panel C
N = 16b
300 µg
  360 µg
360 µg
Panel D
N=7c
480 µg
120 µg
120 µg
a A total of up to 24 participants will participate in Part 2. (Panels A+B+C+D) 
b The sample size for Panel C may be adjusted depending on the number of participants from Panel A that 
continue into Part 2 and the start of Panel D. Panel C will not exceed 16 evaluable participants. Participants 
in Panels B and C will be non-randomly assigned.
c The sample size for Panel D may be adjusted and will be dependent upon the final number of participants 
that are enrolled in Panel C. Panel D will not exceed 8 evaluable participants. Participants in Panel D will be 
non-randomly assigned.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
 
 
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6.3.3
Blinding
In Part 1 (Panel A) of this study, a double-blinding technique will be used. MK-5475 and 
placebo will be packaged identically so that blind is maintained.  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.  Part 2 of this study is conducted as open label; therefore, the Sponsor, 
investigator, and participant will know the intervention administered.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed  
during time periods specified by this protocol for that medication 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.
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.
Certain calcium channel blockers (e.g. amlodipine) not being used for the treatment 
of PAH based on vasoreactivity testing.
5.
Trimetazidine.
6.
Mineralcorticoid receptor antagonists (e.g. spironolactone, eplerenone)
7.
Oral hypoglycemic agents
8.
Diuretics.
 
 
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9.
Digoxin
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.
Local anesthetic (e.g. lidocaine) when performing RHC insertion procedure per site 
SOPs.
13.
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.
All permitted prescribed medications may be taken on the morning of the 
RHC/FRI.
Listed below are specific examples of prohibited concomitant therapy or vaccination:
1.
PDE5 inhibitor for PAH; sildenafil or vardenafil taken up to 24 hours prior to dosing 
of study drug; tadalafil taken within 7 days of anticipated dosing.  PDE5 inhibitor 
treatment may be initiated after 2 days have elapsed from the time of MK-5475 
dosing.
2.
sGC activator for PAH taken up to 24 hours prior to dosing of study drug. sGC 
activator may be initiated after 2 days have elapsed from the time of MK-5475 
dosing.
3.
Nitrate taken up to 24 hours prior to dosing of study drug. Nitrates may be initiated 
after 2 days have elapsed from the time of MK-5475 dosing.
4.
Inhaled prostacyclin taken up to 24 hours prior to dosing of study drug.
5.
Immediate release diltiazem taken up to 24 hours or extended release diltiazem taken 
up to 48 hours prior to dosing of study drug. Dilitazem may be initiated after 2 days 
have elapsed from the time of MK-5475 dosing.
6.
ERAs (e.g. bosentan, ambrisentan, macitentan) taken up to 24 hours prior to dosing of 
study drug. ERAs may be initiated after 2 days have elapsed from the time of MK-
5475 dosing.
7.
Verapamil
•
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.
 
 
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6.5.1
Rescue Medications and Supportive Care
Clinical Research Units (CRUs) will be staffed with medically trained personnel with 
appropriate access to full service acute-care hospitals to facilitate rapid institution of medical 
intervention. Sites will use their standard operating procedures to manage any acute 
hemodynamic changes as deemed clinically appropriate (e.g. Trendelenberg position, 
intravenous fluids).
6.6
Dose Modification (Escalation/Titration/Other)
In Part 1 and Part 2, all dose escalation decisions will be made jointly by the investigator and 
the Sponsor. Each dose escalation decision may occur after at least 4 evaluable participants
in Part 1 (all periods) and 4 evaluable participants in Part 2, Period 1 have completed the 
previous dose level.
Dose escalation decisions will be based on key safety variables including, vital signs, 12-lead
ECG, laboratory safety tests, AEs, and PFTs from the previous dose levels up to at least 24 
hours. Pharmacokinetic data may be included in the dose escalation decisions (Section 8.6 ).
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,
•
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 a Serious Adverse Event considered related to the 
study drug by the investigator.
2.
Two (2) or more participants within a Panel (at the same dose level) report Severe 
Non-serious Adverse Events considered related to the study drug by the investigator.
 
 
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If any of the below stopping rules are met, subsequent higher doses will be lowered based 
upon joint agreement of the Sponsor and investigator in order for the study to continue.
Panel wide stopping criteria
a.
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.
1. Individual stopping criteria:
a.
Hemodynamic changes that exceed the pre-specified limitations (See 
Appendix 10)
6.7
Intervention After the End of the Study
If adequate standard of care (SoC) treatment is not obtainable via the local health insurance 
system, participants who complete the study or discontinue the study for non-personal 
reasons (e.g. AEs, does not meet RHC criteria) may be provided with a standard of care 
treatment (e.g. bosentan) that is determined to be appropriate for the participant by the 
participant’s treating physician. After completion of this phase, participants will be 
reevaluated and transferred to the local standard of care treatment for PAH. For part 1 
participants, this SoC may be provided up to 6 months after study completion. For part 2 
participants, this SoC may be provided up to 12 months after study completion. For part 1 
and Part 2 participants, this SoC may be provided up to 18 months after study completion.
6.8
Clinical Supplies Disclosure
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
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 
 
 
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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 and 8.11.3.
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.
•
Part 1 only: The participant’s treatment assignment has been unblinded by the 
investigator, MSD subsidiary, or through the emergency unblinding call center.
•
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.
•
The participant does not meet the baseline RHC criteria in Part 2 Period 2 or 3 (See 
Section 4.1).
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.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she 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.
 
 
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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 or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
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.
 
 
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The maximum amount of blood collected from each participant over the duration of the study
will not exceed 500 mL (Appendix 8).
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 consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The 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 future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant.
 
 
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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.
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.
At least 2 days should elapse between dosing of MK-5475 and initiating or restarting 
sildenafil, valdenafil or tadalafil, sGC activators, prostacyclins, nitrates, ERAs and/or
diltiazem.
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.
 
 
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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 in Panel A and Panel B will be randomly allocated and all eligible 
participants in Panel C will be allocated, by nonrandom assignment. All participants 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
Administration of study medication will be witnessed by the investigator and/or study staff.
8.1.8.1
Timing of Dose Administration
After it is confirmed that the participant meets eligibility in Period 1 of Part 1 (Panel A) or 
Part 2 (Panels B, C and D), each dose of MK-5475 or placebo (placebo for Part 1 Panel A
participants only) will occur after the completion of predose procedures. The time of the dose 
will be designated as time “0” and the exact time of administration will be recorded. At least 
a 7-day washout will occur between intervention periods.
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 8.11.4) 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 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 principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
 
 
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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.
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.
 
 
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8.1.11
Domiciling
In Part 1 Periods 1-3 and Part 2 Period 1, participants may report to the clinical research unit 
(CRU) the evening prior to the scheduled day of administration of the study intervention at 
the discretion of the investigator. Participants will remain in the unit until the 24-hour, 
postdose procedures have been performed. 
In Part 2, participants will report to the clinic at the time instructed by the CRU in 
preparation for the CT scan and dosing procedures in the FRI period and the RHC and dosing 
procedures in the RHC Period.
In the FRI Period, participants will be discharged approximately 1 hour following completion 
of the 8 hour post dose CT scan but, participants may remain domiciled overnight in 
preparation for the 24 hour CT scan, at the discretion of the investigator.  Those participants 
that are discharged after 8 hour CT scan will be asked to return for the 24 hour CT scan and 
discharge procedures.
In the RHC Period, participants will remain domiciled overnight or may be discharged on the 
same day at the discretion of the investigator if the following discharge criteria are met:

If present, resolution of any hemodynamic-related clinically significant symptoms 
with potential relationship to study intervention/procedure

BP and HR are within 25% of baseline measures

Participants have a SBP ≥ 90 mmHg, HR < 110 bpm (Triplicate HR and BP should 
be measured at least three times separated by a minimum of 15 minutes. The median 
values of each set of measurements must meet the criteria above in order to be 
eligible for same day discharge).

All AEs have been reviewed by the investigator who confirms clinical 
appropriateness for same day discharge.
At the discretion of the investigator, participants may be requested to remain in the CRU 
longer. 
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 is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
 
 
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8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy assessments in this study; surrogate markers of efficacy are 
outlined in Section 8.7.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue 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 Appendix 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. Body weight and height will be obtained with the 
participants shoes off, jacket or coat removed. Body weight will be measured following an 8 
hour fast.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index (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 0.1-0.4 round down and 0.5-0.9 round up.
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.
 
 
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8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a semi-recumbent OR supine position for at least 10 minutes 
prior to having vital sign (VS) measurements obtained. Semi-recumbent OR supine vital 
signs (VS) will include heart rate (HR) and blood pressure (BP). 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 across the study.
Predose heart rate (HR) and blood pressure (BP) will be triplicate measurements, obtained at 
least 1-2 minutes apart within 3 hours of dosing of study drug in Parts 1 and 2 all periods.
The median of these measurements will be used as the baseline to calculate change from 
baseline for safety evaluations (and for rechecks, if needed). Screening, post-dose and post-
study HR and BP measurements will also be done in triplicate measurements, obtained at 
least 1-2 minutes apart. 
In Part 1, Periods 1-3 and Part 2, Period 1, participants will continue to rest semi-recumbent 
from dosing until 4 hours postdose except to stand for the measurement of orthostatic vital 
signs (VS) (if needed) or other study-related procedure.
Body Temperature
The same method must be used for all measurements for each individual participant and 
should be the same for all participants.
8.3.2.2
Oxygen Saturation
In Part 2, RHC Period, O2 saturation will be measured using pulse oximetry on each 
participant at the timepoints noted in the SoA (See Section 1.3)
8.3.2.3
Orthostatic Vital Signs
In Part 1, Periods 1-3 and Part 2, Period 1, orthostatic vital signs (VS) (HR and 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.
8.3.3
Electrocardiograms
Prior to each period, predose electrocardiograms (ECGs) will be obtained in triplicate at       
least 1-2 minutes apart within 3 hours prior to dosing MK-5475 or placebo. The mean of 
these measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed).  Screening, post-study and post-dose ECG 
measurements will be single measurements.
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.
 
 
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Participants should be resting in the semirecumbent OR supine position for at least 10 
minutes prior to each electrocardiogram (ECG) measurement.
The correction formula to be used for QTc is Fredericia.
If repeat electrocardiograms (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.
If the QTc interval is 500 msec, 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.
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 case report form 
(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 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.
8.3.5
Pulmonary Function Tests (PFTs (Spirometry)
At all visits (except Part 2, Periods 2 and 3), 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]. 
 
 
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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.
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 of 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.
The following pulmonary function tests: (FEV1, FVC and FEV1/FVC ratio, PEF), DLCO 
(DLCO, DLCO adjusted for Hb 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.
Spirometry (FEV1, FVC and FEV1/FVC ratio, PEF) will be done at all other timepoints noted 
in the SoA and will be done at the site using calibrated spirometers.
8.3.6
Inhalation Airflow Meter Assessment
At least 3 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.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
 
 
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators 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 consent form is signed 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 
treatment, 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 drug-related.
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 4.
 
 
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Table 4
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:
Nonserious 
Adverse Event 
(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
Serious Adverse 
Event (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:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (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
Note required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication
Report all
Note required
Within 24 
hours of 
learning of 
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, events of clinical interest (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 suspected unexpected serious adverse 
reactions (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 (ECIs)
Selected nonserious and SAEs 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, that is not associated 
with clinical symptoms or abnormal laboratory results.

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
The participant has taken (accidentally or intentionally) any drug administered as part of the 
protocol that exceeds the dose as 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 study operations manual.
8.7
Pharmacodynamics
Pharmacodynamic assessments that are part of the right heart catheterization (RHC) and the 
functional respiratory imaging (FRI) procedures will be performed according to the Study
Operations and CT scan procedures manuals. 
8.7.1
Right Heart Catheterization Procedures
Before beginning the RHC procedure, monitoring equipment should be calibrated and 
zeroed. 
Pressure measurements should be taken at end-expiration and should include at least 3 
complete respiratory cycles.  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 or mean). Cardiac output (CO), oxygen saturation and MVO2 will also be collected 
at timepoints noted in the SoA. 
Investigators may use clinical judgment to determine whether the central catheter may be 
maneuvered during the catheterization procedure for the purpose of measuring RAP, RVSP, 
and RVEDP.  If the investigator determines that the participant’s condition prohibits the 
maneuvering of the catheter during the procedure, the catheter may remain in place for the 
measurements of PAWP, sPAP/dPAP or mPAP, and CO. 
Participants will undergo monitoring of systemic hemodynamics and for adverse events 
throughout the RHC.  The study-related portion of RHC will continue until completion of all 
measurements at the 4.5 hr postdose timepoint after which it may be removed unless 
clinically indicated it is needed to stop earlier.  
Waveform analysis will be performed through the use of a blinded central reader. 
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
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. 
 
 
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For each of the 5 scanning sessions (Pre-dose baseline, 1, 3, 8 and 24 hours post-dose), 
participants will be prepped and placed in a supine position on the scanner bed.
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. 
8.8
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 future biomedical research 
if the participant signs the future biomedical research consent. If the planned genetic
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
•
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 signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
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.
 
 
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 35 days (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 Visit
Part 1
After Period 1 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.  In Periods 1-3, at the 
discretion of the investigator, participants will be discharged from the CRU after completion 
of the 24-hour post-dose procedures. 
Prior to Intervention Periods 2 and 3, clinical (VS, ECG, AEs and spirometry) and laboratory 
safety parameters from the previous intervention period up to 24 hours post dose will be
reviewed by the investigator and the sponsor to confirm advancement to the next higher dose 
level.
Participants from Part 1 may continue into Part 2.  If a participant opts to continue into Part 
2, an assessment of AEs/SAEs will occur via a phone call about 14 days after the last dose of 
study drug in Part 1.
Part 2
After Panel B, C and D, Period 1 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 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 24-hour post-dose procedures. 
 
 
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Prior to Periods 2 and 3, clinical (VS, ECG, AEs and spirometry) and laboratory safety 
parameters from the previous intervention period up to 24 hours post dose will be reviewed 
by the investigator and the sponsor to confirm advancement to the next higher dose level. 
Pharmacokinetic parameters for all 4 participants in Panel B and the first 4 participants in 
Panel C will also be reviewed from Period 1 of each panel before going to Period 2.
In Period 3 (Panel A) and 2 (Panel B, C and D), participants will report to the clinical 
research unit (CRU) at a time as provided by the CRU for CT scanning. MK-5475 
administration and associated procedures as defined in the SoA will be performed.  At the 
discretion of the investigator, participants may be discharged from the CRU after completion 
of the 8 hour postdose scan and pre-discharge procedures or participants may remain 
domiciled overnight at the discretion of the investigator in preparation for the 24 hour CT 
scan.  Participants that were discharged will be asked to return for the 24 hour post dose 
scans and pre-discharge procedures.
In Period 2 (Panel A) and 3 (Panel B, C and D), participants will proceed to RHC procedures
to confirm eligibility based on pulmonary hemodynamic measures as outlined in Sections 4.1 
and 8.7.1 will be performed.
Once baseline RHC measurements are complete and continuation into RHC period is
confirmed, participants 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, including pulmonary and hemodynamic assessments will be 
performed according to the SoA.  Participants may be discharged at 24 hours post dose, or on 
the day of the RHC procedure at the discretion of the investigator if all discharge criteria are 
met (See Section 8.1.11).
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 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.
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
In Part 1 Periods 1- and Part 2 Period 1 of this study, the blood sample for MK-5475 is the 
critical procedure.
 
 
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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, Period 2 (Panel A) and Period 3 (Panels B, C and D) of this study, RHC 
measurements, in particular PVR, is the critical procedure.
At any postdose time point, RHC measurements need 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, Period 3 (Panel A) and Period 2 (Panels B, C and D) of this study, FRI 
measurements are the critical procedure.
At any postdose time point, FRI measurements need 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.
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 5.
Table 5
Pharmacokinetic Blood Collection Windows
PK Collection
PK Collection Window1
0 –  < 6 min
2 min
≥ 6 min to < 1hr
5 min
≥ 1 hr in Part 1 and Part 2 Period 1
≥ 1 hr in Part 2 Period 2/3
15 min
20 min
≥ 24 hr
30 min
1 Window is +/- from collection time
•
Predose standard safety evaluations: vital signs (including HR, BP, RR,body temperature 
and weight) spirometry and ECG up to 3 hrs; laboratory safety tests and physical exam 
up to 24 hrs
 
 
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•
Part 2: Predose inspiratory flow meter assessment up to 3 hours prior to dosing
•
Predose Baseline CT scan: up to 30 minutes prior to dosing
•
Predose RHC, including PAP, measurements: up to 15 minutes from the scheduled 
procedure time
•
Predose arterial O2 saturation (pulse oximetry) and MVO2:  up to 15 minutes from the 
scheduled procedure time
•
Postdose standard safety evaluations: vital signs, ECG, laboratory safety tests, spirometry
and physical exam

0 to < 1 hr postdose within 10 minutes of the theoretical sampling/procedure time

>1 to <24 hr postdose within 15 min of the theoretical sampling/procedure time

≥24 hr postdose within 1 hr of the theoretical sampling/procedure time

Postdose RHC, including PAP and VS measurements: within 15 minutes of the 
theoretical sampling/procedure time

Postdose arterial O2 saturation (pulse oximetry) and MVO2:  within 15 minutes of the 
theoretical sampling/procedure time
•
Postdose CT scan: 
•
>1 to <24 hr postdose within 20 minutes of the theoretical sampling/procedure 
time
•
≥24 hr postdose within 1 hr of the theoretical sampling/procedure time
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 is 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/panel
 
 
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•
Interchange of doses between panels
•
Entire period(s) or panel(s) may be omitted
•
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
•
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 interval between dosing and the post dose RHC measurements in 
Part 2
•
Changes to the time interval between dosing and the post dose CT scans in Part 2 
•
Change sequence of RHC and FRI procedure in Periods 2 and 3 of Part 2.

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 (Section 
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.
 
 
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9
STATISTICAL ANALYSIS PLAN
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
the Statistical Analysis Plan (SAP) (Sections 9.2-9.9).
9.1
Statistical Analysis Plan Summary
Statistical Methods
Primary Objective (PVR): For the primary pharmacodynamic parameter PVR, the peak 
percent reduction compared to baseline in PVR after a single inhaled dose of MK-5475 will 
be analyzed for Part 2, the RHC period. The difference from baseline will be assessed on the 
log scale and then back-transformed for reporting (percent change from baseline).
Primary Objective (Safety): Incidence of AEs will be descriptively summarized. Summary 
statistics and plots will be generated for the change from baseline values in the VS, ECG 
parameters, and selected laboratory safety parameters for participants, as deemed clinically 
appropriate. 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, ECGs, and/or VS may also be computed, as deemed clinically 
appropriate.
Secondary Objective (HR, BP, and PBV): The predose baseline values for HR and BP will 
be obtained as outlined in Section 8.3.2.1.  The mean change from baseline for the HR and 
BP will be calculated at 0.5, 4.5, and 24 hours post-dose for Part 2, Period 2 or 3 only. 
PBV will be measured using CT scans with an IV iodinated contrast agent before and after 
administration of MK-5475. An increase from baseline in measured PBV would be 
calculated at 1, 3 and 8 hours for Part 2, the FRI period only.
Secondary Objective (PK): Separately for each PK parameter (Panel A, Part 1, Periods 1, 2 
and 3, and Panels B-D, Part 2, Period 1), individual values of AUC0-24hr, AUC0-∞, Cmax, C24, 
at each dose level will be natural log-transformed and evaluated with a linear mixed effects 
model containing a fixed effect for treatment, and Panel a random effect for participant. 
Kenward and Roger's method will be used to calculate the denominator degrees of freedom 
for the fixed effects.  Ninety-five percent confidence intervals for the least squares means for 
each treatment will be constructed on the natural log scale and will reference a t-distribution. 
Exponentiating the least-squares means and lower and upper limits of these confidence 
intervals will yield estimates for the population geometric means and confidence intervals 
about the geometric means on the original scale.
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
 
 
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with the Quantitative Pharmacology and Pharmacodynamic Department and Translational 
Pharmacology Department of the Sponsor.
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 Objectives: 

To evaluate the safety and tolerability of MK-5475 in participants with pulmonary 
arterial hypertension (PAH).

To assess the duration and effect following a single inhaled dose of MK-5475 on 
pulmonary vascular resistance (PVR) in participants with pulmonary arterial 
hypertension (PAH).
Secondary Objectives:
•
To estimate the effect of MK-5475 given as single inhaled doses on systemic 
hemodynamic parameters (heart rate (HR), systolic and diastolic blood pressure (BP)) in 
participants with pulmonary arterial hypertension.

To obtain preliminary plasma pharmacokinetic (PK) data of MK-5475 (e.g. area under 
the curve (AUC) 0-24, AUC 0-∞, Cmax, C24, Tmax, t1/2) in participants with 
pulmonary arterial hypertension.

To assess the effect following a single inhaled dose of MK-5475 on pulmonary blood 
volume (PBV) in participants with pulmonary arterial hypertension.
Exploratory Objectives:
•
To explore the relationship of MK-5475 concentration and summarize changes in 
pulmonary vascular resistance, pulmonary arterial pressure, cardiac output/cardiac index 
(CO/CI), systemic vascular resistance, mixed venous oxygen saturation and arterial 
oxygenation in participants with pulmonary arterial hypertension.
•
To explore the effect of single doses of MK-5475 on the ratio of change from baseline in 
pulmonary vascular resistance / change from baseline in systemic vascular resistance.

•To explore the relationship between mean change differences in pulmonary vascular 
resistance (PVR) and baseline changes in pulmonary blood volume (PBV) following a 
single dose of MK-5475.
 
 
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9.4
Analysis Endpoints
Primary Pharmacodynamic
The primary pharmacodynamic variable in this study is PVR in Part 2, Period 2 (Panel A) 
and Period 3 (Panels B, C and D).
Primary Safety
The primary safety endpoints in this study include all types of AEs, in addition to laboratory 
safety assessments, ECGs, PFTs and VS.
Secondary Endpoints for PD
The secondary endpoints in this study include HR and BP.
•
Increases from baseline PBV at 1, 3, 8 and 24 hours postdose in Part 2, Period 3 (Panel A 
and Period 2 (Panels B, C and D).
Secondary Endpoints for PK
The secondary endpoints in this study include AUC0-24hr, AUC0-inf, Cmax, C24hr, Tmax 
and apparent terminal t1/2 after administration of single doses in Panel A Periods 1-3 and 
Panels B, C and D, Period 1.
Exploratory Endpoints

Mean pulmonary artery pressure (mPAP), systemic vascular resistance (SVR), cardiac 
output (CO)/cardiac index (CI) and mixed venous and arterial oxygenation in Part 2,
Period 2 (Panel A) and Period 3 (Panels B, C and D).

PVR/SVR change from baseline at 0.5 through 4.5 hours post-dose Part 2, Period 2 
(Panel A) and Period 3 (Panels B, C and D).

Change from baseline PVR and PBV at 1 and 3 hours postdose in Part 2, Periods 2 and 3.
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 (APasT) – 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 
 
 
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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 primary PD, secondary PK and exploratory PK and PD 
analyses.
9.6
Statistical Methods
Primary (PVR):  Fold change from baseline individual PVR in Part 2, RHC Period only will 
be calculated for each postdose time point. The largest reduction from baseline will be 
identified for each participant.  These reductions will be natural log-transformed and mean 
and 95% confidence interval calculated based on a t-distribution at each dose-level.  These 
will be exponentiated and expressed as percents to obtain the geometric mean and 95% CI 
for percent reduction in PVR.
Primary (Safety): Incidence of AEs will be descriptively summarized. Summary statistics 
and plots will be generated for the change from baseline values in the VS, ECG parameters, 
and selected laboratory safety parameters for participants, as deemed clinically appropriate. 
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, ECGs, and/or VS may also be computed, as deemed clinically appropriate.
Secondary (HR and BP): Each of these parameters will be analyzed separately for Part 2, 
RHC period only.  Individual PD parameters (HR, SBP, and DBP) will be natural log 
transformed and analyzed in a linear mixed effects model with fixed effects for dose, time 
(0.5, 4.5, and 24 hours), dose by time interaction and a random effect for participant.  The 
dependent variable is: PD_postdose – PD_predose (PD=HR, SBP, DBP). An unstructured 
covariance matrix for each time point will be used to allow for unequal variances via the 
REPEATED statement in SAS PROC MIXED (a similar model would be acceptable using 
R) Kenward and Roger's method will be used to calculate the denominator degrees of 
freedom for the fixed effects (DDFM=KR).  If the model fails to converge, a simpler 
covariance structure such as compound symmetry may be used.  The difference in least 
squares means with 95% CI will be calculated for post dose of MK-5475 versus predose of 
MK-5475 at each dose level by time.  
Secondary (PK): Separately for each PK parameter (in Panel A, Part 1, Periods 1~3, and 
Panel B-D, Part 2, Period 1), individual values of AUC0-24hr, AUC0-∞, Cmax, C24 (as 
appropriate, if <50% C24 values are BLOQ) at each dose level will be natural log-
transformed and evaluated with a linear mixed effects model containing a fixed effect for 
treatment and panel, and a random effect for participant. Kenward and Roger's method will 
be used to calculate the denominator degrees of freedom for the fixed effects.  Ninety-five 
percent confidence intervals for the least squares means for each treatment will be 
 
 
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constructed on the natural log scale and will reference the t-distribution. Exponentiating the 
least-squares means and lower and upper limits of these confidence intervals will yield 
estimates for the population geometric means and confidence intervals about the geometric 
means on the original scale.
Secondary (PBV): Individual PBV will be natural log transformed and analyzed in a linear 
mixed effects model with fixed effects for dose, time, dose by time interaction and a random 
effect for subject.  The dependent variable is: log(PBV at X hour) – log(PBV at 0 hour). An 
unstructured covariance matrix for each treatment will be used to allow for unequal variances 
and different correlations across time and treatment via the REPEATED statement in SAS 
PROC MIXED (a similar model would be acceptable using R) Kenward and Roger's method 
will be used to calculate the denominator degrees of freedom for the fixed effects 
(DDFM=KR).  If the model fails to converge, a simpler covariance structure such as 
compound symmetry may be used.  The difference in least squares means on the log scale 
will be calculated for MK-5475 postdose vs. predose at each time point (1, 3, 8 and 24 hours)
at each dose level.  These mean differences will be exponentiated to obtain the ratio of 
geometric means for PBV (MK_postdose / MK_predose) at each dose level.  
Exploratory
The relationship between dose or plasma concentration and pharmacodynamic variables
PVR, pulmonary arterial pressure, cardiac output/cardiac index (CO/CI), systemic vascular 
resistance, mixed venous oxygen saturation and arterial oxygenation in participants with 
pulmonary arterial hypertension will be explored graphically. Upon visual inspection, 
additional model-based analysis might be employed to further explore the pharmacokinetic-
pharmacodynamic relationship.
9.7
Interim Analyses
There is no interim analysis involved in this study.
9.8
Multiplicity
Since there are no hypotheses, no adjustments for multiplicity are needed.
9.9
Sample Size and Power Calculations
There are no variability estimates for PK or PD are available for this participant population
from which to estimate power or precision. Nevertheless, a sample size of twenty, along with 
PD evaluations at 2 dose levels, is considered adequate to meet the needs of the study.
 
 
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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 of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, 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 (ie, 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 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 general principles of 
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, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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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 primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified 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. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
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 representative), 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.
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 to identify potentially eligible participants.
 
 
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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 (eg, 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
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.
 
 
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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 
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.
 
 
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10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (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 Conference on Harmonization 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 Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
 
 
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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 signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
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, 
 
 
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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 will 
promptly notify that study site’s IRB/IEC.
10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 6 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 8.1.2 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.
 
 
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Table 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
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/aPTT
•
Mixed venous oxygen saturation (MVO2)
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential 
only)
•
Serum/Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) 
•
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)] [if applicable] Pregnancy testing requirements for study inclusion are 
described in Section 5.1 
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, 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.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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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:
 
 
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-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the 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 electronic data collection 
(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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
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 follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, 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 include a:
Highly Effective Contraceptive Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen-only subdermal contraceptive implant b,c
●
Intrauterine hormone-releasing system (IUS) c,d
●
Intrauterine device (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 treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant. 
a.) 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 Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation.
c.) Male condoms must be used in addition to the 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 lactational amenorrhea method (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 Research
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 drugs/vaccines may interact with
◦
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 Research.
a.
Participants for Enrollment
 
 
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All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b.
Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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 Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' 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 gender, 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 Usage
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 Research
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 principal 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 Specimens
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 Security
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 Participants
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 Population
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 Research
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 Conference on Harmonization [Internet]: E15: Definitions for 
Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and 
Sample Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-
pharmacogenetics-genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide 
for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable
 
 
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10.8
Appendix 8: Blood Volume Table
Panel A (Part 1 and 2)
Pre-study
Treatment 
Periods
Post-
study
Total 
Collections
mL Per 
Collection
Total mL/ Test a
Laboratory Safety Tests
1
9
1
5.0
55
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
1*
1
5*
5
Serum  βHcg (if applicable)
1*
1
1
5
5
FSH (if applicable)
1*
See footnote
PT aPTT
1
9
1
11
5
55
Mixed Venous Oxygen
8
8
5
40
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for MK-5475
43
43
6 mL
258
* Pre-study HIV/Hepatitis Screen, FSH and Serum HcG will be assayed from a single 5 mL 
blood sample
Total Blood Volume is for participants from Part 1 and continue into Part 2
Female:~
426.5mL
Male: 421.5 mL
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. Note: never to exceed 50 mL.
Panel A (Part 1 only)
Pre-study
Treatment 
Periods
Post-
study
Total 
Collections
mL Per 
Collection
Total mL/ Test
Laboratory Safety Tests
1
6
1
8
5.0
40
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
1*
1
5*
5
Serum βHcg (if applicable)
1*
1
1
5
5
FSH (if applicable)
1*
See footnote
-
-
PT aPTT
1
6
1
8
5
40
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for MK-5475
30
30
6 mL
180
* Pre-study HIV/Hepatitis Screen, FSH and Serum HcG will be assayed from a single 5 mL 
blood sample
Female:~278.5
mL a
Male:273.5 mL a
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. Note: never to exceed 50 mL.
 
 
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Panel B and C
Pre-study
Treatment 
Periods
Post-
study
Total 
Collections
mL Per 
Collection
Total mL/ Test
Laboratory Safety Tests
1
5
1
7
5
35
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
1*
1
5
5
Serum  βHcg (if applicable)
1*
1
1
5
5
FSH (if applicable)
1*
See footnote
-
-
PT aPTT
1
5
1
7
5
35
Mixed Venous Oxygen
8
8
5
40
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for MK-5475
23
23
6 mL
138
* Pre-study HIV/Hepatitis Screen, FSH and Serum HcG will be assayed from a single 5 mL 
blood sample
Female: ~266.5
mLa,
Male: ~ 261.5
mLa,
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood 
(up to 50 mL) may be obtained. Note: never to exceed 50 mL.
Panel D
Pre-study
Treatment 
Periods
Post-
study
Total 
Collections
mL Per 
Collection
Total mL/ Test
Laboratory Safety Tests
1
5
1
7
5
35
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
1*
1
5
5
Serum  βHcg (if applicable)
1*
1
1
5
5
FSH (if applicable)
1*
See footnote
-
-
PT aPTT
1
5
1
7
5
35
Mixed Venous Oxygen
8
8
5
40
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for MK-5475
27
27
6 mL
162
* Pre-study HIV/Hepatitis Screen, FSH and Serum HcG will be assayed from a single 5 mL 
blood sample
Female: ~290.5
mLa,
Male: ~ 285.5 
mLa,
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood 
(up to 50 mL) may be obtained. Note: never to exceed 50 mL.
 
 
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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 not 
clinically significant (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 any of the treatment periods, if a particular participant demonstrates a sustained
change (defined below) in any one of the following parameters, that participant will not 
participate in additional dose escalation. For assessing change from baseline, post-dose 
values will be compared to the Day 1 predose baseline established by 3 semi-recumbent 
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 any of the treatment periods if a particular participant demonstrates change in any one 
of the following parameters lasting ≥ 90 minutes, dose escalation 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
Definitions for HR and BP
Participants must be resting and semirecumbent for at least 10 minutes prior to obtaining any
measurements used to limit dose escalation (except for changes noted while obtaining 
orthostatic signs).
Baseline HR and BP: Predose baseline values will be determined for each specific period. 
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 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 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 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.
Notes
If an assessment of the present and previous periods raises safety and tolerability concerns 
though individual participant/participants do not meet the criteria described above, and after 
discussion with the investigator and the Merck monitor, dose escalation for the entire panel 
may end.
 
 
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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
In the event that 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
AE
adverse event 
BDS
blood drug screen
BP
Blood pressure
CI
Cardiac index
CO
Cardiac output
CRF
Case Report Form 
CRU
clinical research unit
CT
computed tomography 
DILI
drug-induced liver injury
DLCO
Diffusing capacity of the lung for carbon monoxide
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
ERA
Endothelin receptor antagonist
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FRC
functional respiratory capacity
FSH
Follicle stimulating hormone 
FVC
forced vital capacity
GCP
Good Clinical Practice 
Hgb
hemoglobin
HR
Heart rate
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board 
IUD
intrauterine device
MVO2
mixed venous oxygen saturation
MTD
maximum tolerated dose 
NOAEL
no observed adverse effect level 
PAH
pulmonary arterial hypertension
PAP
pulmonary artery pressure
PAWP
Pulmonary artery wedge pressure
PBO
placebo
PBV
pulmonary blood volume
PDE5i
Phosphodiesterase type 5 inhibitor
PEF
peak expiratory flow
PFT
pulmonary function tests
PK
pharmacokinetic
PT
prothrombin time
aPTT
activated partial thromboplastin time
PVR
Pulmonary vascular resistance
QP2
department of quantitative pharmacology and pharmacometrics
RAP
Right atrium pressure
RHC
Right heart catheterization
RNA
ribonucleic acid
 
 
05J3S0
06DQP7


PRODUCT:  MK-5475  
121
PROTOCOL/AMENDMENT NO.:  002-03  
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
Abbreviation
Expanded Term
RR
respiratory rate
RV
residual volume
RVSP
right ventricular systolic pressure
RVEDP
right ventricular end diastolic pressure
SAC
Scientific Advisory Committee
SAE
serious adverse event 
sGC
Soluble guanylate cyclase
SoA
schedule of activities
SVR
Systemic vascular resistance
SUSAR
suspected unexpected serious adverse reaction
TEMP
temperature
TLC
Total lung capacity
UDS
urine drug screen
VC
Vital capacity
WOCBP
woman/women of childbearing potential 
WONCBP
Woman/women of non-childbearing potential
 
 
05J3S0
06DQP7


PRODUCT:  MK-5475  
122
PROTOCOL/AMENDMENT NO.:  002-03  
MK-5475-002-03 FINAL PROTOCOL
16-JUN-2020
11
REFERENCES
[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]
[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]
[Grimminger, F., et al 
2009]
Grimminger F, Weimann G, Frey R, Voswinckel 
R, Thamm M, Bölkow D, et al. First acute 
haemodynamic study of soluble guanylate cyclase 
stimulator riociguat in pulmonary hypertension. 
Eur Respir J 2009;33(4):785-92.
[03RSLP]
 
 
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