A Randomized Double Blind Clinical Trial to Evaluate the Effects of MK-7264 in Participants With Obstructive Sleep Apnea
Phase: PHASE1
Conditions: Obstructive Sleep Apnea (OSA)
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03882801 
Document Date: 
02-APR-2019
A Randomized Double Blind Clinical Trial to Evaluate the Effects of
MK-7264 in Participants with Obstructive Sleep Apnea

PRODUCT: MK-7264  
1
PROTOCOL/AMENDMENT NO.: 039-02 
MK-7264-039-02 FINAL PROTOCOL
02-APR-2019
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 Randomized Double Blind Clinical Trial to Evaluate the Effects of MK-
7264 in Participants with Obstructive Sleep Apnea
Protocol Number: 039-02
Compound Number: MK-7264
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
141,037
EudraCT
2018-004099-37
Approval Date: 02 April 2019
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 02
02-APR-2019
Update prohibited concomitant medications.
Amendment 01
30-JAN-2019
The MK-7264 45 mg assessment was removed.
Original Protocol
11-DEC-2018
Not Applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Following publication of Protocol 039-01, new in vitro data suggesting transporter inhibition by MK-7264 became available. Based on 
this information, pitavastatin has been added to the list of prohibited medications.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Added IND into Regulatory Agency table 
to align with the IND number
The revisions reflect the clarification of 
the IND number in the Regulatory 
Agency table.
Section 1.3: Schedule of Activities (SoA)
Added a line for blood and urine 
collections for in clinic PSG days
The revisions reflect clarification of the 
SoA.
Section 1.3: Schedule of Activities (SoA)
Added additional flexibility for timing of 
admission arrival and procedures.
The revision is to accommodate patient 
and site schedules.
Section 1.3: Schedule of Activities (SoA)
Added that patient allocation number will 
be added to the Participant ID Card at 
randomization.
The revisions reflect clarification of the 
SoA.
Section 2.3: Pharmaceutical and 
Therapeutic Background
Added updated in vitro MK-7264
transporter inhibition data. 
The revisions reflect the inclusion of 
newly available in vitro transporter 
inhibition data.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
Section 5.2: Exclusion Criteria
Added pitavastatin to list of prohibited 
medications.
The revisions reflect the updated 
prohibited medications list based on 
newly available in vitro transporter 
inhibition data.
Section 5.2: Exclusion Criteria
Added history of allergy to sulfonamide-
containing drugs to the exclusion criteria.   
The revision reflects the updated allergy 
exclusion criterion.  
Section 5.2: Exclusion Criteria
Updated eGFR criterion
The revisions reflect the updated eGFR 
exclusion criterion.
Section 5.3.1.1: Diet Restrictions
Clarified diet restrictions for assessment 
visits.
The revisions reflect the clarification of 
diet restrictions.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities (SoA)................................................................................17
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................25
2.3
Pharmaceutical and Therapeutic Background .................................................25
2.4
Preclinical and Clinical Studies..........................................................................25
2.5
Ongoing Clinical Studies.....................................................................................27
2.6
Benefit/Risk Assessment......................................................................................27
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................32
4.2.1.1
Efficacy and Safety Endpoints...........................................................32
4.2.1.2
Pharmacokinetic Endpoints ...............................................................33
4.2.1.3
Pharmacodynamic Endpoints.............................................................33
4.2.1.4
Planned Exploratory Biomarker Research.........................................34
4.2.1.4.1
Planned Genetic Analysis ........................................................34
4.2.1.5
Future Biomedical Research..............................................................34
4.2.2
Rationale for the Use of Placebo .................................................................34
4.3
Justification for Dose...........................................................................................35
4.4
Beginning and End of Study Definition .............................................................35
4.4.1
Clinical Criteria for Early Study Termination .............................................36
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................36
5.2
Exclusion Criteria................................................................................................38
5.3
Lifestyle Considerations......................................................................................44
5.3.1
Meals and Dietary Restrictions....................................................................44
5.3.1.1
Diet Restrictions.................................................................................44
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................44
 
 
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5.3.2.1
Caffeine Restrictions..........................................................................44
5.3.2.2
Alcohol Restrictions...........................................................................44
5.3.3
Tobacco Restrictions....................................................................................44
5.3.4
Activity Restrictions ....................................................................................45
5.4
Screen Failures.....................................................................................................45
5.5
Participant Replacement Strategy......................................................................45
6
STUDY INTERVENTION............................................................................................45
6.1
Study Intervention(s) Administered...................................................................45
6.2
Preparation/Handling/Storage/Accountability .................................................47
6.2.1
Dose Preparation..........................................................................................47
6.2.2
Handling, Storage, and Accountability........................................................47
6.3
Measures to Minimize Bias: Randomization and Blinding..............................48
6.3.1
Intervention Assignment..............................................................................48
6.3.2
Stratification.................................................................................................48
6.3.3
Blinding........................................................................................................48
6.4
Study Intervention Compliance..........................................................................48
6.5
Concomitant Therapy..........................................................................................48
6.5.1
Rescue Medications and Supportive Care ...................................................49
6.6
Dose Modification ................................................................................................49
6.6.1
Stopping Rules.............................................................................................49
6.7
Intervention After the End of the Study............................................................49
6.8
Clinical Supplies Disclosure................................................................................49
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................50
7.1
Discontinuation of Study Intervention...............................................................50
7.2
Participant Withdrawal From the Study...........................................................51
7.3
Lost to Follow-up .................................................................................................51
8
STUDY ASSESSMENTS AND PROCEDURES........................................................51
8.1
Administrative and General Procedures ...........................................................52
8.1.1
Informed Consent.........................................................................................52
8.1.1.1
General Informed Consent.................................................................52
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................53
8.1.2
Inclusion/Exclusion Criteria ........................................................................53
8.1.3
Participant Identification Card.....................................................................53
8.1.4
Medical History ...........................................................................................53
8.1.5
Prior and Concomitant Medications Review...............................................53
8.1.5.1
Prior Medications...............................................................................53
 
 
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8.1.5.2
Concomitant Medications..................................................................54
8.1.6
Assignment of Screening Number...............................................................54
8.1.7
Assignment of Treatment/Randomization Number.....................................54
8.1.8
Study Intervention Administration ..............................................................54
8.1.8.1
Timing of Dose Administration.........................................................55
8.1.9
Discontinuation and Withdrawal .................................................................55
8.1.9.1
Withdrawal From Future Biomedical Research ................................55
8.1.10
Participant Blinding/Unblinding..................................................................56
8.1.11
Domiciling ...................................................................................................56
8.1.12
Calibration of Equipment.............................................................................56
8.2
Efficacy Assessments ...........................................................................................57
8.2.1
Polysomnography ........................................................................................57
8.2.2
Emerald Device Sleep Data Capture............................................................57
8.2.3
Morning Sleep Questionnaire (MSQ)..........................................................58
8.2.4
Epworth Sleepiness Scale (ESS)..................................................................58
8.2.5
Functional Outcomes of Sleep Questionnaire (FOSQ)................................58
8.3
Safety Assessments...............................................................................................58
8.4
Physical Examinations.........................................................................................58
8.4.1
Complete Physical Examinations ................................................................58
8.4.2
Focused Physical Examinations...................................................................59
8.4.3
Calculate Body Mass Index .........................................................................59
8.4.4
Vital Signs....................................................................................................59
8.4.5
Electrocardiograms ......................................................................................59
8.4.6
Renal and Urological Safety Procedures .....................................................60
8.4.7
Pregnancy Testing........................................................................................60
8.4.8
Exploratory Blood and Urine Clinical Biomarkers .....................................60
8.5
Clinical Safety Laboratory Assessments............................................................60
8.6
Other Assessments ...............................................................................................61
8.6.1
Study Intervention Diary..............................................................................61
8.7
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................61
8.7.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................61
8.7.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......63
8.7.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...63
8.7.4
Regulatory Reporting Requirements for SAE .............................................64
8.7.5
Pregnancy and Exposure During Breastfeeding ..........................................64
 
 
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8.7.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................64
8.7.7
Events of Clinical Interest (ECIs) ................................................................64
8.8
Treatment of Overdose........................................................................................65
8.9
Pharmacokinetics.................................................................................................65
8.9.1
Blood Collection for Plasma MK-7264 .......................................................65
8.10
Planned Genetic Analysis Sample Collection....................................................65
8.11
Future Biomedical Research Sample Collection...............................................66
8.12
Visit Requirements...............................................................................................66
8.12.1
Screening......................................................................................................66
8.12.2
Treatment Period..........................................................................................66
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........67
8.12.4
Poststudy......................................................................................................67
8.12.5
Critical Procedures Based on Study Objectives: Timing of Procedure .......67
8.12.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................68
9
STATISTICAL ANALYSIS PLAN .............................................................................69
9.1
Statistical Analysis Plan Summary.....................................................................69
9.2
Responsibility for Analyses.................................................................................69
9.3
Hypotheses/Estimation ........................................................................................70
9.4
Analysis Endpoints...............................................................................................71
9.5
Analysis Populations............................................................................................72
9.6
Statistical Methods...............................................................................................72
9.7
Interim Analyses ..................................................................................................74
9.8
Multiplicity ...........................................................................................................74
9.9
Sample Size and Power Calculations .................................................................74
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................76
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........76
10.1.1
Code of Conduct for Clinical Trials.............................................................76
10.1.2
Financial Disclosure.....................................................................................78
10.1.3
Data Protection.............................................................................................78
10.1.3.1
Confidentiality of Data ......................................................................79
10.1.3.2
Confidentiality of Participant Records...............................................79
10.1.3.3
Confidentiality of IRB/IEC Information............................................79
10.1.4
Publication Policy........................................................................................79
10.1.5
Compliance with Study Registration and Results Posting Requirements ...80
10.1.6
Compliance with Law, Audit, and Debarment ............................................80
 
 
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10.1.7
Data Quality Assurance ...............................................................................81
10.1.8
Source Documents .......................................................................................81
10.1.9
Study and Site Closure.................................................................................82
10.2
Appendix 2: Clinical Laboratory Tests..............................................................83
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................84
10.3.1
Definition of AE ..........................................................................................84
10.3.2
Definition of SAE ........................................................................................85
10.3.3
Additional Events Reported in the Same Manner as SAE...........................86
10.3.4
Recording AE and SAE ...............................................................................86
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................87
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................89
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................90
10.5.1
Definitions....................................................................................................90
10.5.2
Contraception Requirements........................................................................91
10.5.3
Pregnancy Testing........................................................................................92
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................93
10.7
Appendix 7: Country-specific Requirements....................................................98
10.8
Appendix 8: Blood Volume Table ......................................................................99
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ..................100
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...102
10.11 Appendix 11: Abbreviations .............................................................................103
11
REFERENCES.............................................................................................................105
 
 
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LIST OF TABLES
Table 1
Prohibited Medications and Specified Washout Period................................42
Table 2
Study Interventions.......................................................................................46
Table 3
Sample Allocation Schedule.........................................................................48
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events..............................................................................62
Table 5
Protocol-required Safety Laboratory Assessments.......................................83
 
 
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LIST OF FIGURES
Figure 1
Study Design ..................................................................................................16
Figure 2
Putative mechanism of contribution of carotid body activation and HLG 
to OSA............................................................................................................24
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized Double Blind Clinical Trial to Evaluate the Effects of 
MK-7264 in Participants with Obstructive Sleep Apnea
Short Title: MK-7264 Trial in Participants with Obstructive Sleep Apnea
Acronym:
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Male/Female participants with moderate to severe obstructive sleep apnea between the ages 
of 18 and 75 years (inclusive) will be enrolled in this trial.
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of Obstructive Sleep Apnea
Population
Male and female adults with moderate to severe 
obstructive sleep apnea (OSA) who do not use positive 
airway pressure (PAP) therapy.
Study Type
Interventional
Intervention Model
Cross-over
This is a multi-site study in the US and Europe.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 9 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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Number of Participants:
Approximately 16 participants will be allocated/randomized.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Treatment 
Period
All participants
MK-7264 
180 mg
QHS x 7
days
Oral
Period 1 or 2
Placebo
0 mg
QHS x 7
days
Oral
Period 1 or 2
Abbreviations:
QHS: daily at bedtime
Total 
Number
There will be a total of 2 treatment sequences as outlined below. Both 
sequences will have 8 participants.
Treatment 
Sequence
Period 1
Period 2
1
(n=8)
Placebo
MK-7264 180 mg
2
(n=8)
MK-7264 180 mg
Placebo
Duration of 
Participation
Each participant will participate in the study for approximately 10 weeks
from the time the participant signs the Informed Consent Form (ICF) 
through the final contact.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 10.1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.11.
 
 
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1.2
Schema
The study design is depicted in Figure 1
Figure 1
Study Design
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Periods 1 and 2
Follow-up
Notes
Scheduled Visit
Screening 
1
Screening 
2
Screening 
3
Random
ization
Baseline
At-Home 
Dosing
Assessment
At-Home 
Washout
Post-
study 
Visit
Procedures scheduled for
Randomization occur in Period 1 
only
Study Days
Day -36
Day -22
Day -15
Day -1
Day -1
Days 1-6
Day 7
Days 8-13
Day 21
(After 
Period 2
only)
Visit Window (days)
+13
+/- 3
+/- 5
+ 3
+ 2
+/- 2
Visit Windows denote flexibility of 
certain scheduled Visits. “+” means 
Visit can be delayed by X days; “-“ 
means Visit can be scheduled ahead 
by X days.
Administrative Procedures
Assignment of Screening 
Number
X
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Participant Identification 
Card
X
X
Allocation number will be added to 
the Participant ID Card at 
Randomization
Inclusion/Exclusion Criteria
X
X
X
X
Medical History
X
Prior/Concomitant 
Medication Review
X -------------------------------------------------------------------------------------------------------------------------------------- X
Assignment of 
Treatment/Randomization 
Number
X
Site should refer to Study 
Operations Manual for details on 
participant assignment. All safety 
procedures should be completed 
prior to treatment assignment.
Dosing and Other Related Procedures
MK-7264/Placebo and Study 
Intervention Diary 
Dispensing  
X
MK-7264/Placebo 
Administration (at home)
X
Participants should take the 
assigned treatment as instructed by 
the site
 
 
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Study Period
Screening
Periods 1 and 2
Follow-up
Notes
Scheduled Visit
Screening 
1
Screening 
2
Screening 
3
Random
ization
Baseline
At-Home 
Dosing
Assessment
At-Home 
Washout
Post-
study 
Visit
Procedures scheduled for
Randomization occur in Period 1 
only
Study Days
Day -36
Day -22
Day -15
Day -1
Day -1
Days 1-6
Day 7
Days 8-13
Day 21
(After 
Period 2
only)
Visit Window (days)
+13
+/- 3
+/- 5
+ 3
+ 2
+/- 2
Visit Windows denote flexibility of 
certain scheduled Visits. “+” means 
Visit can be delayed by X days; “-“ 
means Visit can be scheduled ahead 
by X days.
Study Intervention Reminder 
Contact
X
Participants will be contacted and 
reminded to self-administer study 
intervention.
Study Intervention Diary (at 
home)
X
Participants should complete the 
study intervention diary after each 
dosing at home
MK-7264/Placebo 
Administration (in clinic)
X
Collection of MK-7264 / 
Placebo bottles and Study 
Intervention Diary as 
applicable
X
Standard Meals  
X
X
X
X
Efficacy/Pharmacodynamic Procedures
Hyperoxia Challenge
X
Polysomnography (PSG)
X
X
X
X
See sub-flow chart below for 
detailed timing of procedures on 
PSG/in-clinic days
Epworth Sleepiness Scale 
(ESS)
X
X
X
Morning Sleep Questionnaire 
(MSQ) Dispensing
X
Morning Sleep Questionnaire 
(MSQ)
X
X
X
X
MSQ should be completed within 
15 minutes of rising as instructed by 
the site
Collection of Completed 
MSQ
X
Functional Outcomes of 
Sleep Questionnaire (FOSQ)
X
X
X
 
 
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Study Period
Screening
Periods 1 and 2
Follow-up
Notes
Scheduled Visit
Screening 
1
Screening 
2
Screening 
3
Random
ization
Baseline
At-Home 
Dosing
Assessment
At-Home 
Washout
Post-
study 
Visit
Procedures scheduled for
Randomization occur in Period 1 
only
Study Days
Day -36
Day -22
Day -15
Day -1
Day -1
Days 1-6
Day 7
Days 8-13
Day 21
(After 
Period 2
only)
Visit Window (days)
+13
+/- 3
+/- 5
+ 3
+ 2
+/- 2
Visit Windows denote flexibility of 
certain scheduled Visits. “+” means 
Visit can be delayed by X days; “-“ 
means Visit can be scheduled ahead 
by X days.
Emerald Device Sleep Data 
Capture 
X
X
X
X
Emerald device will be included for 
US sites only as described in 
Section 8.2.2.
Safety Procedures
Full Physical Examination
X
X
Focused Physical Exam
X
X
Xa
X
X
Height
X
Weight
X
Vital Signs
(BP/HR/RR/Body 
Temperature)
X
X
X
X
X
SpO2 will be assessed at Screening 
Visit 1 for I/E Criteria
12-lead ECG
X
X
X
Urine or Serum Pregnancy 
Test (WOCBP only)
X
Xa
X
X
HIV, Hepatitis B and C 
Screen (per site SOP)
X
Urine Drug Screen (UDS) 
(per site SOP)
X
Xa
X
Laboratory Safety Tests 
(Chemistry, Hematology, 
Urinalysis (with microscopy))
X
Xa
X
X
X
AE/SAE review
X -------------------------------------------------------------------------------------------------------------------------------------- X
 
 
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Study Period
Screening
Periods 1 and 2
Follow-up
Notes
Scheduled Visit
Screening 
1
Screening 
2
Screening 
3
Random
ization
Baseline
At-Home 
Dosing
Assessment
At-Home 
Washout
Post-
study 
Visit
Procedures scheduled for
Randomization occur in Period 1 
only
Study Days
Day -36
Day -22
Day -15
Day -1
Day -1
Days 1-6
Day 7
Days 8-13
Day 21
(After 
Period 2
only)
Visit Window (days)
+13
+/- 3
+/- 5
+ 3
+ 2
+/- 2
Visit Windows denote flexibility of 
certain scheduled Visits. “+” means 
Visit can be delayed by X days; “-“ 
means Visit can be scheduled ahead 
by X days.
Pharmacokinetics
Blood for Plasma MK-7264 
X
Blood for MK-7264 PK will be 
collected at the following time 
points: Day 7 of each Period: 
predose, 30 minutes post dose, and 
lights on.
Biomarkers
Blood (DNA) for Planned 
Genetic Analysisb, c
X
Collect from randomized 
participants at Period 1 only.
Blood (serum and plasma) for 
Clinical Biomarkers c
X
X
Urine for Clinical 
Biomarkersc
X
X
a Events that are marked for both Randomization (Day -1) and Period 1 Baseline (Day -1) should only be performed once. They should not be duplicated.
b This 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 that 
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 analyses are not approved, but future biomedical research is approved, and consent is given, this sample will be collected for the purpose of future 
biomedical research
c Leftover from these samples are subject to FBR as described in Section 8.11.
Detailed Schedule of Activities for In Clinic PSG Days
Note: the purpose of the table below is to provide details on the timing in relation of the procedures on PSG days. Not every single 
procedure is scheduled for each PSG day. Please refer to the Schedule of Activities above to see which procedures are applicable 
during each visit.
 
 
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Arrival
(within
-6 hours)
Within -4 
hours
-1.5
hour
-1.0 hour
‘Lights 
Off’
0 hour
‘Lights On’
8 hour
1 hour post 
‘Lights 
On’
Discharge
Randomization Procedures (as 
described in SoA above, Period 1 
Baseline only)
X
Collection of MK-7264/Placebo 
Bottles, Study Intervention Diary, and 
MSQ (only on assessment days)
X
Safety Procedures (Focused Physical 
Examd, Vital Signs)
X
Vital Signs 
X
X
Blood Collection for MK-7264 PK a
(only on assessment days)
X
X
X b
MK-7264/Placebo Administration
(only on assessment days)
X
Standard Meal
X
X
PSG Set-Up
X------------------------------X
PSG including Finger Pulse Oximetry 
(SaO2 monitoring)
X----------------------X
Hyperoxia Challenge (Screening Visit 
3 only)
X----------------------X
Emerald Device Sleep Data Capture
X----------------------X
Laboratory Safety Tests (Chemistry, 
Hematology, Urinalysis)
X b
Clinical Biomarker Sample Collection
(urine & blood)
X b
Morning Sleep Questionnaire (MSQ) c
X
Epworth Sleepiness Scale (ESS)
X
Functional Outcomes of Sleep 
Questionnaire (FOSQ)
X
Dispense study medication / Drug 
Diary, Morning Sleep Questionnaire 
(MSQ)
X
 
 
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Arrival
(within
-6 hours)
Within -4 
hours
-1.5
hour
-1.0 hour
‘Lights 
Off’
0 hour
‘Lights On’
8 hour
1 hour post 
‘Lights 
On’
Discharge
a Blood for MK-7264 PK will be collected at the following time points: Days 7 of each Period: predose, 30 minutes postdose, and lights on.
b Blood and urine collection for biomarker/PK samples collected at “lights-on” should be drawn at the same time. PGA sample collected at Baseline, Period 1 may also be 
collected at this time.
c MSQ should be completed within 15 minutes of rising as instructed by the site.
d Physical exam may be performed within 1 hour of “Lights-On”.
 
 
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2
INTRODUCTION
Approximately twenty six percent of American adults suffer from obstructive sleep apnea 
(OSA) [Peppard, P. E., et al 2013]. Patients with OSA are at increased risk for multiple co-
morbidities, including, but not limited, to hypertension, diabetes, stroke, depression, and 
early mortality [Young, T., et al 2009] [Pagel, J. F. 2007] [Hale, C. S. 2005] [Parish, J. M., et 
al 2007]. This burden is amplified by the fact that health care utilization and costs among 
OSA patients are double those of age, body mass index (BMI), and gender matched controls 
[Pagel, J. F. 2007]. The first-line treatment for OSA is a positive airway pressure (PAP)
device, which reduces but does not eliminate the co-morbidities associated with OSA [Pagel, 
J. F. 2007]. Unfortunately, PAP is cumbersome and poorly tolerated, leading to low long-
term adherence rates of approximately 50% [Weaver, T. E., et al 1997] [Means, M. K., et al 
2004] [Rotenberg, B. W., et al 2016] [Rotenberg, B. W., et al 2016]. Thus, an oral 
pharmacological treatment that can either increase the efficacy of PAP or supplant the need 
for PAP completely would be a significant medical advance for OSA patients.
Pathophysiology of OSA: OSA is a heterogeneous syndrome that results from obstructive
(mechanical/anatomic), central (absence of inspiratory effort) or mixed (obstructive plus 
central) features. In all cases of OSA, there is dysregulation of respiratory motor drive to 
upper airway muscles, which can lead to airways that either have ineffective dilation or 
prematurely collapse [Dempsey, J. A., et al 2014] (Figure 2). Additional factors that 
contribute to OSA are low arousal threshold, prolonged circulation time and High Loop Gain 
(HLG). HLG is an engineering term applied in respiratory research to describe the 
relationship of the magnitude of a ventilatory response evoked by a ventilatory disturbance 
[Dempsey, J. A., et al 2014]; HLG describes a situation in which the ventilatory response is 
inappropriately high relative to the ventilatory disturbance. The exaggerated response to the 
levels of O2 and CO2 by the peripheral chemoreceptors in the carotid body (e.g. from poor 
circulation or autonomic dysregulation) can lead to high ventilatory drive in patients with 
HLG such that, following even a brief, mild apneic event, the airways open and 
hyperventilation occurs. This in turn restarts the cycle of hypocapnia and a paradoxical apnea 
or hypopnea.  In patients with HLG, supplemental oxygen increases SaO2 and effectively 
reduces the disconnect between the perception of hypoxia by peripheral chemoreceptors and 
the actual gas levels in the periphery.  In a subgroup of patients with oxygen responsive or 
chemoreflex-dependent OSA (high loop gain and milder pharyngeal collapsibility), lowering 
loop gain (with supplemental O2) greatly improves OSA severity; approximately 25% of 
patients lowered Apnea-Hypopnea Index (AHI) by > 50% and 1 in 6 patients had no OSA on 
treatment [Sands, S. A., et al 2018]. HLG is found in approximately 33% of patients with 
OSA, including those with mechanical obstruction, and contributes to the pathophysiology
by causing exaggerated oscillation between hyper- and hypoventilation [Dempsey, J. A., et al 
2014]. 
 
 
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Figure 2
Putative mechanism of contribution of carotid body activation and HLG to OSA
This response results in respiratory instability and recurrent cycles of hypopnea and/or apnea 
during sleep [Dempsey, J. A., et al 2014] [Younes, M. 2014] (Figure 2). Antagonism of the 
carotid body afferents could normalize HLG and treat OSA [Paton, J. F. R., et al 2013].
2.1
Study Rationale
The inability of patients to receive maximal benefit from PAP supports the development of 
new drug treatments for OSA that can either replace or supplement PAP by increasing its 
clinical efficacy. Drug treatments for OSA have been sought for many years, but effective 
agents remain to be identified. A series of proof-of-principle studies have been performed 
using the respiratory stimulant acetazolamide, a carbonic anhydrase inhibitor [Edwards, B. 
A., et al 2012] [Edwards, B. A., et al 2012] [Nussbaumer-Ochsner, Y., et al 2012]. 
Acetazolamide produces a metabolic acidosis, which increases the baseline ventilatory drive
in patients with OSA. This response can lower loop gain and the AHI [Edwards, B. A., et al 
2012]. However, chronic acetazolamide treatment is not a viable long-term therapy as it leads 
to harmful metabolic changes. These studies support the hypothesis that lowering loop gain 
pharmacologically can have a beneficial impact on patients with OSA.
This trial is a Phase 1b proof of concept (PoC) placebo-controlled, double-blind, crossover 
study that will test the hypothesis that MK-7264 will reduce OSA severity (AHI) in 
chemoreflex-dependent patients with OSA. A positive outcome of this study would support
further study of agents, such as MK-7264, that normalize carotid body inputs in patients with 
OSA.
 
 
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2.2
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-7264.
2.3
Pharmaceutical and Therapeutic Background
MK-7264 is a P2X3 receptor antagonist. P2X3 is a ligand-gated ion channel that is primarily 
expressed on afferent sensory c-fibers and that opens in response to extracellular ATP 
released by cell damage in inflamed tissues or released as a neurotransmitter from 
presynaptic vesicles. P2X3 receptors can be homotrimer (containing only P2X3) or 
heterotrimer (containing P2X2/3). MK-7264 is a selective P2X3 receptor antagonist and is a 
potent inhibitor with an IC50 of 20-70 nM for P2X3 and 150-300 nM for P2X2/3, with at 
least 100-fold selectivity over other P2X channels [North, R. A. 2004].
In vitro studies assessing the potential for MK-7264 to inhibit the human transporters 
Organic Anion Transporting Polypeptide 1B1 (OATP1B1), OATP1B3, Organic Cation 
Transporter 1 (OCT1), OCT2, Organic Anion Transporter 1 (OAT1), OAT3, Multidrug and 
Toxin Extrusion Protein 1 (MATE1), MATE2K, Breast Cancer Resistance Protein (BCRP), 
and Bile Salt Extrusion Pump (BSEP) were performed. 
No clinically meaningful inhibition of OCT2, OAT1, OAT3, BCRP and BSEP was 
measured. At an in vitro concentration approximately equivalent to that achieved with a 
180 mg QD dose, MK-7264 has the potential to inhibit OATP1B1- and OATP1B3-mediated 
hepatic uptake, with in vitro IC50 values of 35 µM and 97 µM, and calculated R-values (the 
predicted ratio of the victim drug’s AUC in the presence and absence of perpetrator drug) of 
1.5 and 1.2 for OATP1B1 and -1B3, respectively. MK-7264 also has the potential to inhibit 
OCT1-mediated hepatic uptake (IC50=17.2 µM, R=1.9), MATE1 (IC50=34.7 µM; 
Cmax,u/IC50=0.07), and MATE2K (IC50=31.5 µM; Cmax,u/IC50=0.08) mediated apical 
efflux in renal proximal tubule cells. Based on these observations, the likelihood of a 
clinically significant DDI with substrates of OATP1B1, OATP1B3, OCT1, MATE1 and 
MATE2K is considered to be low, but cannot be excluded.
2.4
Preclinical and Clinical Studies
Aberrant sympathetic nervous system excitation is linked to the pathology and morbidity of a 
variety of cardiorespiratory disorders, and one factor contributing to sympathoexcitation is 
OSA [Taylor, K. S., et al 2018]. Additionally, OSA can exacerbate ventilatory instability
[Younes, M. 2014]. It has been shown that supplemental oxygen can treat ventilatory 
instability by reducing the sensitivity of the carotid bodies, resulting in a reduction of the 
AHI [Edwards, B. A., et al 2014]. In dogs, carotid body denervation reduced apneas and 
periodic breathing resulting from transient hyperventilations and hypercapnia [Nakayama, 
H., et al 2003]. An animal model of heightened sympathetic activity, the spontaneously 
hypertensive rat (SHR), was used to demonstrate the role of P2X3 in peripheral 
chemoreceptors in the carotid body [Paton, J. F. R., et al 2013] [Pijacka, W., et al 2016]. In 
this series of studies, electrophysiological recordings from the carotid sinus nerve innervating 
the carotid body demonstrated the exaggerated response to hypoxia in SHRs relative to 
 
 
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Wistar rat controls. This hyperreflexic response to hypoxia in the SHR was restored to the 
normal magnitude of response seen in the Wistar through pharmacological blockade with a 
selective P2X3/P2X2/3 antagonist (‘AF-353’, a close analogue to MK-7264). Additionally, 
treatment with MK-7264 significantly reduced renal sympathetic nerve activity [Pijacka, W., 
et al 2016].
The apneas of prematurity that occur in newborn rats is a model for OSA [Bairam, A., et al 
2013]. In this model, blockade of P2X3 and P2X2/3 by ‘AF-454’ (another close analogue of 
MK-7264) had no effect on breathing under normoxic conditions but dramatically reduced 
hypoxia-induced hyperventilation and significantly reduced the frequency of apneas as 
measured by plethysmographic recordings [Katayama, P. L., et al 2017]. These pre-clinical 
studies support the hypothesis that P2X3 antagonism could treat sleep disordered breathing in 
patients with OSA.
As of 31-AUG-2018, MK-7264 has been administered to 360 study subjects in 12 completed 
and 2 ongoing (clinically complete) Phase 1 clinical trials. Single oral doses, 10 to 1800 mg, 
and multiple oral doses, 7.5 mg to 1800 mg BID for up to 14 days, were administered to 
healthy subjects. The efficacy of MK-7264 has been investigated in 11 completed Phase 2 
clinical trials. Eight of these trials included subjects with chronic cough; 2 studies were 
conducted in subjects with idiopathic pulmonary fibrosis (IPF) related cough. Efficacy of 
MK-7264 was also evaluated in other indications, such as osteoarthritis pain, interstitial 
cystitis/bladder pain syndrome, and asthma. Across studies, MK-7264 was well tolerated, the 
most common AEs being dose-dependent effects on taste sensation - eg, dysgeusia, ageusia, 
hypogeusia. Subjects also described oral paresthesia (tingling sensation in the mouth and/or 
throat) and oral hypoesthesia (numbness/reduced sensitivity often limited to a specific place 
in mouth, eg, side of the tongue, lip, back of throat). The taste disturbances and oral 
paresthesia/hypoesthesia were fully and rapidly reversible after discontinuation of the drug.
Pharmacokinetics of MK-7264 has been evaluated in a wide dose range from 7.5 mg to 1800 
mg. MK-7264 is rapidly absorbed, with a median Tmax of 1.0 to 2.0 hours, and has a half-life 
of approximately 7 to 10 hours. The exposure to MK-7264 increases in proportion to the dose 
until 450 mg and it increase in a less than dose proportional manner beyond it. Steady state 
appears to be achieved within 2 to 3 days of BID dosing, with accumulation ratio of 
approximately 1.2- to 1.4 fold in the clinical dose range. However, with once daily 
administration the accumulation is expected to be minimal. Elimination of MK-7264 occurs 
primarily via renal excretion of intact MK-7264 as approximately 64% of the MK-7264 dose 
was recovered as parent drug in urine. Metabolism is a relatively minor pathway of 
elimination, with approximately 15% of an oral dose appearing in urine and feces as 
metabolites in healthy adult male subjects. The exposure of MK-7264 is inversely related to 
renal function. Based on linear regression analyses between eGFR and PK parameters, AUC 
was predicted to be 2.74 and 3.68 times higher and Cmax 1.70 and 1.99 times higher in 
subjects with moderate and severe impairment, respectively, compared with healthy subjects 
with normal renal function.
No studies have been conducted so far to support the OSA indication.
 
 
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2.5
Ongoing Clinical Studies
Approximately 2300 participants are to be enrolled in the ongoing MK-7264 clinical trials: 2 
Phase 1 studies (clinically complete), 3 Phase 2 studies (1 clinically complete), and 3 Phase 3 
studies. 
Two ongoing Phase 1 studies are being conducted to evaluate the safety, tolerability, and PK 
of MK-7264 in 46 healthy adult male Japanese subjects, and to characterize the PK
performance of different formulations of MK-7264, respectively.
Three Phase 2 studies are currently ongoing; one is evaluating the efficacy of MK-7264 in 
the treatment of endometriosis related pain (ERP); one is evaluating the efficacy, safety and 
tolerability of MK-7264 on acute cough in participants with induced viral upper respiratory 
tract infection, and the last one is evaluating the efficacy and safety of MK-7264 in adult 
Japanese participants with unexplained or refractory chronic cough. 
There are three on-going Phase 3 studies of MK-7264. Two ongoing Phase 3 studies, in 
which oral doses of 15 and 45 mg BID for 52 weeks are administered to over 2000 
participants with chronic cough, are being conducted to evaluate the efficacy of MK-7264 in 
patients with chronic cough. A third on-going Phase 3 study (in Japan only) is being 
conducted to evaluate the long-term safety of MK-7264.
For more information, please refer to the MK-7264 Investigator’s Brochure.
2.6
Benefit/Risk Assessment
This study is the first to test the potential efficacy of MK-7264 in treating participants with 
moderate and severe OSA and will provide critical insights into the benefits and risks of 
MK-7264 compared to placebo. The benefits for participants with OSA from treatment with 
MK-7264 are unknown. The risk of OSA participants taking MK-7264 is also unknown.
However, it is not anticipated that new safety signals will emerge in this population. Additional 
details regarding specific benefits and risks for participants 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.
Male/Female participants with moderate to severe obstructive sleep apnea between the ages 
of 18 and 75 years (inclusive) will be enrolled in this study.
 
 
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Objectives
Endpoints
Primary
•
Primary Objective:
•
To evaluate the effect of multiple dose 
administration of MK-7264 on the Apnea 
Hypopnea Index (AHI) in participants 
with moderate to severe OSA without 
Positive Airway Pressure (PAP).
•
Primary Hypothesis: 
•
Multiple dose administration of MK-7264 in 
participants with moderate to severe OSA 
reduces the AHI relative to placebo. A 30% 
reduction in AHI as compared to placebo is 
expected.
•
Apnea-Hypopnea Index (AHI)
change from baseline compared with 
placebo as calculated from 
polysomnography (PSG)
Secondary
•
To evaluate the safety and tolerability of MK-
7264 in participants with moderate to severe 
OSA.
•
Adverse events, safety laboratory 
assessments, ECGs and vital signs.
Exploratory
•
To evaluate the pharmacokinetics of 
MK-7264 QHS in participants with moderate 
to severe OSA.
•
MK-7264 (plasma PK): Cmax, 
AUC0-24, CL and t1/2
•
To evaluate arousal index following multiple 
dose administration of MK-7264 in 
participants with moderate to severe OSA.
•
Arousal Index
•
To evaluate the proportion of stage N1 non-
REM sleep to TST following multiple dose 
administration of MK-7264 in participants 
with moderate to severe OSA.
•
Duration of stage N1 non-REM 
sleep to TST
•
To estimate mean SaO2 during total sleep 
time (TST), NREM, REM, and awake time 
following the administration of multiple doses 
of MK-7264 in participants with moderate to 
severe OSA. 
•
Mean SaO2 during TST, NREM, 
REM and awake time
 
 
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Objectives
Endpoints
•
To evaluate the proportion of the night during 
TST and sleep stages in which SaO2 is less 
than 90% following multiple dose 
administration of MK-7264 in participants 
with moderate to severe OSA 
•
Proportion of the night during TST 
and sleep stages in which SaO2 is 
less than 90%
•
To evaluate loop gain following multiple dose 
administration of MK-7264 in participants 
with moderate to severe OSA.
•
Loop gain
•
To evaluate morning systolic and diastolic 
blood pressure following multiple dose 
administration of MK-7264 in participants 
with moderate to severe OSA.
•
Morning systolic and diastolic blood 
pressure
•
To evaluate daytime sleepiness following 
multiple dose administration of MK-7264 in 
participants with moderate to severe OSA.
•
Morning Sleep Questionnaire 
•
Epworth Sleepiness Scale (ESS)
score (0-24), units on a scale. 
•
Functional Outcomes of Sleep 
Questionnaire (5-20).
•
To evaluate the performance of the Emerald 
Device to capture sleep data 
•
Emerald Device sleep data 
•
To evaluate blood and urine biomarkers
•
Exploratory biomarkers
•
To explore the relationship between genetic 
variation and response to the treatment(s) 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in this study
•
Germline genetic variation
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, crossover, double-blind multi-site study of MK-
7264 in participants with OSA.
The majority of study assessments and procedures for each participant will be conducted 
during the 6 overnight clinic visits. Eligible participants from Screening 1 will be asked to 
arrive at the clinic on Day -22 for Screening 2. The participants will have a PSG recording 
during Screening 2 where their diagnosis of OSA is confirmed. 
The participants with confirmed OSA from Screening 2 will be asked to return to the clinic 
on Day -15 for Screening 3. During Screening 3, the participants will undergo a second PSG
with supplemental inspired oxygen to assess whether their sleep apnea is “chemoreflex 
dependent”. While asleep during the PSG, supplemental oxygen will be delivered via face 
mask (40% inspired oxygen) as an addition to the standard sleep study [Narkiewicz, K., et al 
2016] [Sands, S. A., et al 2018]. In some participants the addition of supplemental oxygen 
will decrease carotid body hyperreflexia thereby lowering loop gain and leading to reduced
AHI in those with “chemoreflex dependent” OSA. The number of AHI episodes, as verified 
by a central reader will be determined. If the participant has a > 30 percent decrease in AHI 
events as well as airflow-based hypopnea events (>30% reduction in airflow) that do not 
meet normal criteria (3% desaturation or arousal) compared to Screening 2 (see Operations 
Manual for details), he/she will be eligible to be randomized into the study and may return to 
the clinic on Day -1 for Period 1 of the study.
During Periods 1 and 2 participants will have a baseline PSG and will receive study 
intervention for at-home dosing. Participants will begin self-administering study drug at-
home (in the evening) for 6-days. Participants will return to the clinic on Day 7 for the last 
day study drug administration and an assessment PSG. Study drug will be discontinued for a 
7-day washout at home before the second period.
Following completion of Period 2, participants will return to the clinic 14 days following the 
last study drug administration for a follow-up visit.
Because this is a Phase 1 assessment of MK-7264 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.
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.
 
 
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4.2
Scientific Rationale for Study Design
This study is designed to test the efficacy and safety of MK-7264 in participants with 
chemoreflex-dependent (i.e. responsive to hyperoxia) OSA. These participants are 
specifically predicted to respond to MK-7264 based on the shared underlying biological 
pathways of the hyperoxia and MK-7264 interventions. To select for this population, 
screening PSG studies will be performed to confirm that each participant has OSA 
(Screening 2) and that the OSA is responsive to hyperoxia (Screening 3) prior to 
randomization.
A two-period crossover design was selected so that each participant receives both MK-7264 
and placebo in the study, thus permitting for within-subject assessment of treatment effect. A 
baseline PSG is included in each period to control for any period and/or carryover effects that 
may be present. A dosing duration of approximately 7 days in each period was selected based 
on the observation that this compound demonstrated maximal inhibition of chronic cough, 
believed to have a similar mechanism of action as OSA, after 4 days of dosing (See 
Investigator’s Brochure). 
A single high MK-7264 dose (discussed in Section 4.3) was selected to test the P2X3 
mechanism in OSA. 
Rationale for Amendment 039-01: The original protocol, 039-00, included a lower dose of 
MK-7264 of 45 mg to further assess dose-response. However, the 180 mg dose proposed was 
deemed sufficient to assess the objectives of the study. With the removal of the low dose, the 
study design was altered to a 2 period cross over study with decreased number of PSGs as 
well as other study related activities which improves the operational feasibility.
Rationale for Amendment 039-02: Following publication of Protocol 039-01, new data on in 
vitro testing of transporter inhibition by MK-7264 became available. These data are 
described in Section 2.3 and indicate the potential for inhibition of OATP1B1/3, MATE1/2K 
and OCT1 at the 180 mg dose level of MK-7264. Based on this information, pitavastatin has 
been added to the list of prohibited medications.
MK-7264 is a weak inhibitor of OATP1B1/3 and corresponding increases in OATP1B1/3 
substrates are predicted to be modest. Pitavastatin is excluded as a concomitant medication 
from the protocol as its elimination is believed to be primarily dependent on OATP1B1/3. 
Other statins are permitted without dose adjustment based upon the presence of alternate 
elimination pathways (including OAT3 for rosuvastatin and pravastatin, CYP3A for 
simvastatin and atorvastatin, etc.).
Potent MATE1/2K inhibitors result in less than three-fold increases in exposures of the 
substrate metformin. As MK-7264 is a weak inhibitor in vitro, any effect of MK-7264 would 
be predicted to be significantly less (below two-fold), and therefore there are no exclusions 
or dose adjustments of MATE1/2K substrates. Potent inhibition of OCT1 has been reported 
to reduce metformin efficacy without increases in metformin exposure. MK-7264 is a weak 
inhibitor of OCT1 in vitro and any potential effect would be anticipated to be minimal and 
not clinically significant in this study.  
 
 
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy and Safety Endpoints
One goal of the clinical development program for MK-7264 is to demonstrate its efficacy in 
the treatment of OSA. The primary efficacy endpoint is the change from baseline in AHI. For 
this PoC study, the primary efficacy endpoint addresses a quantitative measurement of 
improved sleep that is calculated from data obtained from the PSG studies. This endpoint has 
been published as the primary endpoint in many trials in clinical development programs for 
OSA [Wellman, A., et al 2008] [Edwards, B. A., et al 2014] [Younes, M. 2014] [Paton, J. F. 
R., et al 2013] [Edwards, B. A., et al 2012] [Sands, S. A., et al 2018].
The secondary objective is to evaluate the safety and tolerability of MK-7264 in participants 
with moderate to severe OSA. This is the first-time patients with known OSA are being 
dosed with MK-7264. These patients can have multiple co-morbidities as well as medications 
that may influence the safety of MK-7264. Therefore, adverse events, safety laboratory 
assessments, ECGs and vital signs will be captured (see Section 8 for details). 
The first exploratory objective will evaluate the pharmacokinetics of MK-7264 QHS in 
participants with moderate to severe OSA. Due to the extensive experience with dosing 
MK-7264 in healthy volunteers and trial participants a well-established PK model is 
available.  PK measurement in this study will help to develop PK/PD relationships for
various efficacy and safety endpoints.     
The second exploratory endpoint is to evaluate the frequency of nighttime arousals (as 
defined by the arousal index) following multiple dose administration of MK-7264 in 
participants with moderate to severe OSA without PAP. Nighttime arousals in patients with 
OSA occur as a result of profound apnea and are a reflexive response to re-initiate breathing 
[Dempsey, J. A., et al 2014]. If MK-7264 ameliorates the number and/or severity (duration 
and extent of hypoxia) of apnea events, then a decrease in nighttime arousals should occur. 
The number of nighttime arousals is associated with the overall restorative capacity of sleep 
and can correlate with daytime sleepiness, a significant quality of life measure for patients 
with OSA [Peppard, P. E., et al 2013] [Young, T., et al 2009] [Dempsey, J. A., et al 2014]. 
The third exploratory endpoint is to evaluate the proportion of stage N1 non-REM sleep 
following multiple dose administration of MK-7264 in participants with moderate to severe 
OSA without PAP. In participants with OSA, apneas are more common and severe during 
Stage N1 non-REM sleep [Sands, S. A., et al 2018]. Defining the proportion of TST a
participant is in stage N1 non-REM and the number/severity of AHI events will be important 
to assess the efficacy of MK-7264 in treating OSA.
The fourth exploratory endpoint is to estimate mean oxygen saturation (SaO2) during total 
sleep time (TST), NREM, REM, and awake time following the administration of multiple 
doses of MK-7264 in participants with moderate to severe OSA. SaO2 is a clinically relevant 
measurement for potential abnormal gas exchange in OSA patients. As MK-7264 is 
anticipated to normalize, not block, sympathetic tone and decrease hyperventilation due to 
 
 
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HLG, it is important to compare SaO2 during TST following administration of MK-7264 and 
placebo. 
The fifth exploratory endpoints will evaluate the effect of multiple dose administration of 
MK-7264 in participants with moderate to severe OSA on the proportion of the total sleep 
time and sleep stage in which SaO2 is less than 90%. MK-7264 should normalize carotid 
body tone and minimize hyperventilation. By normalizing carotid body tone, MK-7264 
should decrease the number of reflective apneas that occur due to hypocarbia after 
hyperventilation. Decreasing the number and/or duration of the apnea events should decrease 
the extent of hypoxia the participant experiences while treated with MK-7264. 
The sixth exploratory endpoint is to evaluate loop gain following multiple dose 
administration of MK-7264 in participants with moderate to severe OSA without PAP. Loop 
gain will be calculated from PSG data, and it reflects carotid body tone.
The seventh exploratory endpoint is to evaluate morning systolic and diastolic blood pressure 
following multiple dose administration of MK-7264 in participants with moderate to severe 
OSA without PAP. As sympathetic overdrive can contribute to hypertension, MK-7264 
treatment could have an added benefit of normalizing blood pressure. 
The eighth exploratory endpoint is to evaluate daytime sleepiness following multiple dose 
administration of MK-7264 in participants with moderate to severe OSA without PAP. 
Daytime sleepiness is a significant morbidity associated with OSA [Dempsey, J. A., et al 
2014]. If MK-7264 can decrease AHI and nighttime arousals, it should decrease the 
symptoms of daytime sleepiness. Changes in daytime sleepiness using the Epworth 
Sleepiness Scale (ESS), Morning Sleep Questionnaire and Functional Outcomes of Sleep 
Questionnaire (FOSQ) will be captured. 
The ninth exploratory endpoint is to evaluate sleep endpoints using data gathered by the 
Emerald Device (Section 8.2.2). These may include sleep staging, respiratory rate, AHI, and 
total sleep time.
The tenth exploratory endpoint is to evaluate blood and urine biomarkers. These may 
include, but are not limited to, renin, angiotensin II, and vanillylmandelic acid.
4.2.1.2
Pharmacokinetic Endpoints
The relationship between MK-7264 plasma concentrations/exposure and AHI /side effects 
will be explored (as described above). Exploratory population PK analyses will be conducted 
to obtain the exposure data in order to understand the exposure-response relationships 
between MK-7264 and efficacy and safety data.
4.2.1.3
Pharmacodynamic Endpoints
No pharmacodynamics biomarkers are planned for this study. 
 
 
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4.2.1.4
Planned Exploratory Biomarker Research
4.2.1.4.1
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.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
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 this future biomedical research substudy are presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
A placebo period is included in this study to maintain the study blinding, allowing for an 
unbiased assessment of efficacy and safety. It will also serve as comparator to MK-7264 for 
assessing PSG endpoints.  Participants may discontinue the study intervention at any time. 
Since there are no oral treatments for OSA available on the market, the use of a placebo is 
justified.
 
 
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4.3
Justification for Dose
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 
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 8.12.6.
The dose of MK-7264 that might have efficacy in OSA is currently unknown. To select the 
dose for treatment of sleep apnea, prior exposure–response (cough rate reduction and taste 
disturbance) experience was leveraged, keeping in mind that increasing the dose of MK-7264 
will increase the likelihood for increased incidence rate of taste disturbance, which could lead 
to participant non-acceptance, noncompliance and study drop-out. The dose selected for the 
current study was based on the assumption: i) similarity of the P2X3-related mechanism of 
action for hypersensitivity in conditions including sleep apnea and cough; ii) similar 
exposure-response between cough and sleep apnea and; iii) as well as to mitigate potential 
rightward shift of exposure-response for sleep apnea to cough (ie, potential that sleep apnea 
is less sensitive than cough reflex). In efficacy assessments of MK-7264 for cough to date, 45 
mg BID was found to have near-maximal efficacy with an acceptable taste disturbance 
profile. To assess the efficacy of MK-7264 for the treatment of sleep apnea, 180 mg qHS was 
selected which provides ~3 fold higher Cmax relative to 45 mg BID, and a modest increase 
(100%) in AUC on a 24 hour basis. The expected Cmax following 180 mg (1593 ng/mL) is 
approximately 40% of that observed following 900 mg BID in a 14 day multiple dose study 
(Cmax of 3960 ng/mL). The assumption with this qHS dose is that it provides higher 
exposure in the night time when the efficacy is most desirable and yet it maintains the 
concentrations that will be similar to 45 mg BID during the day hours. The dynamic 
concentration range with this dose relative to 45 mg BID dose is not expected to substantially 
increase the likelihood of higher taste incidence, as higher concentrations will be limited to 
only night time when the subjects are asleep.
The appropriateness of the 180 mg QHS dose is also supported by preclinical data, as the 
concentration range of 170-793 ng/mL was found to be efficacious in preclinical models for 
neuropathic, arthritic and inflammatory conditions and overlaps with the expected steady 
state concentration in humans.
This dose will additionally provide important information on taste disturbance following 
QHS dosing regimen. The taste disturbance information available thus far is with BID dosing 
regimen and will not be relevant to extrapolate for the sleep apnea indication, as the time 
course of the drug exposure will be different with the proposed QHS regimen compared to 
BID regimen. 
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 
 
 
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from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and 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.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/Female participants with moderate to severe obstructive sleep apnea between the ages 
of 18 and 75 years (inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Has an International Classification of Sleep Disorders (ICSD-3) diagnosis of Obstructive 
Sleep Apnea, based on:
i.
Investigator's assessment of the OSA history and diagnostic interview, which 
must include: Documented sleep study (i.e. nighttime diagnostic PSG in a 
sleep lab or home sleep testing (HST)) in the past that confirmed the OSA
diagnosis without significant prior medical intervention including but not 
limited to: weight loss surgery or other surgical interventions to improve 
sleep quality.
2. Has AHI ≥ 20 events/hour at Screening 2.
3. Has not used positive airway pressure device (PAP) within the preceding 1 month or a 
dental appliance within the preceding 7 days prior to Screening 2 Visit, and is not 
allowed to use PAP or a dental appliance throughout the study (including washout 
intervals between treatment periods) and until the poststudy visit.
 
 
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4. Has hyperoxia response as assessed during Screening 3 hyperoxia challenge with a 
reduction in AHI of ≥30% as well as airflow-based hypopnea events (>30% reduction in 
airflow) that do not meet normal criteria (3% desaturation or arousal) upon supplemental 
oxygen therapy.
5. Has a baseline SpO2 ≥ 94% at Screening 1 to ensure that carotid body response to 
hyperoxia is not impaired.
6. Has a Body Mass Index (BMI) ≤ 35 kg/m2 at the pre-study (Screening 1) visit.
7. Is judged to be in good health based on medical history, physical examination, vital sign 
measurements, and laboratory safety tests (see Appendix 10.2) performed at the pre-
study (Screening 1, 2 or 3) visit and/or Baseline 1. Participants with hypertension, Type 
2 diabetes, or hypothyroidism may be included if well-controlled on stable doses of 
appropriate therapy for ≥ 1 month prior to Screening Visit 2.
8. Has no clinically significant abnormality on electrocardiogram (ECG) performed at the 
pre-study (Screening 1) visit and/or prior to administration of the initial dose of study 
drug.
Demographics
9. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent.
Male Participants
10. Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
11. Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
-
Is not a woman of childbearing potential (WOCBP)
OR
 
 
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-
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long 
term and persistent basis), as described in Appendix 10.5 during the intervention 
period and for at least 1 week after the last dose of study intervention. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine as required by 
local regulations) within 72 hours before the first dose of study intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 5.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
12. Provides written informed consent/assent for the study. The participant may also provide 
consent/assent for future biomedical research. However, the participant may participate 
in the main study without participating in future biomedical research.
Additional Categories
13. Has a consistent sleep-wake schedule that is not subject to any other unusual changes in 
sleeping routine (i.e., bedtimes and wake times do not vary more than 1-2 hours except 
on rare occasions).
14.
Is able to maintain sleep for at least 4 consecutive hours based on self-report.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Other than OSA, has evidence of another clinically significant, active pulmonary disorder 
such as bronchiectasis, emphysema, or asthma documented by history, physical 
examination, or chest x-ray.
 
 
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2. Has either a history within the past 6 months prior to the prestudy visit or current 
evidence of an unstable or clinically significant cardiovascular disorder, including but not 
limited to:

Acute coronary syndrome

Unstable angina

Congestive heart failure

Cardiogenic syncope

Cardiomyopathy

Any symptomatic arrhythmia

Orthostatic hypotension

Uncontrolled hypertension

Chronic kidney disease

Kidney transplant
3. Has abnormal pre-randomization laboratory values per the guidance below or other
clinically significant, unexplained laboratory abnormality in the opinion of the 
investigator:

Alanine transaminase (SGPT or ALT) > 1.5 x the upper limit of normal 
(x ULN)

Aspartate transaminase (SGOT or AST) > 1.5 x ULN

Direct bilirubin > 1.5 x ULN

Serum Creatinine of > 2 mg/dL
See Appendix 2 for an algorithm for assessing out-of-range laboratory values.
4. Has a history or diagnosis of any of the following conditions, in the opinion of the 
investigator:

Narcolepsy (with or without cataplexy) or Idiopathic Hypersomnia

Circadian Rhythm Sleep Disorder
 
 
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
Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking 
disorder, and REM behavior disorder

Periodic Limb Movement (PLM) Disorder

Restless Legs Syndrome

Chronic Insomnia
5. Is a WOCBP who has a positive urine or serum pregnancy test within 24 hours before the 
Baseline 1 of study intervention (see Appendix 10.5). If the urine test cannot be 
confirmed as negative, a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive.
6. Has a history of clinically significant or poorly-controlled endocrine, gastrointestinal, 
cardiovascular, hematological, hepatic, 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.
7. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening 1) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder. Participants who have had situational 
depression may be enrolled in the study at the discretion of the investigator.
8. Has, in the opinion of the investigator, a history or current evidence of any condition, 
therapy, lab or ECG abnormality or other circumstances that might confound the results 
of the study, or interfere with the participant's participation for the full duration of the 
study, such that it is not in the best interest of the participant to participate. Examples of 
excluded disorders include, but are not limited to: active endocrine disorders (however, 
participants with well-controlled non-insulin-dependent diabetes, or hypothyroidism are 
allowed if on stable doses of appropriate therapy for ≥ 1 month prior to Screening 
Visit 2).
9. Has any history of a neurological disorder, including but not limited to seizure disorder 
(other than single episodes of childhood febrile seizures), stroke, transient ischemic
attack, multiple sclerosis, cognitive impairment, or significant head trauma with sustained 
loss of consciousness within the last 10 years
10. 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.
11. Has a history of anaphylaxis or cutaneous adverse drug reaction (with or without 
systemic symptoms) to sulfonamide antibiotics or other sulfonamide-containing drugs.
 
 
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12. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
13. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies that have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (e.g., malignancies that
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
14. Has an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 based on the 
Cockcroft-Gault (CG) Equation.
Cockcroft-Gault Equation: 
ClCr = (140-age[yr])(body wt [kg])
(72)(serum creat [mg/dL])
[When creatinine is measured in micromole/litre, use this formula]
ClCr = (140-age[yr])(body wt[kg])
(72)(serum creatinine [micromol/L] x 0.0113)
For females, multiple the result by 0.85.
At the discretion of the investigator a measured creatinine clearance, as determined by a 
24-hour urine collection, may be used in place of, or in conjunction with, the estimate of the 
creatinine clearance.
Participants who have a measured creatinine clearance of up to 10% below 60 mL/min may 
be enrolled in the study at the discretion of the investigator.
Prior/Concomitant Therapy
15. Is unable to refrain from or anticipates the use of certain medications, including 
prescription and nonprescription drugs or herbal remedies beginning approximately 2 
weeks (or 5 half-lives) prior to Screening 1, 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). A list of prohibited medications is
provided in the table below. The table below is not all inclusive and the participant may 
be excluded if taking other medications based on the discretion of the Sponsor or the 
Investigator.
 
 
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Table 1
Prohibited Medications and Specified Washout Period
Treatment
Interval*
Investigational compounds
4 weeks prior to Screening 1 or 5 half-
lives (see exclusion below)
Antihistamines (sedating)
2 weeks
Hypnotics (OTC as well as prescriptions)
2 weeks or 5 half-lives** prior to 
Screening 1
Other Psychotropics:
Antidepressants (other than fluoxetine)
Fluoxetine
2 weeks
4 weeks
Anticonvulsants
2 weeks
Antipsychotics
2 weeks or 5 half-lives
Anxiolytics (benzodiazepines, non-
benzodiazepines)
2 weeks or 5 half-lives
Centrally acting anticholinergics
2 weeks
Any CNS depressants
2 weeks
Mood Stabilizers
2 weeks
Stimulants
2 weeks
Supplements with possible psychotropic 
effects
2 weeks
Other Medications:
Anticoagulants
2 weeks
Systemic glucocorticoids
2 weeks
Isotretinoin
2 weeks
Diet pills
2 weeks
Pitavastatin
1 week
* Interval notes minimum washout period. Washout should occur for 5 half-lives or the minimum 
specified period (2 or 4 weeks), whichever is longer to systematically eliminate the compound.
** The indicated hypnotic/anxiolytic washout applies to intermittent use only (defined as use of < 4 
times/week). For those participants chronically using a hypnotic or anxiolytic (defined as use of ≥ 4 
times/week) a 4-week washout (or 5 half-lives, whichever is greater) must occur prior to completion of 
Screening 1. Please see Section 6.5 for more information.
Prior/Concurrent Clinical Study Experience
16. Has participated in another investigational study within 4 weeks prior to the prestudy 
(screening 1) visit. The window will be derived from the date of the last visit in the 
previous study.
Diagnostic Assessments
None
 
 
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Other Exclusions
17. Is under the age of legal consent.
18. Has a need for more than 3 toilet visits during the night.
19. Has traveled across 3 or more time zones in the last 1 week prior to study start.
Participant should not anticipate traveling across 3 or more time zones during the study.
20. 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.
21. 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.
22. Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict 
smoking to ≤10 cigarettes per day or is unwilling to follow the smoking restrictions 
defined by the CRU. Participants who smoke ≤10 cigarettes per day may be enrolled as 
long as they do not have significant lung disease related to their smoking. 
23. Has had upper airway surgery for obstructive sleep apnea.
24. Has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or 
participated in another investigational study within 4 weeks prior to the prestudy 
(Screening 1) visit. The 4 week window will be derived from the date of the last study 
procedure (i.e. poststudy, AE follow-up, etc.) in the previous study to the
prestudy/Screening 1 visit of the current study.
25. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 3 months. Participants must have a negative urine drug 
screen (UDS) prior to randomization.
26. 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.
27. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
 
 
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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Section 8.0.
On PSG Assessment Visits, participants will fast from all food and drinks except water 
between study drug administration and the next scheduled meal the following morning. 
Water will be provided during study drug administration. Water will be restricted 1 hour 
prior to and 1 hour after study drug administration only on PSG Assessment Visits.
On all visits, meals and snack(s) will be provided by the investigator at time points indicated 
in the study flow chart. Participants will fast from all food and drinks except water between 
meals and snacks. At all other times and while at home, meals and snacks will be unrestricted 
in caloric content, composition and timing.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants can consume caffeinated beverages or xanthine-containing products at their
normal daily amount but not to exceed more than 6 units per day amounts (1 unit = 120 mg 
of caffeine). Participants should avoid drinking caffeinated beverages 4 hours before their 
anticipated bedtime at home. Caffeinated beverages will not be served to participants at the 
clinic prior to sleep study. Participants should not drink any caffeinated beverages up to 10
hours prior to their scheduled in-clinic sleep study. 
5.3.2.2
Alcohol Restrictions
Alcohol consumption is limited to no more than approximately 3 alcoholic beverages or 
equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 
ounces], or distilled spirits [29.5 mL/1 ounce]) per day. Participants should avoid drinking 
alcoholic beverages 4 hours before their anticipated bedtime at home. Alcoholic beverages 
will not be served to participants at the clinic. Participants should not drink any alcoholic 
beverages on the day of their scheduled in-clinic sleep study.
5.3.3
Tobacco Restrictions
Smoking should be limited to ≤ 10 cigarettes per day and follow the smoking restrictions 
defined by the CRU while on site.
 
 
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5.3.4
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc.) from the prestudy (Screening 1) visit until administration of the initial dose of 
study drug, throughout the study (including washout intervals between treatment periods) and 
until the poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information 
may be included, as outlined in the 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 prior to 
completion of Period 2 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 period/dose, 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 MK-7264 and placebo 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.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
 
 
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra
-tion
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Placebo
Other
Placebo 
Matching 
MK-7264
Other
Tablet
0 mg
4 tablets 
QHS
Oral
Period 1, or 2
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
MK-7264
Experi
mental
MK-7264
Drug
Tablet
45 mg
4 tablets 
QHS
Oral
Period 1, or 2
Experimental
IMP
Provided 
centrally 
by the 
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending 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
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly to one of two treatment sequences according to a 
computer-generated allocation schedule.
The sample allocation schedules are shown below in Table 3:
Table 3
Sample Allocation Schedule
Subjects
Period 1
Period 2
N=8
Pbo
MK-7264
N=8
MK-7264
Pbo
a The suggested doses may be adjusted downward based 
on evaluation of safety, tolerability, and/or 
pharmacodynamics data.
Note: Subjects who drop out will be replaced.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-7264 and placebo will 
be packaged identically so that blind is maintained. If applicable for certain site(s), 
MK-7264 and placebo will be packaged as open label bulk supplies and will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified study site 
personnel. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the intervention assignments.
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
If a participant does not discontinue all prohibited medications in Table 1, he/she may be 
included in the study if the investigator can rationalize that the specific use of a prior 
medication is either medically required or not clinically relevant within the context of the 
study.
 
 
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Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
during the ongoing study (ie, after randomization or intervention allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult. The participant will be allowed to continue in the study if both the 
Sponsor and the investigator agree. The subject may be asked to repeat a period or skip a 
period due to any medical issues or concomitant medication use.
Paracetamol/acetaminophen or low dose non-steroidal anti-inflammatory drugs 
(ibuprofen/naproxen) may be used for minor ailments without prior consultation with the 
Sponsor.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
Not Applicable 
6.6.1
Stopping Rules
The following stopping rules will be employed during the conduct of this study.
If the below stopping rule is 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 investigators), 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.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity. The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
 
 
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period/vaccination regimen will still continue to participate in the study as specified in
Section 1.3 and Section 8.1.9, or if available, a protocol clarification letter.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9 and 8.12.3.
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.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant interrupts study intervention administration for more than 2 consecutive 
days or has 4 cumulative missed doses.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention (including recommendation to discontinue 
participant from study treatment as part of monitoring for crystalluria/urolithiasis, see 
Section 8.4.6–Renal and Urological Safety Procedures).
•
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.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
 
 
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
 
 
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 235 mL (Appendix 10.8).
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 
 
 
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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 the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
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 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 14 days before starting the study (Screening Visit 1). 
 
 
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment 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 intervention will occur at home and in-clinic as described in Section 
1.3 Schedule of Activities. 
The distribution of study intervention will be witnessed by the investigator and/or qualified 
designee at the study visits. Participants will receive one bottle of study intervention at each 
baseline visit. Each bottle will contain MK-7264 45 mg or placebo matched to 45 mg MK-
7264. Participants will be instructed on how to administer study intervention by the site staff.
Participants will be provided with study intervention at the beginning of each period and will 
receive enough study intervention to last between study site visits. Study intervention should 
begin on the day following the baseline visit in each period. Participants will be contacted by 
the site and instructed to self-administer study intervention in the evening approximately one
and a half hours before bedtime. Subsequent doses should occur at approximately the same 
time each evening. Participants will record time of dosing in a drug diary.
Participants will return to clinic at the end of each period for the assessment visit. If the visit 
assessment is delayed by 1-2 days as allowed in the Visit Window, the participant should 
continue study intervention as instructed by the site. During the assessment visit, participants 
will receive the assigned study intervention in the evening, approximately one and a half 
hour before bedtime. Administration of study intervention during in-clinic assessments will 
be witnessed by the investigator and/or study staff.
Water will be provided during study drug administration. 
 
 
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While taking the study intervention at home, participants who vomit after dosing or miss a 
dose should be instructed to continue with the next scheduled dose. However, on clinic PSG 
days, if the participant vomits within 1 hour of study drug administration, the participant 
should take an additional dose of study intervention.  
8.1.8.1
Timing of Dose Administration
Study intervention will be administered orally in the evening approximately one and a half 
hours prior to bedtime.
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. If a participant discontinues for any reason at any 
time during the course of the study, 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 8.12.4
(approximately 14 days post the last dose of study intervention for a poststudy visit) to have 
the applicable procedures conducted. However, the investigator may decide to perform the 
poststudy procedures at the time of discontinuation or as soon as possible after 
discontinuation. If the poststudy visit occurs prior to the safety follow-up time frame as 
specified in Section 8.4.1, the investigator should perform a follow-up telephone call at the 
end of the follow-up period ( Section 8.4.1) to confirm if any AEs have occurred since the 
poststudy clinic visit. Any AEs that are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
 
 
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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.
8.1.11
Domiciling
Participants will be instructed to report to the sleep center on the evening of scheduled 
baseline and assessment visits as described in Section 1.3. Participants will remain in the 
clinic overnight and will be discharged upon completion of assessments as described in 
Section 1.3. 
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
 
 
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8.2
Efficacy Assessments
8.2.1
Polysomnography
PSG is a diagnostic sleep study that collects EEG, EOG, EMG, ECG, airflow, respiratory 
effort, oximetry, and sleep position. The PSG will be used to assess entry into the study and 
will be used as an efficacy assessment at the time points indicated in the SoA. The details of 
the PSG procedure including participant preparation and lead placement will be described in 
the study operations manual.
Sleep parameters including, but not limited to, total sleep time (TST), Sleep Latency (SL), 
Stage of Sleep (i.e. REM, non-REM), Arousal Index (AI), oxygen saturation (SaO2), Apnea-
Hypopnea Index (AHI), and others will be calculated by a central reader as described in the 
study operations manual. 
The time of bedtime in the lab should approximate the participant’s bedtime at home (median 
habitual bedtime), where "bedtime" is defined as the time when the participant
intends/attempts to fall asleep, e.g., lying down or reclining with eyes closed. The median 
bedtime reported by the participant at Screening 1 (within ±1 hour) will be used as the 
bedtime ("Lights-Off") for all subsequent PSGs. During “Lights-On”, a trained study staff 
will enter the room to wake the patient (if applicable), stop the PSG recording, and turn on 
the light.   
Hyperoxia Challenge and Assessment of Loop Gain
At Screening Visit 3 the PSG described above will be augmented using continuous 
supplemental inspired oxygen. The hyperoxia challenge is the addition of inhaled 40% 
oxygen delivered through a face mask. The AHI will be scored as described above and 
compared to the number of AHI events as well as airflow-based hypopnea events (>30% 
reduction in airflow) that do not meet normal criteria (3% desaturation or arousal) (see 
Operations Manual for details) recorded at Screening Visit 2. If the AHI and/or airflow-based 
hypopnea events decreases by 30% between the two screening visits the participant will have 
a confirmed hyperoxia response. 
8.2.2
Emerald Device Sleep Data Capture
For US sites with IRB approval (ex-US site(s) excluded) the Emerald device will be included 
during standard PSG for sleep data capture at screening, baseline, and assessment visits as 
described in the SoA. This device uses passive monitoring of radio wireless local area 
network (Wi-Fi) signals in combination with machine learning algorithms to determine
respiratory signal, sleep stages, and periods of apnea. The concordance between Emerald-
derived endpoints and PSG measures will be explored. The details of the Emerald device 
procedure will be described in the Study Operations Manual.
 
 
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8.2.3
Morning Sleep Questionnaire (MSQ)
In each treatment period participants will be required to complete a morning sleep 
questionnaire to record items related to the previous night’s sleep. The MSQ should be 
completed in the morning, within 15 minutes of rise time or as instructed by the site. 
Exact clock time must be recorded on the MSQ (hour and minute). The participants will be 
asked to complete the morning sleep questionnaire as indicated in the SoA. 
Participants will bring the completed questionnaires to clinic at assessment visits and the 
contents will be reviewed. Any participant who demonstrates non-compliance in completing 
the diary in Period 1 should receive additional diary training with emphasis on the 
importance of completing the diary each morning.
8.2.4
Epworth Sleepiness Scale (ESS)
The ESS is a self-administered questionnaire designed to measure sleep propensity in a
subjective but standardized way. The ESS consists of 8 questions that take approximately 5 
minutes to answer. Participants will be asked to rate, on a 4-point scale (0-3), their chances of 
dozing off or falling asleep while engaged in eight different situations that involve low levels 
of stimulation. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The 
higher the ESS score, the higher that person’s average sleep propensity in daily life (ASP). 
The participants will be asked to complete the ESS as indicated in the SoA.
8.2.5
Functional Outcomes of Sleep Questionnaire (FOSQ)
The FOSQ is a 30 item self-administered questionnaire which determines functional status in 
adults; measures are designed to assess the impact of disorders of excessive sleepiness on 
multiple activities of everyday living and the extent to which these abilities are improved by 
effective treatment [Weaver, T. E., et al 1997]. The participants will be asked to complete the 
FOSQ as indicated in the SoA.
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.
8.4
Physical Examinations
8.4.1
Complete Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. At a minimum, the 
 
 
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examination will include assessments of the following: general appearance; skin and 
lymphatic; eyes, ears, nose, throat; cardiovascular system; respiratory system; 
abdomen/gastrointestinal system; urological system; musculoskeletal and neurological 
systems. Other body systems may be examined. Height (cm) and weight (kg) will also be 
measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.4.2
Focused Physical Examinations
A brief focused physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) as per institutional standard. At a 
minimum, the examination will include assessments of the following: cardiovascular system, 
respiratory system, abdomen/gastrointestinal system, and extremities. Other body systems 
may be examined.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
A brief focused physical exam may be performed at any study site visit that does not already 
include a physical exam if deemed necessary by the investigator due to signs/symptoms. A 
physical exam (complete or focused) can be performed at any unscheduled visit if deemed 
necessary by the investigator.
8.4.3
Calculate Body Mass Index
BMI will be calculated (weight/height2 in kg/m2) by the investigator or qualified designee 
based on participant’s height and weight at Screening Visit 1 to ensure the participant meets 
study Inclusion Criteria (see Section 5.1).   
8.4.4
Vital Signs
Vital signs will be measured in a sitting position after approximately 5 minutes rest and will 
include oral or tympanic temperature (in centigrade), systolic and diastolic blood pressure 
(mm Hg), respiratory rate, and heart rate (beats per minute). Vital signs should be performed 
prior to any blood draws at the same timepoint. All blood pressure measurements during the 
study should be performed on the same arm, preferably by the same person.
Any clinically significant abnormalities in vital signs noted after Screening Visit 1 will be 
recorded as AEs in the eCRF.
8.4.5
Electrocardiograms
For screening purposes, a single 12-lead electrocardiogram (ECG) will be obtained using 
local standard procedures and reviewed by an investigator or medically qualified designee 
(consistent with local requirements) as outlined in the SoA.
 
 
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8.4.6
Renal and Urological Safety Procedures
Urinalysis (including microscopy) will be collected as outlined in the SoA. Participants who 
have either crystals or unexplained hematuria will be further evaluated. The decision 
regarding continuing treatment with MK-7264 and/or continued participation in the study 
will be made on a case-by-case basis in consultation with the Sponsor.
8.4.7
Pregnancy Testing
Urine or serum pregnancy testing will be performed at the investigator site as indicated in the 
SoA. 
8.4.8
Exploratory Blood and Urine Clinical Biomarkers
Exploratory blood and urine for biomarkers will be collected as indicated in the SoA.
8.5
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 local laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
 
 
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8.6
Other Assessments
8.6.1
Study Intervention Diary
In each treatment period participants will be required to complete a diary to record at-home 
administration of study intervention. The diary should be completed after each evening dose 
of study drug. The exact clock time of each dosing must be recorded on the diary. 
Participants will bring the diary to clinic at assessment visits and the contents will be
reviewed. Any participant who demonstrates non-compliance in completing the diary in 
Period 1 should receive additional diary training with emphasis on the importance of 
completing the diary each evening.
8.7
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 10.3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators 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.
8.7.1
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.
 
 
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Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
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
 
 
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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:
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
Not required
Within 5 
calendar
days of 
learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication
Report all
Not required
Within 24 
hours of 
learning of 
event
8.7.2
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.
8.7.3
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 10.3.
 
 
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8.7.4
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.
8.7.5
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.
8.7.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not Applicable
8.7.7
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: 
1. An overdose of Sponsor's product, as defined in Section 8.8, that is not associated with 
clinical symptoms or abnormal laboratory results.
 
 
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2. 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.
8.8
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.
8.9
Pharmacokinetics
8.9.1
Blood Collection for Plasma MK-7264
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the study operations manual.     
8.10
Planned Genetic Analysis Sample Collection
This 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 subject signs the FBR consent. If the 
planned genetic analysis is not approved, but FBR is approved and consent is given, this 
sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
 
 
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8.11
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
•
Leftover main study urine from clinical biomarkers assay 
•
Leftover main study serum from clinical biomarkers assay 
•
Leftover main study plasma from clinical biomarkers assay
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Approximately 5 weeks prior to intervention randomization, potential participants will be 
evaluated over multiple screening visits to determine that they fulfill the entry requirements 
as set forth in Section 5.
Screening Visit 1 will assess medical history, vital signs, concomitant medications, ECG, and 
laboratory safety tests as described in Section 1.3
During Screening Visit 2 participants will undergo a PSG to confirm diagnosis of moderate 
to severe sleep apnea. Participants must demonstrate AHI ≥ 20 events/hour to continue in the 
study. 
During Screening Visit 3 participants will undergo a PSG with hyperoxia challenge to 
confirm presence of loop gain. Participants demonstrating a 30% reduction in AHI during 
hyperoxia challenge will be randomized into the study.  
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. 
8.12.2
Treatment Period
The trial will consist of three treatment periods. 
During Periods 1 and 2, participants will have a baseline PSG and will receive study 
intervention for at-home dosing. Participants will begin self-administering study drug at-
home (in the evening) for 6-days. Participants will return to the clinic on Day 7 for the last 
day study drug administration and an assessment PSG. Study drug will be discontinued for a 
7-day washout at home before the next period.
 
 
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Following completion of Period 2, participants will return to the clinic 14 days following the 
last study drug administration for a follow-up visit.
8.12.3
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, 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.
8.12.4
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.
8.12.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the PSG is the critical procedure.
At any postdose time point, the PSG needs to be started as close to the exact start time
relative to dosing as possible. All other procedures should be performed 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.
•
PSG Lights-Off Time for Baseline and Assessment Visits (+/- 1 hour)
•
Predose PK Collection: - 60 minutes from scheduled time within PSG day
•
Postdose PK Collection: + 60 minutes from scheduled time within PSG day
•
Laboratory Safety Tests: +120 minutes from scheduled time within PSG day
•
Predose Vital Signs: - 60 minutes from scheduled time within PSG day
•
Postdose Vital Signs: +120 minutes from scheduled time within PSG day
 
 
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8.12.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-7264 in sleep apnea participants, 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.
•
Entire period(s) may be omitted or repeated
•
Decrease in the duration of study intervention administration (eg, number of days)
•
Lengthening of the wash-out period between doses
•
Addition of trial pause to assess efficacy and/or safety
•
Instructions to take study intervention with or without food or drink may be modified 
based on newly available data
•
Modification of the sample processing and shipping details based on newly available data
•
Modification or removal of the Emerald Sleep Capture Device 
•
Modification, removal, or decision not to analyze the clinical biomarkers 
•
Maximum Body Mass Index (BMI) for inclusion criteria may be reduced
If necessary, a participant must be discontinued for the reasons described in Section 7.
If it is determined that incomplete or aberrant data has been captured during the baseline 
and/or assessment PSG at any post-randomization study visit, the participant may be asked to 
repeat the baseline and/or assessment PSG or the entire treatment period. 
The window between screening visits, the window between Screening Visit 3 and baseline, 
and the wash-out between Period 1 and Period 2 may be increased for individual participants
by mutual agreement of the Sponsor and investigator.
The evaluation to determine whether the PSG or treatment period is to be repeated will be 
done on an individual participant basis, and the decision will be reached by mutual 
agreement of the Sponsor and investigator. Up to 2 PSGs or 1 treatment period per 
participant may be repeated. Repeating treatment periods may result in an increase of the 
 
 
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participant’s cumulative exposure and/or may increase the total blood volume by 74 mL per 
repeated period and 37 mL per repeated PSG. The resulting exposure or blood volume 
increases will be deemed acceptable by the Sponsor and investigator for that participant. The 
total blood volume should remain <500 mL. If there are >2 failed PSGs or >1 failed 
treatment period for a certain participant, the participant may be discontinued from the study 
intervention and replaced.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
The analysis for the primary endpoint will be on the natural log scale of the AHI data. 
Natural log-transformed fold change from baseline values for AHI will be analyzed using a 
linear mixed effects model. The dependent variable is natural log (treatment/baseline), and 
the independent variables in the model include terms for treatment, sequence, and period. In 
addition, the between-treatment difference in baseline AHIs (Xdiff_AB = ln(baseline of MK-
7264/baseline of Placebo)) will be used as a covariate in the model, along with a treatment by 
Xdiff_AB interaction; the latter term allows for the fact that the correlation between change 
from baseline and baseline may differ by treatment. An unstructured covariance matrix will 
be used to allow for unequal treatment variances and to model the correlation between 
treatment measurements within each subject via the REPEATED statement in SAS PROC 
MIXED. Least square means and 95% confidence intervals will be calculated for each 
treatment. These least square means and 95% CIs will be exponentiated to obtain the 
geometric mean fold change from baseline for each treatment. The least square mean 
treatment differences (MK-7264 - Placebo) and corresponding 90% CIs in natural log 
transformed change from baseline will be calculated from the model. The treatment 
differences and CIs will be exponentiated to obtain the geometric mean treatment fold 
differences (MK-7264/placebo) and corresponding CIs.  If the upper limit of this 90% CI is 
less than 1.00, then it will be concluded that the administration of MK-7264 has statistically 
significantly lowered the AHI, thus satisfying the primary hypothesis.
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 
with the Quantitative Pharmacology and Pharmacometrics 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.
 
 
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9.3
Hypotheses/Estimation
Primary:
Hypothesis: Multiple dose administration of MK-7264 in participants with moderate to 
severe OSA reduces the AHI relative to placebo. A 30% reduction in AHI as compared to 
placebo is expected.
Secondary:
Objective: To evaluate the safety and tolerability of MK-7264 following multiple dose 
administration of MK-7264.
Exploratory Objectives:

To evaluate the pharmacokinetics of MK-7264 in participants with moderate to 
severe OSA.

To evaluate arousal index following multiple dose administration of MK-7264 in 
participants with moderate to severe OSA.

To evaluate the proportion of stage N1 non-REM sleep following multiple dose 
administration of MK-7264 in participants with moderate to severe OSA.

To estimate mean SaO2 during total sleep time (TST), NREM, REM, and awake time 
following the administration of multiple doses of MK-7264 in participants with 
moderate to severe OSA. 

To evaluate the proportion of the night during TST and sleep stages in which SaO2 is 
less than 90% following multiple dose administration of MK-7264 in participants 
with moderate to severe OSA 

To evaluate loop gain following multiple dose administration of MK-7264 in 
participants with moderate to severe OSA.

To evaluate morning systolic and diastolic blood pressure following multiple dose 
administration of MK-7264 in participants with moderate to severe OSA.

To evaluate daytime sleepiness following multiple dose administration of MK-7264 
in participants with moderate to severe OSA.

To evaluate the performance of the Emerald Device to capture sleep data

To evaluate blood and urine biomarkers
 
 
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
To explore the relationship between genetic variation and response to the treatment(s) 
administered, and mechanisms of disease. Variation across the human genome may 
be analyzed for association with clinical data collected in this study
9.4
Analysis Endpoints
Primary:
AHI, which is sum of the apnea and hypopnea indices, is the primary outcome measure. The 
apnea index for each participant will be calculated as the number of apneas divided by the 
total sleep time. The hypopnea index for each participant is calculated as the number of 
hypopneas divided by the total sleep time. The AHI will be calculated as the number of 
apneas and hypopneas divided by the total sleep time. Baseline AHI for each period are 
obtained on Day-1.  Individual AHI fold-change from baseline in each treatment period will 
be calculated as the ratio (on-treatment AHI/baseline AHI).
Secondary:
Adverse experiences and other safety measurements (e.g., vital signs, ECGs, laboratories)
Exploratory Endpoints:

MK-7264 (plasma PK): Cmax, AUC0-24, CL, and t1/2

Arousal Index for TST, REM, and NREM

Mean SaO2 for TST, REM, NREM, and Awake time. Baseline mean SaO2 for each 
period is obtained on Day-1.  Individual mean SaO2 fold-change from baseline in 
each treatment period will be calculated as the ratio (on-treatment mean 
SaO2/baseline mean SaO2).

Proportion of the night during TST, REM, NREM, and Awake time in which SaO2 
<90%.

Proportion of stage N1 non-REM to TST

Loop Gain at various sleep stages

Change in Systolic and Diastolic blood pressure (BP at Lights on – BP at -1.5 hr)

ESS, Morning Sleep Questionnaire (MSQ), and FOSQ scores

Emerald Device sleep data (Not in the scope of the current analysis plan.  A separate 
statistical analysis plan will be drafted, and a separate memo will be prepared)
 
 
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9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data.  All participants
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Participants as Treated (ASaT): The All Participants as Treated Population consists of all
participants who received at least one dose of treatment.  This population will be used for 
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of participants who comply with the protocol sufficiently to ensure that these data will
be likely to exhibit the effects of treatment, according to the underlying scientific model. 
Compliance covers such considerations as exposure to treatment, availability of 
measurements and absence of important protocol deviations.  Important protocol deviations 
will be identified to the extent possible prior to unblinding by individuals responsible for data 
collection/compliance, and its analysis and interpretation.  Any participants or data values 
excluded from analysis will be identified, along with their reason for exclusion, in the CSR.  
At the end of the study, all participants who are compliant with the study procedure as 
aforementioned and have available data from at least one treatment will be included in the 
Per-Protocol dataset. This population will be used for the PK and efficacy analyses.
9.6
Statistical Methods
Primary Endpoint
The analysis for the primary endpoint AHI will be on the natural log scale.  Natural log-
transformed fold change from baseline values for AHI will be analyzed using a linear mixed 
effects model and the following step wise procedure. 
The primary hypothesis will be evaluated by first comparing 180mg MK-7264 versus 
placebo using data from all two periods.  The dependent variable is natural log 
(treatment/baseline), and the independent variables in the model include terms for treatment, 
sequence, and period. In addition, the between-treatment difference in log-baseline AHIs 
(Xdiff_AB = ln(baseline of MK-7264/baseline of Placebo)) will be used as a covariate in the 
model, along with a treatment by Xdiff_AB interaction; the latter term allows for the fact that 
the correlation between change from baseline and baseline may differ by treatment. An 
unstructured covariance matrix will be used to allow for unequal treatment variances and to 
model the correlation between treatment measurements within each subject via the 
REPEATED statement in SAS PROC MIXED. If the model fails to converge a simpler 
covariance structure, Type=CS, will be used. Kenward and Roger's method will be used to 
calculate the denominator degrees of freedom for the fixed effects (DDFM=KR).  Least 
square means and 95% confidence intervals will be calculated for MK-7264 and placebo. 
These least squares means and 95% CIs will be exponentiated to obtain the geometric mean 
fold change from baseline for each treatment.  The least squares mean treatment difference 
(MK-7264 - Placebo) and corresponding 90% CI in natural log transformed change from 
baseline will be calculated from the model. The treatment difference and CI will be 
 
 
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exponentiated to obtain the geometric mean treatment fold difference (MK-7264/placebo) 
and corresponding CI.  If the upper limit of this 90% CI is less than 1.00, then it will be 
concluded that the administration of 180 mg MK-7264 has statistically significantly lowered 
the AHI, thus satisfying the primary hypothesis. This CI will be examined for the 
containment of 0.70 which translates into a 30% reduction in AHI with treatment. 
PROC MIXED DATA=all;
CLASS seq prd trt subjid;
MODEL log(value/base) =seq trt prd xdiff_AB xdiff_AB*trt/ ddfm=kr; 
  REPEATED trt/SUBJECT= subjid(seq) TYPE=UN;
LSMEANS trt/AT xdiff_AB=0 DIFF CL ALPHA=0.1;
RUN;
The posterior probability that the true mean percent reduction in AHI after multiple doses of 
MK-7264 compared to placebo exceeds 10, 20, 30, 40 and 50% will also be obtained, 
assuming normality and a non-informative prior.
Secondary Endpoints
Safety and tolerability will be evaluated following multiple doses of MK-7264 administered 
to the participants with OSA by clinical assessment of adverse experiences and other safety 
measurements (vital signs, ECGs, laboratories). Summary statistics will be provided as 
appropriate.
Exploratory Endpoints
Population pharmacokinetics approach will be utilized for evaluating MK-7264 plasma PK 
parameters, Cmax, AUC0-24, CL, and t1/2. The population PK results will be presented in a 
separate memo.
Mean SaO2: The analysis for the mean SaO2 will be on the natural log scale.  Natural log-
transformed fold change from baseline values for mean SaO2 will be analyzed using the 
above described model. Baseline is defined as the mean SaO2 during total sleep time on day-
1 for each period.  The mean SaO2 during REM, NREM and Awake time will be analyzed in 
a similar fashion. 
Proportion of the Night SaO2 <90%: Summary statistics will be provided for the percentage of 
participants who experience a SaO2 level less than 90% during the TST by treatment.
Summary statistics will also be provided for the proportion of the night during total sleep 
time in which SaO2 is <90% by treatment. The proportion of the night SaO2<90% during 
various sleep stages, REM, NREM, and Awake time will also be summarized.
Descriptive summary statistics will be provided for the following exploratory endpoints 
including arousal index, loop gain at various sleep stages, and proportion of stage N1 NREM 
to TST. Some of these parameters may also be analyzed in models as previously described to 
explore the effect of MK-7264 on these parameters.
 
 
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To assess the day time sleepiness and quality of life improvement, descriptive statistics will 
be provided for ESS, MSQ, and FOSQ scores. The relationship between the AHI and loop 
gain at different sleep stages and the relationship of AHI and various scores (ESS, MSQ, and 
FOSQ) will be explored graphically.  
To explore the effect of MK-7264 on diastolic (DBP) and systolic blood pressure (SBP), the 
difference (BP at Lights on – BP at -1.5 hr) will be computed on the original scale.  Summary 
statistics for this difference in the BP for both diastolic and systolic blood pressure readings 
will be computed.
Analysis of the sleep data from Emerald device will not be a part of the current analysis plan. 
A separate statistical plan will be drafted, and the results of the analysis will be presented in a 
separate memo.
Analysis of blood and urine biomarkers and the evaluation of the relationship of genetic 
variation and response to the treatment and mechanism of disease will not be a part of current 
analysis plan.  Results of these analysis may be presented in a separate memo.
All data will be examined for departures from the assumptions of the model(s), i.e., 
heteroscedasticity, outliers, and non-independence and nonnormality of the error terms.
Suitable data transformations may be applied. Distribution-free methods may be used if a 
serious departure from the assumptions of the model(s) is observed.
Individual listings for each of the endpoints by treatment will be provided. Baseline 
summary statistics will also be provided.
9.7
Interim Analyses
No Interim analyses are planned
9.8
Multiplicity
No multiplicity adjustment procedure will be applied, as there is only one hypothesis to be 
tested
9.9
Sample Size and Power Calculations
Primary endpoint: AHI 
A study with 16 completing subjects in a 2-period crossover design has ~92% probability to 
detect (alpha=0.05, 1-sided) a statistically significant difference between treatments if the 
true underlying geometric-mean ratio, GMR (MK7264/Placebo), is 0.70 (which translates 
into a 30% reduction in AHI after treatment with MK-7264 compared to placebo). This 
estimate is based on 2000 simulated trials of size N=16 in which individual AHI values were 
generated assuming a true reduction in AHI of 30%, total variance of 0.36 (natural log scale) 
and between-measurement correlation of 0.75. These variance estimates were obtained from 
MK-4305 P036.   Fold-change from baseline was then calculated for each trial and analyzed 
 
 
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with the above-described linear mixed effects model. The power was obtained as the 
percentage of trials showing a statistically significant between-treatment difference.
Power calculations
Sample size
GMR=0.70
30% reduction
Correlation=0.75
GMR=0.70
30% reduction
Correlation=0.60
GMR=0.70
30% reduction
Correlation=0.50
N=16
92
78
71
 
 
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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 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
 
 
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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.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 5 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 5
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea Nitrogen 
(BUN)/Urea
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
Phosphorus
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose nonfasting
Calcium
Alkaline phosphatase
Routine Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte esterase] 
•
Microscopic examination 
Other Screening 
Tests
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
•
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines) if applicable
•
Urine/Serum 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)
NOTES:
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.”
 
 
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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:
1.
Results in death
2.
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.
3.
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.
4.
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.
5.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
6.
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 in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a cancer (that is not a condition of the study)
•
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.
 
 
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of causality
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
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.
 
 
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•
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
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•Progestogen- only contraceptive implantb,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.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence
•Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
•Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
•Male or female condom with or without spermicide
•Cervical cap, diaphragm, or sponge with spermicide
•A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)e
 
 
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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.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation
d.
IUS is a progestin-releasing IUD.
e.
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods.
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 and female condom should not be used together (due to risk of failure with friction).
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
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 8.11 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 the 
future biomedical research substudy
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 this substudy. 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 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 
 
 
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specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data 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
Pre-study
Treatment Periods
Post-study
Total 
Collections
mL Per 
Collection
Total 
mL/ Test
Laboratory Safety Tests
(Chemistry, Hematology, 
Urinalysis)
1
4
1
6
12.5
75
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
1
1
3.5
3.5
Blood for Planned Genetic 
Analysis
1
8.5
8.5
Blood (Plasma and Serum) 
for Clinical Biomarkers
4
4
20
80
Blood for MK-7264
6
6
3
18
Total Blood Volume per Participanta
185 mL
a
If additional pharmacokinetic/pharmacodynamic/efficacy and/or safety analysis is necessary, additional blood (up to 
50 mL) may be obtained. 
 
 
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR <40 
bpm
Junctional Rhythm with HR <40 
bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation (newly 
diagnosed and untreated)
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With Left Anterior 
Hemiblock (LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior 
Hemiblock (LPHB)
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms  + Increase of 15 ms; 
or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
Incomplete Right BBB 
(ICRBBB) (QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation 
Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 ms
QTc (F)
Male
QTc 470 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 ms
From Baseline
 
 
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale or 
P Pulmonale
Definite Evidence of P Mitrale or P 
Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH Plus 
Strain Pattern
Voltage Criteria  for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day -1; ms=milliseconds, mm=millimeter
 
 
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10.10 Appendix 10: 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:
i.
The participant may be excluded from the study;
ii.
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).
iii.
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
iv.
The abnormal test may be repeated (refer items a. and b. below for 
continuation of algorithm for repeated values).
If the repeat test value is within the normal range, the participant may enter the study.
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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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living  
AHI
Apnea-Hypopnea Index
AE
adverse event 
BDS
blood drug screen
CAC
Clinical Adjudication Committee
CNS
central nervous system 
CRF
Case Report Form 
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
eCTA
exploratory Clinical Trial Application
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEG
electroencephalogram
EMA
European Medicines Agency
EMG
electromyography
EOC
Executive Oversight Committee 
EOG
electrooculography
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board 
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MTD
maximum tolerated dose 
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
OSA
Obstructive sleep apnea
PET
positron emission tomography 
PK
pharmacokinetic
PSG
Polysomnography 
QP2
department of quantitative pharmacology and pharmacometrics
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
siDMC
Standing Internal Data Monitoring Committee
SoA
schedule of activities
 
 
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Abbreviation
Expanded Term
SUSAR
suspected unexpected serious adverse reaction
UDS
urine drug screen
WOCBP
woman/women of childbearing potential 
 
 
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11
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05349D
 
 
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