A Phase 2a, Proof of Concept, Randomized, Double-Blind, Placebo-Controlled Clinical Trial, to Evaluate the Efficacy and Safety of MK-7264 in Women With Moderate to Severe Endometriosis-Related Pain
Phase: PHASE2
Conditions: Endometriosis-related Pain
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03654326 
Document Date: 
09-May-2018
A Phase 2a, Proof of Concept, Randomized, Double-blind, Placebo-
controlled Clinical Trial, to Evaluate the Efficacy and Safety of 
MK-7264 in Women with Moderate to Severe Endometriosis-related 
Pain

PRODUCT: MK-7264 
1
PROTOCOL/AMENDMENT NO.: 034-00
MK-7264-034-00 FINAL  PROTOCOL
09-MAY-2018
Title Page
THIS PROTOCOL 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 Phase 2a, Proof of Concept, Randomized, Double-blind, Placebo-controlled 
Clinical Trial, to Evaluate the Efficacy and Safety of MK-7264 in Women with Moderate to 
Severe Endometriosis-related Pain
Protocol Number: 034-00
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
EudraCT
138646
2018-001098-26
Approval Date: 09-MAY-2018
 
 
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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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09-MAY-2018
Table of Contents
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities (SoA) ................................................................................16
2
INTRODUCTION..........................................................................................................20
2.1
Study Rationale....................................................................................................20
2.2
Background ..........................................................................................................21
2.2.1
Pharmaceutical and Therapeutic Background .............................................21
2.2.2
Information on Other Study-related Therapy ..............................................23
2.3
Benefit/Risk Assessment......................................................................................23
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................24
4
STUDY DESIGN............................................................................................................26
4.1
Overall Design ......................................................................................................26
4.2
Scientific Rationale for Study Design.................................................................27
4.2.1
Rationale for Endpoints ...............................................................................28
4.2.1.1
Efficacy Endpoints.............................................................................28
4.2.1.2
Safety Endpoints ................................................................................30
4.2.1.3
Pharmacokinetic Endpoints ...............................................................30
4.2.1.4
Pharmacodynamic Endpoints.............................................................30
4.2.1.5
Planned Exploratory Biomarker Research.........................................30
4.2.1.5.1
Planned Genetic Analysis ........................................................30
4.2.1.6
Future Biomedical Research..............................................................31
4.2.2
Rationale for the Use of Comparator/Placebo .............................................31
4.3
Justification for Dose ...........................................................................................31
4.3.1
Starting Dose for This Study........................................................................31
4.3.2
Maximum Dose/Exposure for This Study ...................................................32
4.3.3
Rationale for Dose Interval and Study Design ............................................32
4.4
Beginning and End of Study Definition .............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................33
5
STUDY POPULATION ................................................................................................33
5.1
Inclusion Criteria.................................................................................................34
5.2
Exclusion Criteria ................................................................................................36
5.3
Lifestyle Considerations ......................................................................................39
5.3.1
Caffeine, Alcohol, and Tobacco Restrictions ..............................................39
5.3.2
Activity Restrictions ....................................................................................39
5.4
Screen Failures.....................................................................................................40
 
 
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5.5
Participant Replacement Strategy......................................................................40
6
STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................40
6.1.1
Medical Devices...........................................................................................42
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................43
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Rescue Medications and Supportive Care ...................................................44
6.6
Dose Modification ................................................................................................44
6.7
Intervention After the End of the Study............................................................44
6.8
Clinical Supplies Disclosure................................................................................45
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................45
7.1
Discontinuation of Study Intervention...............................................................45
7.2
Participant Withdrawal From the Study...........................................................46
7.3
Lost to Follow-up .................................................................................................46
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................47
8.1
Administrative and General Procedures ...........................................................47
8.1.1
Informed Consent.........................................................................................47
8.1.1.1
General Informed Consent.................................................................48
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................48
8.1.2
Inclusion/Exclusion Criteria ........................................................................48
8.1.3
Participant Identification Card.....................................................................48
8.1.4
Medical History ...........................................................................................49
8.1.5
Gynecological History .................................................................................49
8.1.6
Prior and Concomitant Medications Review ...............................................49
8.1.6.1
Prior Medications...............................................................................49
8.1.6.2
Concomitant Medications ..................................................................49
8.1.7
Rescue Medication (Naproxen Sodium) Dispensing and Instructions for 
Use ...............................................................................................................50
8.1.8
Rescue Medication Accountability..............................................................50
 
 
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8.1.9
Home Pregnancy Test Dispensing ...............................................................50
8.1.10
Assignment of Screening Number...............................................................50
8.1.11
Placebo Dispensing (for Run-In Period)......................................................50
8.1.12
Assignment of Treatment/Randomization Number .....................................50
8.1.13
Study Intervention Administration ..............................................................51
8.1.13.1
Timing of Dose Administration.........................................................51
8.1.14
Discontinuation and Withdrawal .................................................................51
8.1.14.1
Withdrawal From Future Biomedical Research ................................51
8.1.15
Participant Blinding/Unblinding..................................................................52
8.1.16
Calibration of Equipment.............................................................................53
8.2
Efficacy Assessments ...........................................................................................53
8.2.1
Electronic Patient-reported Outcomes .........................................................53
8.2.1.1
eDiary Dispensing and Instructions...................................................53
8.2.1.2
Pelvic Pain Severity Numeric Rating Scale.......................................54
8.2.1.3
Vaginal Bleeding or Non-bleeding Days...........................................54
8.2.1.4
Use of Rescue Medication (Naproxen sodium) .................................54
8.2.1.5
Use of Pain Relief Medication Other than Rescue Medication .........54
8.2.1.6
Impact of Pelvic Pain.........................................................................55
8.2.1.7
Endometriosis Health Profile-5..........................................................55
8.2.1.8
Patient Global Impression of Change ................................................55
8.2.2
eDiary Compliance ......................................................................................55
8.2.3
Collect eDiary..............................................................................................56
8.3
Safety Assessments...............................................................................................56
8.3.1
Complete Physical Examinations ................................................................56
8.3.2
Focused Physical Examinations...................................................................56
8.3.3
Calculate Body Mass Index .........................................................................57
8.3.4
Gynecological Examination.........................................................................57
8.3.5
Breast Examination......................................................................................57
8.3.6
Vital Signs....................................................................................................57
8.3.7
Electrocardiograms ......................................................................................57
8.3.8
Clinical Safety Laboratory Assessments .....................................................57
8.3.8.1
Renal and Urological Safety Procedures ...........................................58
8.3.9
Pregnancy Testing........................................................................................58
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................59
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information.............................................................................59
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......61
 
 
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...61
8.4.4
Regulatory Reporting Requirements for SAE .............................................61
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................61
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs ................................................................................................62
8.4.7
Events of Clinical Interest (ECIs) ................................................................62
8.5
Treatment of Overdose........................................................................................62
8.6
Pharmacokinetics.................................................................................................63
8.6.1
Blood Collection for Plasma MK-7264 .......................................................63
8.7
Pharmacodynamics..............................................................................................63
8.8
Biomarkers ...........................................................................................................63
8.8.1
Planned Genetic Analysis Sample Collection..............................................63
8.9
Future Biomedical Research Sample Collection...............................................64
8.10
Visit Requirements...............................................................................................64
8.10.1
Screening......................................................................................................64
8.10.2
Placebo Run-In.............................................................................................64
8.10.3
Treatment Period..........................................................................................65
8.10.4
Post-Treatment Period .................................................................................65
8.10.5
Discontinued Participants Continuing to be Monitored in the Study ..........65
9
STATISTICAL ANALYSIS PLAN .............................................................................66
9.1
Statistical Analysis Plan Summary.....................................................................67
9.2
Responsibility for Analyses/In-house Blinding .................................................68
9.3
Hypotheses/Estimation ........................................................................................69
9.4
Analysis Endpoints...............................................................................................69
9.4.1
Efficacy Endpoints.......................................................................................69
9.4.2
Safety Endpoints ..........................................................................................70
9.4.3
Pharmacokinetic Endpoints .........................................................................70
9.5
Analysis Populations............................................................................................70
9.5.1
Efficacy Analysis Populations .....................................................................70
9.5.2
Safety Analysis Populations ........................................................................71
9.6
Statistical Methods...............................................................................................71
9.6.1
Statistical Methods for Efficacy Analyses ...................................................71
9.6.2
Statistical Methods for Safety Analyses ......................................................74
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses76
9.7
Interim Analyses ..................................................................................................76
9.8
Multiplicity ...........................................................................................................77
9.9
Sample Size and Power Calculations .................................................................77
9.10
Subgroup Analyses...............................................................................................78
 
 
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9.11
Compliance (Medication Adherence).................................................................79
9.12
Extent of Exposure...............................................................................................79
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .....................................................................................................80
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........80
10.1.1
Code of Conduct for Clinical Trials.............................................................80
10.1.2
Financial Disclosure.....................................................................................82
10.1.3
Data Protection.............................................................................................82
10.1.3.1
Confidentiality of Data ......................................................................82
10.1.3.2
Confidentiality of Participant Records...............................................83
10.1.3.3
Confidentiality of IRB/IEC Information............................................83
10.1.4
Committees Structure...................................................................................83
10.1.4.1
Internal Data Monitoring Committee.................................................83
10.1.5
Publication Policy........................................................................................83
10.1.6
Compliance with Study Registration and Results Posting Requirements ...84
10.1.7
Compliance with Law, Audit, and Debarmen .............................................84
10.1.8
Data Quality Assurance ...............................................................................85
10.1.9
Source Documents .......................................................................................86
10.1.10
Study and Site Closure.................................................................................86
10.2
Appendix 2: Clinical Laboratory Tests..............................................................87
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................89
10.3.1
Definition of AE ..........................................................................................89
10.3.2
Definition of SAE ........................................................................................90
10.3.3
Additional Events Reported.........................................................................91
10.3.4
Recording AE and SAE ...............................................................................91
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor94
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................96
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................97
10.5.1
Definitions....................................................................................................97
10.5.2
Contraception Requirements........................................................................97
10.5.3
Pregnancy Testing........................................................................................98
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................99
10.7
Appendix 7: Country-specific Requirements ..................................................104
10.8
Appendix 8: Abbreviations ...............................................................................105
11
REFERENCES.............................................................................................................107
 
 
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LIST OF TABLES
Table 1
Prohibited Medications and Other Substances ..........................................38
Table 2
Study Interventions ....................................................................................41
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...........................................................................60
Table 4
Statistical Methods for Efficacy Endpoints ...............................................73
Table 5
Analysis Strategy for Safety Parameters....................................................75
Table 6
Boundary Properties for Planned Interim Analysis ...................................77
Table 7
Power Calculation Based on Different Dropout Rates ..............................78
Table 8
Power Calculation for Different Assumptions of SD with 140 Evaluable 
Subjects......................................................................................................78
Table 9
Protocol-required Safety Laboratory Assessments....................................87
 
 
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................15
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2a, Proof of Concept, Randomized, Double-blind, Placebo-controlled 
Clinical Trial, to Evaluate the Efficacy and Safety of MK-7264 in Women with Moderate to 
Severe Endometriosis-related Pain
Short Title: MK-7264 Phase 2a in Women with Endometriosis-related Pain
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
In premenopausal female participants between the ages of 18 and 49 years (inclusive) with 
moderate to severe endometriosis-related pain (ERP [cyclic and non-cyclic]):
Primary Objectives
Primary Endpoints
- To evaluate the efficacy of MK-7264 versus  
placebo in reducing average daily pelvic pain 
(cyclic and non-cyclic, combined) during 
Treatment Cycle 2 (TRC2) as measured by a 
numeric rating scale (NRS) in the daily eDiary
- Hypothesis 1 (H1): MK-7264 is superior to 
placebo in reducing the average daily pelvic 
pain score (cyclic and non-cyclic, combined) 
during TRC2.
- Daily pelvic pain score 
- To evaluate the safety and tolerability of MK-
7264 
- Adverse events (AEs)
- Discontinuation of study intervention due to 
AEs
Secondary Objectives
Secondary Endpoints
- To evaluate the efficacy of MK-7264 versus 
placebo in reducing average daily cyclic pelvic 
pain during TRC2 as measured by an NRS in 
the daily eDiary
- Daily cyclic pelvic pain score 
- To evaluate the efficacy of MK-7264 versus 
placebo in reducing average daily non-cyclic 
pelvic pain during TRC2 as measured by an 
NRS in the daily eDiary
- Daily non-cyclic pelvic pain score 
 
 
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of moderate to severe ERP
Population
Premenopausal female participants with moderate to severe 
ERP between the ages of 18 and 49 years (inclusive) will be 
enrolled in this study.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Participant
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 14 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 166 participants will be randomized.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
MK-7264
MK-7264
45 mg
1 tablet bid
oral
Double-
blind 
Treatment 
Period 
(Visit 4 up 
to Visit  6)
Experimental
Placebo
Placebo
matching 
MK-7264
0 mg
1 tablet bid
oral
Double-
blind 
Treatment 
Period 
(Visit 4 up 
to Visit 6)
Placebo
Abbreviations: mg = milligrams; bid = twice a day
Total 
Number of 
Arms
2
Duration of 
Participation
Each participant will participate in the study for approximately 24 weeks from 
the time the participant signs the Informed Consent Form (ICF) through the 
final contact. After a screening phase of approximately 8 weeks, each 
participant will enter a single-blind, placebo run-in phase which consists of 
1 menstrual cycle (approximately 4 weeks). Naproxen sodium rescue 
medication will be provided to participants to use if needed starting at Visit 2.  
Upon completion of placebo run-in, eligible participants will be randomized to 
receive assigned double-blind treatment for approximately 8 weeks (ie, 
2 menstrual cycles). After the double-blind treatment period, participants will 
continue in the study for 1 additional menstrual cycle (approximately 4 weeks) 
during which they will no longer take the study intervention 
(MK-7264/placebo), but may continue to use rescue medication as needed. 
During this last post-treatment cycle, a follow-up telephone call will be 
conducted approximately 14 days after the last dose of the double-blind study 
intervention.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
The Data Monitoring Committee for this study is a Standing Internal Data Monitoring 
Committee (SiDMC). 
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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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
Placebo 
Run-in 
Treatment Period
Post Treatment
Period
Notes
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Telephone
Contact
Visit 7
DC
End of menses = end of any visible 
menstrual flow
Asterisk (*) in DC column indicates 
procedures not required if DC after V6. 
See Section 8.10.5 for procedures 
performed after DC.  
Scheduled Day
~1 week 
before 
menses
Day
after end 
of  
menses 
Begin 
SC
Day after 
SC
menses 
ends
Begin 
BC
Day after BC
menses ends
Day1/
Randomization
Day
after 
TRC1
menses 
ends
Day
after 
TRC2
menses 
ends
2 weeks after 
last dose of 
study 
intervention
Day 
after 
PTC
menses 
ends
Scheduling Window
-14 
days
+3 days
+3 days 
+3 days
+3 days
+3 days
+3 days
+3 days
Administrative 
and 
General 
Procedures
Written Informed Consent
X
Screening may occur over several days 
after consent is signed.
Informed 
Consent 
for 
Future 
Biomedical Research (FBR)
X
Participant may participate in main 
study without participating in FBR. 
Assignment of Screening Number
X
Participant Identification Card
X
At the time of randomization, site will 
add randomization number to participant 
identification card
Inclusion/Exclusion Criteria
X
X
X
X
Evaluate entry criteria at each visit, See 
Section 5.
Medical History
X
Gynecological History
X
Prior/Concomitant Medications
X
x
X
X
X
X
X
X
X
Rescue 
Medication 
(Naproxen 
sodium) Dispensing and Instructions 
for Use
X
X
X
X
X
 
 
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Study Period
Screening
Placebo 
Run-in 
Treatment Period
Post Treatment
Period
Notes
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Telephone
Contact
Visit 7
DC
End of menses = end of any visible 
menstrual flow
Asterisk (*) in DC column indicates 
procedures not required if DC after V6. 
See Section 8.10.5 for procedures 
performed after DC.  
Rescue 
Medication 
(Naproxen 
sodium) Accountability
X
X
X
X
X
X
Home Urine Pregnancy Test (UPT)
Dispensing
X
If any menstrual cycle is 2 weeks later 
than expected, participant must perform 
UPT and contact clinic to schedule visit 
as soon as possible. Sponsor must be 
consulted. Additional UPT can be 
dispensed as needed.
Treatment Randomization
X
Placebo Dispensing (For Run-In)
X
MK-7264/Placebo dispensing (For 
Double-Blind Treatment)
X
X
MK-7264/placebo accountability 
X
X
X
X*
V4: Participant must be ≥80% compliant 
with placebo run-in to be randomized.  
After randomization, see Section 6.4 for 
guidance if study intervention 
compliance is ˂80%.
Efficacy Assessments
eDiary 
Dispensing; 
eDiary 
Instructions
X
Pelvic Pain Severity NRS
Daily
If Visit 2 is ˃ 1 day after last day of the 
previous menses, will be completed by 
participant using eDiary at site during 
Visit 2 (based on previous day).
Also completed on evening of Visit 2 
(based on Visit 2 day), and every 
subsequent evening.  
Vaginal bleeding/Non-bleeding Day
Use of rescue medication (naproxen 
sodium) 
Use of pain relief medication other 
than rescue medication provided by 
the Sponsor 
Impact of Pelvic Pain
eDiary compliance
X
X
X
X
X
X
X
Participant compliance with daily eDiary 
entries must be ≥75% to be randomized. 
See Section 5.1.  No compliance checks 
needed at visits after DC. 
EHP-5
X
X
X*
 
 
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Study Period
Screening
Placebo 
Run-in 
Treatment Period
Post Treatment
Period
Notes
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Telephone
Contact
Visit 7
DC
End of menses = end of any visible 
menstrual flow
Asterisk (*) in DC column indicates 
procedures not required if DC after V6. 
See Section 8.10.5 for procedures 
performed after DC.  
PGIC 
X
X*
Collect eDiary
X
X
If participant discontinues study 
intervention and agrees to be followed, 
collection of eDiary will occur at last 
study visit.
Safety Assessments
Complete Physical Examination
X
Focused Physical Examination
X
X*
Focused physical exam: cardiovascular 
system, respiratory system, 
abdomen/gastrointestinal system, and 
extremities only.
Height 
X
Weight
X
X
X
X
X
Calculate Body Mass Index (BMI)
X
Gynecological Examination
X
Exam includes speculum insertion and 
bimanual examination.
Breast Examination
X
Vital Signs (heart rate, blood 
pressure, temperature)
X
X
X
X
X
X
X
12-Lead Electrocardiogram 
X
Hematology and Chemistry
X
X
X
X*
Urinalysis (with microscopy)
X
X
X
X*
Participants with crystals/hematuria will 
be further evaluated (Section 8.3.8.1).
Urine Pregnancy Test
X
X
X
X
X
If local regulations indicate that urine 
pregnancy testing should be performed 
more frequently, follow local regulations 
where applicable. 
Serum Pregnancy Test
X
X
X
X
X
In addition to visits specified, serum 
pregnancy test also required any time 
pregnancy is suspected or if urine 
pregnancy test is positive (unless 
pregnancy already confirmed by 
ultrasound).
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
 
 
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Study Period
Screening
Placebo 
Run-in 
Treatment Period
Post Treatment
Period
Notes
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Telephone
Contact
Visit 7
DC
End of menses = end of any visible 
menstrual flow
Asterisk (*) in DC column indicates 
procedures not required if DC after V6. 
See Section 8.10.5 for procedures 
performed after DC.  
Pharmacokinetics/Biomarkers
Pharmacokinetic Sample (blood)
X, X
X
X
X*
Sample Collection Times:
V4: pre-dose and 2 hours post-dose 
V5 and V6: Pre-dose 
DC: No specified time 
Blood for Genetic Analysis
X
If planned genetic analysis is not 
approved, but FBR is approved and 
consent is given, sample will be 
collected for the purpose of FBR. 
Collected from randomized participants 
only; see Sections 8.8 and 8.9.
SC=Screening Cycle; BC=Baseline Cycle; TRC1=Treatment Cycle 1; TRC2=Treatment Cycle 2; DC=Discontinuation; NRS=numeric rating scale; eDiary=electronic diary; EHP-5=Endometriosis 
Health Profile-5; PGIC=Patient Global Impression of Change; V=visit; FBR=future biomedical research; TC=telephone contact; V=visit; UPT=urine pregnancy test
 
 
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2
INTRODUCTION
MK-7264, a selective P2X3 receptor antagonist, is being developed for treatment of ERP. It 
is among the first clinical agents being developed to target this receptor. 
The P2X3 receptor is a ligand-gated ion channel primarily expressed on afferent sensory C-
fibers which opens in response to extracellular adenosine triphosphate (ATP) released by 
damaged, stressed, and inflamed tissues [North, R. A. 2004].
P2X3 antagonists have demonstrated benefit in preclinical pain disease models and in ERP
(rodent endometriosis/dyspareunia model) [Davenport, A., et al 2017]. MK-7264 was 
assessed for analgesic and anti-hyperalgesic activity in rodent models of inflammatory, 
arthritic, and neuropathic pain, and was found to have dose-dependent efficacy for reducing 
allodynia and hyperalgesia. MK-7264 has previously been evaluated for treatment of 
refractory chronic cough, interstitial cystitis (IC)/ bladder pain syndrome (BPS), and 
osteoarthritis (OA) pain.
Eight Phase 2 trials included chronic cough subjects. These completed studies showed that 
participants who took MK-7264 had reductions in cough frequency and improvements in 
patient-reported outcomes. The effect of MK-7264 on pain was studied in the IC/BPS and 
OA trials.  Though the primary objective of the OA study was not achieved, trends in pain 
relief and generally consistent improvements in Patient Global Impression of Change 
(PGIC), Clinical Global Impression of Change (CGIC), and the Short Form 36 (SF-36) 
health survey were demonstrated. The IC/BPS study was stopped for operational reasons 
after the second interim analysis; however, nominally significant improvements in Mean Pain 
Intensity, Mean Urgency Rating Analysis, Genitourinary Pain Index, and Quality of Life 
were demonstrated. (Refer to the Investigator’s Brochure [IB] for more information). 
Protocol 034 is a proof of concept (PoC) of MK-7264 in participants with moderate to severe 
ERP.
2.1
Study Rationale
Current medical treatments for ERP are frequently inadequate and have significant safety and 
tolerability issues that limit their use, often leading patients to surgical treatment. There is a 
compelling unmet medical need for a new, non-hormonal medical therapy for treatment of 
ERP, such as an oral P2X3 receptor antagonist, which can avoid the limitations and liabilities 
of hormonal treatment.
The purpose of this Phase 2a study is to determine the safety and efficacy of MK-7264 in 
premenopausal women who have moderate to severe ERP. Evaluation of efficacy will be 
based on average overall, cyclic and non-cyclic pelvic pain scores and use of rescue 
medication collected using a proprietary electronic Patient Reported Outcome (ePRO). The 
ePRO instrument for this study will be an electronic diary (eDiary).
 
 
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2.2
Background
Refer to the IB for detailed background information on MK-7264.
2.2.1
Pharmaceutical and Therapeutic Background
Endometriosis is an inflammatory, chronic, progressive disease defined by the presence of 
endometrial glands and stroma outside of the uterus. The condition affects 6-10% of 
reproductive age women, with worldwide prevalence estimated at approximately 176 million. 
The pathogenesis is unknown, but leading theories include retrograde menstruation, altered 
immunity, metaplasia of the germinal epithelium, and metastatic spread [Guidice, L. C. 
2010] [Fritz, M. A. 2011]. 
Approximately 80% of the population with endometriosis suffers from chronic pelvic pain;
additionally, ~20% are infertile. Endometriosis-related pelvic pain can be cyclic with menses 
(dysmenorrhea) and non-cyclic with ovulation, micturition, defecation, intercourse, etc.
Approximately 60% of the population has moderate to severe pelvic pain. Endometriosis 
affects quality of life and interpersonal relationships. It has negative psychological 
consequences; it is a significant cause of absenteeism; (ie, responsible for more than 10 hours 
of work loss per week), and results in a substantial economic burden [Guidice, L. C. 2010] 
[Fuldeore, M. J. 2017] [Parazzini, F., et al 2017].
There is no cure for endometriosis. Hormonal treatments (see below) may delay the 
progression of the disease (based on laparoscopic findings) but they provide suboptimal pain 
control. Recurrence of pain requiring additional therapy is common (~30% to 60% of cases) 
within 6 to 12 months after treatment [Guidice, L. C. 2010].
Pathophysiology
ERP is triggered by many factors, and periodic bleeding accumulation and inflammation are 
determinant contributors in pathophysiology. Periodic bleeding accumulation from monthly 
shedding of the ectopic (ie, extra-uterine) endometrium plays a critical role in the 
pathophysiology of pain, and adhesion and endometrioma formation. In addition, 
inflammation is mediated by the liberation of pro-inflammatory substances (eg, 
prostaglandins, interleukins, TNFα, ATP) to excite P2X3 receptors, among others, within the 
eutopic (ie, within the endometrium) and ectopic endometrial implants. Nerve growth factor 
is abundantly liberated in the peritoneal micro-environment, generating neuronal migration 
that produces a higher number of pain-mediating C-fibers, with abundant P2X3 nociceptors. 
The released ATP acts as a neurotransmitter on P2X3 receptors to relay messages about 
irritation and inflammation to pain centers in the central nervous system. C-fibers were found 
in higher proportion and in closer proximity to the peritoneal implant in patients with 
endometriosis with pain versus patients without pain [Tokushige, N., et al 2006]. P2X3 
receptor expression in eutopic and ectopic endometrium of patients with ERP was directly 
correlated with pain as measured by a visual analog scale [Anaf, V., et al 2002] [Morotti, M., 
et al 2014] [Ding, S., et al 2017]. Taken together, the data support that ATP and P2X3 
receptors both play a key role in neural excitability and pain in patients with ERP and 
 
 
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therefore antagonism of the P2X3 receptor by MK-7264 has the potential to address chronic 
visceral pain of endometriosis.
ERP Treatment
Scientific societies have proposed guidelines for the treatment of ERP. For empirical therapy 
(ie, before direct visualization by laparoscopy or laparotomy), combined hormonal 
contraceptives (CHCs) or progestins, plus nonsteroidal anti-inflammatory drugs (NSAIDs)
are generally recommended. Surgery provides confirmation of the diagnosis and treatment of 
macroscopic disease. In surgically confirmed endometriosis, medical therapy, which may 
follow inadequate response to surgery, includes a 6-month cycle of a gonadotropin-releasing 
hormone (GnRH) agonist which provokes a temporary menopausal state. Pain management 
may require repeated courses of medical therapy and multiple surgical treatments, potentially 
up until menopause. All hormonal therapies used to treat endometriosis suppress ovulation or 
inhibit endometrial proliferation, which prevents pregnancy, despite many patients’ chief 
complaint being related to the infertility associated with the disease [Schleedoorn, M. J., et al 
2016] [Practice Committee of the American Society for Reproductive Medc 2014] 
[Dunselman, G. A. J, et al 2014] [Leyland, N., et al 2010].
Efficacy in pain relief is comparable between different hormonal compounds and therefore, 
the choice of treatment should be based on safety with long-term use, side effect profile and 
costs [Berlanda, N., et al 2016].
CHCs have been prescribed off-label for decades to treat endometriosis. They have been 
prescribed cyclically or continuously however, better results have been demonstrated with 
the continuous (ie, without a hormone-free interval each month) prescription.
Contraindications or precautions to the use of CHCs limit their utility in patients with 
endometriosis harboring other conditions such as migraine, history of thromboembolic 
disease, liver disease, and smoking in patients >35 years of age. NSAIDs are prescribed 
despite their efficacy not being demonstrated in well-conducted, randomized clinical trials
and the safety concerns associated with chronic use [Taylor, H. S., et al 2017] [Harada, T., et 
al 2008].
Progestins and injectable GnRH agonists, the only FDA-approved medical treatments for 
endometriosis, have numerous safety and tolerability issues. Pain control with progestins is 
due to the inhibition of endometrial growth, antimitotic activity with decidualization, and 
endometrial atrophy. Progestins (eg, medroxyprogesterone acetate, norethindrone, dienogest, 
etc.) generally are not indicated for long-term use (ie, greater than 6 to 12 months) and are 
associated with breakthrough bleeding, weight gain, breast tenderness, mood changes, 
worsening of the metabolic profile (eg, hypertriglyceridemia) and bone loss [Brown, J. 
2014].
GnRH agonists (eg, leuprolide acetate), exert a potent and continuous action on the GnRH 
receptors, leading to an initial short stimulatory (flare-up) effect on the gonadotropin 
secretion, followed by a deep depression. GnRH agonists, often administered by depot 
formulation, induce a profound hypoestrogenic state, amenorrhea and endometrial atrophy,
which create tolerability issues, and safety concerns that limit treatment duration. Common 
 
 
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side effects include hot flushes, decreased libido, and vaginal dryness. Bone loss occurs at a 
rate that is greater than in natural menopause (~1% loss in bone mineral density/month). Use 
is limited to 6 months when administered alone, or 12 months when combined with ‘add-
back’ hormonal therapy to protect against bone loss [Guidice, L. C. 2010]. Opioids are 
described only as the last management option in patients with chronic pelvic pain secondary 
to endometriosis that is refractory to conventional treatment [Martinez, B., et al 2013].
In summary, current medical treatments for ERP provide similar, suboptimal pain control and 
have safety and tolerability issues that limit their use, often leading patients to surgical 
treatment. Furthermore, hormonal treatments inhibit fertility in this population of 
reproductive-age women. Thus, there is a compelling, unmet medical need for a new, non-
hormonal medical therapy for treatment of ERP.
2.2.2
Information on Other Study-related Therapy
Naproxen sodium, an NSAID which is commonly used for cyclic pain and has been used as a 
rescue medication in other studies of endometriosis [Taylor, H. S., et al 2017] will be used as 
rescue medication in this trial. The dose of naproxen will be according to the local guidance. 
See Section 6.5.1 for additional details.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
MK-7264 has been evaluated in an extensive nonclinical program. To date, there is little 
evidence from nonclinical studies that MK-7264 has any direct cellular or direct target organ 
toxicity. 
In the completed and ongoing clinical studies, no major safety concerns have been noted.
Across studies, taste-related AEs were the most frequently reported AEs. The rationale for 
taste modification exists with P2X2/3 antagonism because of the putative participation of 
ATP, acting via this receptor, in transducing taste signals from taste bud cells to gustatory 
afferent pathways. The taste-related AEs are considered mechanism-based, non-serious 
adverse drug reactions and are expected for MK-7264. To date, they have been fully and 
rapidly reversible after discontinuation of the drug.
Participants also described oral paresthesia (eg, tingling sensation in the mouth and/or 
throat). In many instances, participants reported oral paresthesia or hypoesthesia concurrent 
with taste alterations. Both the taste-related and the oral paresthesia/hypoesthesia AEs are 
considered mechanism-based, non-serious adverse drug reactions expected for MK-7264.
In pre-clinical studies, crystals of MK-7264 in urine with no evidence of urinary tract injury 
(eg, microhematuria) were only detected at a dose of 1800 mg bid over 14 days. Repeated 
measurements of post-void residual volume have not shown any evidence of urinary 
 
 
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retention related to the use of MK-7264. In clinical studies conducted to date in the dose 
range up to 900 mg bid, there has been no evidence of MK-7264 crystalluria or urolithiasis 
despite exhaustive clinical, laboratory, and radiographic (in the early clinical studies) safety 
monitoring. No MK-7264 crystals have been observed in any of the Phase 2 studies.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
In premenopausal female participants between the ages of 18 and 49 years (inclusive) with 
moderate to severe endometriosis-related pain (ERP [cyclic and non-cyclic]):
Objectives
Endpoints
Primary
•
To evaluate the efficacy of MK-7264 
versus placebo in reducing average daily 
pelvic pain (cyclic and non-cyclic, 
combined) during Treatment Cycle 2 
(TRC2) as measured by a numeric rating 
scale (NRS) in the daily eDiary
•
Hypothesis 1 (H1): MK-7264 is superior 
to placebo in reducing the average daily 
pelvic pain score (cyclic and non-cyclic, 
combined) during TRC2.
•
Daily pelvic pain score 
•
To evaluate the safety and tolerability of 
MK-7264
•
Adverse events (AEs)
•
Discontinuation of study intervention due 
to AEs
Secondary
•
To evaluate the efficacy of MK-7264 
versus placebo in reducing average daily 
cyclic pelvic pain during TRC2 as 
measured by an NRS in the daily eDiary
•
Daily cyclic pelvic pain score
•
To evaluate the efficacy of MK-7264 
versus placebo in reducing average daily
•
Daily non-cyclic pelvic pain score
 
 
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Objectives
Endpoints
non-cyclic pelvic pain during TRC2 as 
measured by an NRS in the daily eDiary
Tertiary/Exploratory
•
To evaluate the average daily use of 
naproxen sodium rescue medication 
taken for daily pelvic pain (cyclic and 
non-cyclic, combined and separately) 
during TRC2 by number of tablets, 
compared to the Baseline Cycle (BC)
•
Use of naproxen sodium rescue 
medication for daily pelvic pain 
•
To evaluate the efficacy of MK-7264 as 
measured by the proportion of 
participants with at least 1-point
reduction in average daily pelvic pain 
score (cyclic and non-cyclic, combined 
and separately) as compared to baseline 
during TRC2 and 
•
Irrespective of analgesic use
•
With no increase in average daily 
use of rescue medication by 
number of tablets
•
With no increase in average daily 
use of rescue medication and no 
use of concomitant pain 
medication 
•
With no increase in average daily 
use of rescue medication and no 
use of concomitant pain 
medication for ERP 
•
Daily pelvic pain score 
•
Use of naproxen sodium rescue 
medication 
•
Use of  concomitant pain medication 
 
 
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Objectives
Endpoints
•
To evaluate the efficacy of MK-7264 
versus placebo in reducing average daily 
pelvic pain (cyclic and non-cyclic, 
combined and separately) during
Treatment Cycle 1 (TRC1) as measured 
by an NRS in the daily eDiary
•
Daily pelvic pain score 
•
To evaluate average daily pelvic pain
(cyclic and non-cyclic, combined and 
separately) during the Post-treatment
Cycle (PTC) after the completion of 
TRC2, compared to the Screening Cycle
(SC)
•
Daily pelvic pain scores 
•
To assess the PGIC rating, the impact 
scores of pelvic pain and Endometriosis 
Health Profile-5 (EHP-5) on health-
related quality of life during TRC 2
•
PGIC ratings
•
Impact score of pelvic pain
•
EHP-5
•
To evaluate the exposure-response 
relationship for endometriosis-related 
pain and taste disturbance
•
Plasma exposure of MK-7264
•
Daily pelvic pain scores (cyclic and non-
cyclic, combined and separately)
•
Taste-related AEs 
•
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
4
STUDY DESIGN
4.1
Overall Design
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
 
 
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This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind, efficacy 
and safety study of MK-7264 in participants with moderate to severe ERP (cyclic and non-
cyclic).
The study will be approximately 24 weeks in duration for each participant, and include 1 
menses during screening before Visit 2, followed by 5 complete menstrual cycles, as detailed 
below: 

One SC during the screening period: 
o
Starts at Visit 2, 1 day after the last day of the previous menses

One BC during the single-blind, placebo run-in period:
o
Starts at Visit 3, 1 day after the last day of the SC menses 

TRC1 and TRC2 after randomization:
o
Start at Visit 4 or 5, 1 day after the last day of the BC or TRC1 menses, 
respectively.

One PTC after the participant has stopped taking study intervention (ie, completed 
TRC2), but may continue to use rescue medication:
o
Starts at Visit 6, 1 day after the last day of TRC2 menses.
o
A telephone contact will occur approximately 14 days after Visit 6. 
o
Visit 7 occurs 1 day after the last day of PTC menses
At Visit 2, participants will receive the eDiary which will be used daily through the end of 
the study to collect pelvic pain score, vaginal bleeding/non-bleeding days, use of naproxen 
sodium rescue medication, any use of pain relief medication other than the naproxen sodium 
provided by the Sponsor, and impact of pelvic pain.
This study will use a group sequential design based on prespecified criteria. There will be 1
futility interim analysis (IA). The IA will be conducted when 84 participants have completed 
TRC2 (ie, 60% of the participants who are expected to complete TRC2). Results of the IA
will be reviewed by the Standing Internal Data Monitoring Committee (SiDMC), which will 
make recommendations to continue or end the study according to the plan described in 
Section 9 - Statistical Analysis Plan and in a separate SiDMC Charter (see more information 
in Section 10.1.4.1).
4.2
Scientific Rationale for Study Design
Screening Cycle: Visit 2 to Visit 3
Participants will be dispensed an eDiary and rescue medication at Visit 2 and instructed on 
their use.  The information collected during the SC will allow the investigator to ascertain 
and verify that the participant meets requirements for study entry (ie, length of menstrual 
 
 
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cycle, average pelvic pain score, compliance with eDiary entries, and compliance with rescue 
and other pain relief medications) as noted in the Inclusion Criteria (Section 5.1).  
Baseline Cycle: Visit 3 to Visit 4/Day 1
At Visit 3, single-blind placebo run-in medication will be dispensed. Thus, in addition to 
continued monitoring to ensure the participant meets inclusion criteria as noted above, this 
baseline menstrual cycle has the purpose of familiarizing the participants with the study 
treatment regimen and excluding participants with a placebo response (ie, participants who 
have an average pain score during the SC of >5, and average pain score during the BC of ˂5, 
as measured by the NRS in the Daily eDiary). In addition, participants who are not compliant 
with the blinded placebo before randomization will be excluded. Baseline measurements for 
change from baseline analyses will be obtained during this cycle. 
Treatment Cycle 1 and 2: Visit 4/Day 1 to Visit 6
TRC1 and TRC2 provide 2 complete menstrual cycles to evaluate the safety and efficacy of 
MK-7264. Two cycles have been proposed as an adequate timeframe for the efficacy of the 
medication to be observed. The primary efficacy will be assessed by the change from 
baseline in average daily pelvic pain score (cyclic and non-cyclic) during TRC2. Efficacy 
will also be assessed at TRC1 via an exploratory objective.  
Post-treatment Cycle: Visit 6 to Visit 7
The purpose of the PTC is to assess the pain scores after participants have stopped double-
blind study intervention. Pain scores from the PTC will be compared to pain scores from the 
SC, as the participants will be under the same clinical circumstances (ie, only rescue 
medication being used as needed) during both cycles.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The goal of the clinical development program for MK-7264 is to demonstrate its efficacy in 
the treatment of ERP. The primary efficacy endpoint is the change from baseline in average 
daily pelvic pain score (cyclic and non-cyclic, combined) during TRC2. For this PoC study, 
the primary efficacy endpoint addresses daily pelvic pain that represents the most clinically 
relevant symptom of endometriosis. This endpoint has been published as the primary 
endpoint in many Phase 2 trials in clinical development programs for endometriosis
[Diamond, M. P., et al 2013].
At the end of each day, participants will enter a score in their eDiary rating the worst pelvic 
pain that they can recall in the past 24 hours, regardless of the use of rescue or other pain
relief medication.  Pelvic pain severity will be measured using a 0-10 NRS anchored with 0 
(no pain) and 10 (extremely severe pain). The average of the daily pelvic pain scores entered 
in the eDiary will be calculated for each cycle of the study. In addition, each day they will 
also record any vaginal bleeding, use of rescue medication, use of pain relief medication 
 
 
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other than the naproxen sodium provided by the Sponsor, and impact of pelvic pain. For 
rescue medication use, the number of tablets taken will be recorded. 
The secondary efficacy endpoints evaluate the change from baseline in the average cyclic 
and non-cyclic pelvic pain scores, separately, during TRC2. Cyclic and non-cyclic pelvic 
pain during TRC1 and 2 have also been measured in other clinical development programs for 
endometriosis and provide additional details regarding the timing of the most severe pain. A 
differential effect in cyclic and non-cyclic pain score is expected due to differences in 
pathophysiology. The former represents the pathologic event at the eutopic endometrium, 
involving a higher number of unmyelinated C-fibers, nociceptors, and P2X3 receptors. The 
latter represents the inflammatory component triggered by the ectopic endometrium over 
different peritoneal locations (eg, bowel, bladder, Pouch of Douglas, etc.) where multiple 
proinflammatory substances (prostaglandin, cytokines, ATP, etc.) play a role in pain 
generation [Howard, F. M. 2009].
The first exploratory endpoint is the average daily use of naproxen sodium rescue medication 
by number of tablets taken for daily pelvic pain (cyclic and non-cyclic, combined and 
separately) during TRC2, as compared to the BC. Rescue medication use and the difference 
in usage between the MK-7264 and placebo treatment groups will be indicators of treatment 
efficacy in pain control. 
The proportion of participants with at least 1-point reduction in average daily pelvic pain 
score (cyclic and non-cyclic, combined and separately) as compared to baseline during TRC2 
is another exploratory endpoint. This endpoint is to evaluate the proportions of participants 
who have had pain reduction from the study intervention irrespective of analgesic use. 
However, to further evaluate that pain reduction is not due to use of analgesics, composite 
endpoints with reduction in pelvic pain and no increased use of rescue medication or other 
analgesic use will be evaluated. Therefore, the following exploratory endpoints will also be 
evaluated for this purpose: 

The proportion of participants with at least 1-point reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline 
during TRC2, and no increase in average daily use of rescue medication by number of 
tablets;

The proportion of participants with at least 1-point reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline 
during TRC2, and no increase in average daily use of rescue medication, and no use 
of concomitant pain medication;

The proportion of participants with at least 1-point reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline 
during TRC2, and no increase in average daily use of rescue medication, and no use 
of concomitant pain medication for ERP.
While this study is designed to further explore the clinical importance of changes in pelvic 
pain score, for this PoC study, a 1-point reduction in average daily pelvic pain is the 
 
 
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minimum that will be considered clinically meaningful. Reductions greater than 1-point (ie, 
2-point and 3-point reductions) will also be analyzed as part of this objective. 
The comparison of pain scores (cyclic and non-cyclic, combined and separately) at PTC
versus SC will be used to evaluate the potential change in pain scores after the completion of 
double-blind study intervention, without the intervention of MK-7264 as in the SC (ie, 
participants are only exposed to rescue medication).
The PGIC is an exploratory endpoint, to be assessed at the end of TRC2. It is a 7-point scale 
in the eDiary to collect a participant’s rating of overall change in her ERP relative to her
condition before initiation of the treatment.
The EHP-5 is an exploratory endpoint to be assessed at baseline and at the end of TRC2. It is 
an endometriosis-specific questionnaire in the eDiary to assess participant’s health-related 
quality of life at the beginning of the run-in period and at the end of TRC2.
Participants will also answer questions in the eDiary to assess the impact of pelvic pain by 
determining if their pelvic pain causes any limitations in work/school, physical activities, 
leisure/social activities, and sleep. Responses to these questions, the EHP-5, and the PGIC
will help to determine the effect of pelvic pain on health-related quality of life.  
4.2.1.2
Safety Endpoints
The safety data for MK-7264 to date has been described in detail in Section 2.3 and in the IB. 
In support of the safety objective to evaluate the safety and tolerability profile of MK-7264, 
the safety and tolerability endpoints will be assessed by clinical evaluation of AEs (including 
taste-related AEs as Tier 1 events) and inspection of other study parameters including vital 
signs, physical examination, and standard laboratory safety tests at time points specified in 
the SoA. AEs are graded and recorded according to Section 8.4.
4.2.1.3
Pharmacokinetic Endpoints
The relationship between MK-7264 plasma concentrations/exposure and pelvic pain score 
(cyclic, non-cyclic, combined and separately)/side effects will be explored. Exploratory 
population pharmacokinetic (PK) analyses will be conducted to understand the exposure-
response relationships between MK-7264 and efficacy and safety data. 
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamics biomarkers are planned for this study. 
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
 
 
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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 will be used for research related to the study intervention(s), the disease under 
study, and 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 or the analysis of 
genetic markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on DNA specimens for which consent 
was provided during this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
A placebo group is included in this study to maintain the study blinding, allowing for an 
unbiased assessment of efficacy and safety. Participants may discontinue the study 
intervention at any time. Since naproxen sodium rescue medication will be provided, the use 
of a placebo is justified.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
The dose of MK-7264 will be 45 mg bid throughout the study. See Section 4.3.3. 
 
 
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4.3.2
Maximum Dose/Exposure for This Study
The maximum dose will be 45 mg bid. Participants will be exposed to MK-7264 for 
approximately 8 weeks. For more information, see Section 6 - Study Intervention and Section
4.3.3.
4.3.3
Rationale for Dose Interval and Study Design
Of the indications studied, the clinical development of MK-7264 has progressed the furthest 
for the chronic cough indication. In Protocol 010, a Phase 2, crossover, dose escalation study 
in refractory chronic cough, 7 doses were evaluated (7.5, 15, 30, 50, 100, 150, and 200 mg 
bid). After 4 days of treatment, participants in the 30 and 50 mg bid dose groups experienced 
a near maximal, statistically significant reduction in cough. Taste disturbances (ie, ageusia, 
dysgeusia, and hypogeusia), which are common side effects, were less frequent at doses <50 
mg bid.
The largest and longest phase 2 study completed to date was Protocol 012, in participants 
with chronic cough. It was a 12-week, parallel design, 4-arm study (placebo and MK-7264 at 
7.5, 20, or 50 mg bid), with 253 participants enrolled. A statistically significant reduction in 
the primary endpoint (mean change from baseline in objective awake coughs per hour at 
Week 12) relative to placebo was observed for the 50-mg bid dose. Taste disturbances, the 
most common AEs reported, were dose related: 10% at 7.5 mg, 49% at 20 mg, and 81% at 
50 mg bid. At the 50 mg bid dose, 10% of participants discontinued treatment due to altered 
taste effect AEs.
These results suggest a relatively close association between dose/exposure, efficacy (ie, 
cough rate reduction) and taste disturbances. Based on these results, an exposure-response 
model was developed to support the dose selection for the Phase 3 studies of MK-7264 for 
chronic cough with an aim to select doses which maximize the efficacy (high dose) and 
minimize the taste disturbance (low dose). According to this model, the AUC50 (area under 
the curve required to achieve 50% of the maximal response) was 721 ng.hr/mL, which would 
result from a dose of 10 mg. Considering a 2-3 fold higher dose is required to achieve a 
maximum cough suppression response, a dose of 30 mg is expected to provide a near 
maximal response (29% reduction in cough rate, placebo adjusted). The model based 
simulations also indicated that an increase in the dose from 30 mg to 45 mg would result in 
an additional 2.2% reduction in cough frequency and a 9.6% increase in taste disturbance 
incidence rate (ie, from 57.4% to 67%).
To select the dose for treatment of ERP, previous 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 higher incidence 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 of similarity of the P2X3-related mechanism 
of action for pain and for cough and similar exposure-response between cough and pain, as 
well as to mitigate potential rightward shift of exposure-response for pain relative to cough 
(ie, potential that ERP is less sensitive than cough reflex). Thus, to assess the efficacy of 
MK-7264 for the treatment of ERP, a dose of 45 mg bid was selected. 
 
 
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The appropriateness of this dose is also supported by preclinical data. The concentration 
range (170-793 ng/mL) that was found to be efficacious in preclinical models for 
neuropathic, arthritic and inflammatory conditions brackets the steady state Cmax following 
45 mg bid (569 ng/mL). Additionally, the Cmax values are expected to be ~3.5-fold above 
the Ki value for P2X3 after accounting for protein binding and plasma to tissue partition. 
Taken together, data from preclinical in vitro and animal studies and human experience in 
pain (OA of the knee and IC/BPS [reference the IB for additional information]) and cough,
including dropout rates and taste tolerability, support the selection of the 45 mg bid dose for 
the current study.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the following specified criteria:
One formal IA will be conducted when 84 participants (ie, 60% of the participants who are 
expected to complete TRC2) have completed TRC2. Results of the IA will be reviewed by 
the SiDMC, which will make recommendations to continue or end the study according to the 
plan described in Section 9 - Statistical Analysis Plan.
5
STUDY POPULATION
Female participants with moderate to severe endometriosis-related pelvic pain (cyclic and 
non-cyclic) between the ages of 18 and 49 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.
 
 
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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Participant has been surgically (laparoscopy or laparotomy) diagnosed with 
endometriosis within 10 years of study entry as documented by medical records.
2. Participant has cyclic (secondary dysmenorrhea) AND non-cyclic, moderate to severe 
endometriosis-related pelvic pain, as confirmed by an overall score of ≥5 at Visit 1 based 
on the participant’s last 2 menstrual cycles using an NRS (0-10 anchored with 0 [no pain] 
and 10 [extremely severe pain]).
3. Participant has had spontaneous, (ie, without hormonal therapy) regular, menstrual cycles 
with a cycle length between 24 to 38 days (inclusive) for the past 2 months before Visit 1.
Demographics
4. Participant is a female.
5. Participant is from 18 years to 49 years of age inclusive, at the time of signing the 
informed consent.
6. Participant’s body mass index (BMI) is between 18 kg/m2 to 40 kg/m2 inclusive, at Visit 
1.
Female Participants
7. Participant is not pregnant, not breastfeeding, and the following condition applies:
The participant agrees to follow the contraceptive guidance in Appendix 5 from the 
time of signing informed consent through the last day of the post-treatment cycle of 
the study (Visit 7) or for at least 14 days after the last dose of double blind study 
intervention if the participant discontinues study intervention.
Informed Consent
8. The participant (or legally acceptable representative, if applicable) provides written 
informed consent for the study. Participant must be willing and able to comply with all 
aspects of the protocol, including the use of the eDiary, to the satisfaction of the 
investigator/qualified designee before randomization. The participant may also provide 
consent for future biomedical research. However, the participant may participate in the 
main study without participating in future biomedical research.
Study Participation
9. Participant must agree to switch from her usual analgesic medication to only that which is 
permitted in the study (ie, naproxen sodium rescue medication provided by the Sponsor).
 
 
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At Visit 3 (Before Placebo Run-in) 
10. Participant’s menstrual cycle before Visit 3 (SC) was 24 to 38 days (inclusive) as 
documented in the eDiary.
11. Participant reports at least moderate pelvic pain during the SC as defined by average 
daily pelvic pain (cyclic and non-cyclic) score >5.
Note:  Pain severity score will be measured using 0-10 NRS anchored with 0 (no 
pain) and 10 (extremely severe pain).
12. Participant has demonstrated compliance with >75% of daily eDiary entries (ie, pelvic 
pain score, vaginal bleeding, rescue medication intake, intake of pain relief medication 
other than naproxen sodium provided by Sponsor, and impact of pelvic pain) during the 
SC.
Note: eDiary compliance will be automatically calculated by the eDiary vendor 
partner and a report will be provided. The investigational site should review the report 
before the participant’s scheduled visit to assess eligibility.
13. Participant has taken only the study provided rescue medication, at a dose not exceeding 
the maximum dose determined by the investigator according to the local label, for control 
of ERP during the SC as evidenced in the eDiary. 
Note: Short term use (ie, ≤3 days) of other non-opioid pain medications for acute 
conditions other than ERP is permitted.
At Visit 4 (Before Randomization)
14. Participant’s menstrual cycle before Visit 4 (BC) was 24 to 38 days (inclusive) as 
documented in the eDiary.
15. Participant reports at least moderate pelvic pain during the BC as defined by average 
daily pelvic pain (cyclic and non-cyclic) score >5.
Note:  Pain severity score will be measured using 0-10 NRS anchored with 0 (no 
pain) and 10 (extremely severe pain).
16. Participant has demonstrated compliance with >75% of daily eDiary entries (ie, pelvic 
pain score, vaginal bleeding, rescue medication intake, intake of pain relief medication 
other than naproxen sodium provided by Sponsor, and impact of pelvic pain) during the 
BC.
Note: eDiary compliance will be automatically calculated by the eDiary vendor 
partner and a report will be provided. The investigational site should review the report 
before the participant’s scheduled visit to assess eligibility.
 
 
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17. Participant is ≥80% compliant with the placebo run-in medication (as determined by site-
performed tablet count).
18. Participant has taken only the study provided rescue medication, at a dose not exceeding 
the maximum dose determined by the investigator according to the local label, for control 
of endometriosis-related pelvic pain during the BC as evidenced in the eDiary. 
Note: Short term use (ie, ≤3 days) of other non-opioid pain medications for acute 
conditions other than ERP is permitted.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Participant had no pelvic pain for more than 50% of the days in her last menstrual cycle 
according to the participant’s recollection.
2. Participant has a surgical history of hysterectomy and/or bilateral oophorectomy. 
Note: Participants who have undergone surgical sterilization (eg, bilateral salpingectomy, 
tubal ligation) are permitted in the trial.
3. Participant had undiagnosed (unexplained), abnormal, vaginal bleeding within the past 6 
months before screening. 
4. Participant has chronic pelvic pain not caused by endometriosis that requires chronic 
analgesic or other chronic therapy (including, but not limited to, pain caused by IC, BPS, 
adenomyosis [as confirmed by imaging], symptomatic uterine fibroids, irritable bowel 
syndrome, vulvodynia, or hysteroscopic sterilization).
5. Participant has chronic, non-pelvic pain not caused by endometriosis that requires chronic 
analgesic or other chronic therapy (including, but not limited to, fibromyalgia, chronic 
back pain or chronic headaches).
6. Participant has a clinically significant gynecologic condition identified in the screening 
evaluation including, but not limited to, endometriomas of any size, persistent (present 
longer than 4 months) complex ovarian cysts larger than 3 cm, simple ovarian cysts 
larger than 5 cm, or an active sexually transmitted disease. Participants may be 
rescreened after completing treatment for infection or for simple ovarian cysts.
7. Participant plans to schedule elective surgery during the study execution or had surgery 
in the past 6 months before screening that continues to require pain management.
8. Participant has a history of anaphylaxis or cutaneous adverse drug reaction (with or 
without systemic symptoms) to sulfonamide antibiotics or other sulfonamide-containing 
drugs. (Note: MK-7264 contains a sulfonamide moiety.)
 
 
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9. Participant has a known allergy/sensitivity or contraindication to MK-7264 or its 
excipients (Note:  refer to the IB for details regarding excipients of MK-7264).
10. Participant has an allergy/sensitivity/intolerance to naproxen sodium (rescue medication) 
or any contraindication to its use, or has experienced asthma, urticaria, or allergic-type 
reactions after taking aspirin or other NSAIDs.
Note:  Proton pump inhibitors (PPIs) may be used per investigator discretion as needed.
11. Participant has an estimated glomerular filtration rate <50 mL/min/1.73 m2 (using the 
Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] formula) at Visit 1.
12. Participant has systolic blood pressure >160 mm Hg or diastolic blood pressure >90 mm 
Hg at Visit 1.
13. Participant is, at the time of signing informed consent, a user of recreational or illicit 
drugs or has had a recent history (within the last year) of drug or alcohol abuse or 
dependence, per the investigator’s discretion.  Participants are asked to follow the 
protocol-specified restrictions on alcohol use during the study (Section 5.3.1). 
14. Participant has a history of ERP that was non-responsive to treatment with CHCs, GnRH
antagonists, GnRH agonists, progestins, or aromatase inhibitors. 
Note: Participants who achieved a partial response or were treatment failures due to 
side effects should not be excluded.
15. Participant has a history of malignancy ≤5 years before signing informed consent except 
for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
16. Participant has donated or lost ≥1 unit of blood (approximately 300 mL) within 8 weeks 
before the first dose of MK-7264.
17. Participant has a positive urine pregnancy test at any time before randomization. If the 
urine test cannot be confirmed as negative, a serum pregnancy test is required. In such 
cases, the participant must be excluded from participation if the serum pregnancy result is 
positive.
Prior/Concomitant Therapy
18. Participant has required more than 2 weeks of continuous use of narcotics for treatment 
of ERP within 6 months of Visit 1. 
19. Participant has received any treatment listed in Table 1 more recently than the “Last 
Allowable Use” as indicated in the table, or must continue to receive any treatment listed 
in Table 1 during the study.
 
 
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Table 1
Prohibited Medications and Other Substances
Prohibited Medications1:  Hormones
Last Allowable Use
GnRH agonists with 1-month duration or GnRH antagonists, 
aromatase 
inhibitors, 
menotropins 
and 
human 
chorionic 
gonadotropin (hCG)
3 months before
Visit 1
Injectable GnRH agonist with 3-month duration (eg, leuprolide)
10 months before
Visit 1
Oral, patch, and implanted contraceptives; vaginal ring, and 
medicated 
intrauterine 
device 
(IUD); 
oral 
progestins 
(eg, 
norethindrone acetate and dienogest)
2 months before 
Visit 12
Injectable hormonal contraception with 1-month duration
3 months before 
Visit 1
Injectable hormonal contraception with 2-month duration
6 months before
Visit 1
Injectable hormonal contraception with 3-month duration; injectable 
medroxyprogesterone acetate; injectable depomedroxyprogesterone 
acetate
9 months before
Visit 1
IUD (non-hormonal)
Before Visit 13
Prohibited Medications1:  Analgesics 
Last Allowable Use

NSAIDs (eg, aspirin, ketorolac) 
o
Protocol-specified naproxen sodium rescue medication is 
permitted. 

COX-2 inhibitors 

Other 
non-specified 
analgesics 
(eg, 
acetaminophen 
or 
paracetamol)
At Visit 24

Opioid analgesics (eg, tramadol and tapentadol)
5 days before Visit 2
Prohibited Medications1:  Other
Last Allowable Use

Herbal remedies containing Hypericum perforatum (eg, Kava 
kava and St. John's wort)

Glucocorticoids (oral or intravenous) 

Anti-Tumor Necrosis Factor (TNF)/Anti-Nerve Growth Factor 
(NGF)
At Visit 1
2 months before Visit 
1
1Excluded from the time point specified above and throughout the study.
2Not including emergency contraceptive pills.
3Intrauterine device (non-hormonal) must be removed before the day of screening visit.
4Short term use (ie, ≤3 days) of non-opioid pain medications for acute conditions (other than ERP) is permitted. 
 
 
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Prior/Concurrent Clinical Study Experience
20. Participant has received MK-7264 in a previous clinical study.
21. Participant is currently participating in or has participated in an interventional clinical 
study with an investigational compound or device within 30 days of participating in the
current study. 
Diagnostic Assessments
22. Participant has clinically significantly abnormal laboratory tests at Screening, including:
a.
Alkaline phosphatase (AP), alanine aminotransferase (ALT, SGPT), aspartate 
aminotransferase (AST, SGOT) >200% of the upper limit of normal, or total 
bilirubin >150% of the upper limit of normal.
b. Hemoglobin <10 gm/dL, white blood cell count <2500 mm3, neutrophil count 
<1500 mm3, platelet count <100 × 103/mm3. 
Other Exclusions 
23. Participant has other severe, acute, or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the Investigator or Sponsor, would make the participant 
inappropriate for entry into this study. 
24. Participant is or has an immediate family member (eg, spouse, parent/legal guardian, 
sibling, or child) who is investigational site or Sponsor staff directly involved with this 
study.
5.3
Lifestyle Considerations
5.3.1
Caffeine, Alcohol, and Tobacco Restrictions
Based on the known metabolism of MK-7264, there are no effects of alcohol, caffeine, or 
tobacco associated with the study treatment. 
However, during the study, participants are asked to refrain from consuming more than 
3 alcoholic beverages or equivalent (1 glass is approximately equivalent to: beer 
[354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2
Activity Restrictions
No activity restrictions are required.
 
 
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies [study intervention(s) provided by the Sponsor] will be packaged to support 
enrollment. 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 
Administration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Placebo
Other
Placebo 
Matching MK-
7264
Other
Tablet
0 mg
1 tablet 
bid
Oral
Visits 3 to 4
(Run-in 
Period)
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
MK-7264
Experiment
al
MK-7264
Drug
Tablet
45 mg
1 tablet 
bid
Oral
Visits 4 to 6 
(Treatment 
Period)
Experiment
al
IMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo 
Comparator
Placebo 
Matching MK-
7264
Other
Tablet
0 mg
1 tablet 
bid
Oral
Visits 4 to 6 
(Treatment 
Period)
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Rescue 
Medicatio
n for both 
Treatment 
Arms
Other
Naproxen 
sodium
Drug
Tablet
275 mg
Per local 
guidance
Oral
Visits 2 to 7 
(Screening, 
Run-in, 
Treatment 
and Post-
treatment 
Periods)
Rescue 
Medication
NIMP
Provided 
centrally 
by the 
Sponsor
 
 
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All supplies indicated in Table 2 will be provided per the “Sourcing” row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number.
Refer to Section 8.1.13 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Medical devices are not used in this study. 
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
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to MK-7264 study intervention and placebo study intervention, 
respectively.
6.3.2
Stratification
Treatment allocation/randomization will be stratified according to the following factors:

Severity of pelvic pain
o
Moderate (ie, average score of ≥5 to ˂8 on the NRS in the eDiary during
the BC), or
o
Severe (ie, average score of ≥8 on the NRS in the eDiary during the BC)
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-7264 and matching 
placebo will be packaged identically so that blind is maintained. The participant, the 
investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention
administration or clinical evaluation of the participants are unaware of the group 
assignments.
See Section 8.1.15 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Records of treatment compliance for each participant will be kept during the study. 
Compliance will be based on tablet count. In cases in which tablet count cannot be 
performed, participant reporting will be used to assess compliance. Issues with compliance 
should be discussed with the participant and addressed as deemed appropriate by the 
investigator.
Interruptions from the protocol specified treatment plan in which a participant’s compliance
is ˂80% require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
Sponsor consultation and written documentation of collaborative decision on participant 
management is not required if reason for <80% compliance is due to an AE. Such instances 
of <80% compliance will not be considered a protocol deviation. Consultation should occur 
in a timely manner upon site learning of poor study intervention compliance. While awaiting 
Sponsor feedback, the investigational site should conduct participant counseling regarding 
importance of study intervention adherence, and the investigator can dispense study 
 
 
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intervention after such counseling, if in their medical judgment, the participant is able to 
comply moving forward with study intervention instructions.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed from the time 
specified for each medication in Table 1 (Section 5.2) until early discontinuation or end of 
the post-treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy rests with the investigator and/or the 
participant’s primary physician. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
6.5.1
Rescue Medications and Supportive Care
Naproxen sodium 275 mg tablets will be provided to participants for use as rescue 
medication for ERP from Visit 2 until early discontinuation or last study visit. Since the 
maximum appropriate dose varies by region, the dose of naproxen sodium will be based on 
investigational site’s recommendation and the local guidance.
Participants will be instructed that they should not take pain medications other than site 
dispensed naproxen sodium for ERP during the study, and that naproxen sodium is to be used 
only as a rescue medication for ERP, not prophylactically or routinely. 
The naproxen sodium tablets provided as rescue medication should not be used for the 
treatment of conditions other than ERP during the study. Participants must return all 
remaining naproxen sodium at each study visit, or discontinuation visit.
Note: Short term use (ie, ≤3 days) of other non-opioid pain medications for acute conditions 
(other than ERP) is permitted. However, the investigator should caution the participants on 
the use of other NSAIDs on the same day that the participant uses the naproxen sodium 
rescue medication. 
6.6
Dose Modification
Participants will be randomized to a fixed dose regimen of MK-7264, 45 mg bid or matching 
placebo for the duration of the study. 
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study. Participants should be 
advised to return to the care of their primary physician and/or obstetrician/gynecologist.
 
 
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6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.15). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
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 will still continue to participate in the study as specified in Section 1.3 and Section 
8.10.5.
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 Section 8.10.5.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places 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 8.3.8.1–Renal and Urological Safety Procedures). 
 
 
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•
The participant has a confirmed positive serum pregnancy test.
•
In case of clinically significant and potentially drug-related rash or signs and/or 
symptoms consistent with allergic drug reaction or anaphylaxis to study treatment.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.Section 
8.10.5 describes the procedures to be completed at each specified visit.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment 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 8.1.14. 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.
 
 
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Study File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be 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 be approximately 62.5 mL.
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 
 
 
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majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to 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
 
 
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allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare 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 (refer to 
electronic case report form [eCRF] entry guidelines).
8.1.5
Gynecological History
A gynecological history (including menstrual history) will be obtained by the investigator or
qualified designee for all participants. Special attention should be given to the gynecologic-
related inclusion and exclusion criteria (eg, surgical confirmation of endometriosis, history of 
pelvic pain, characteristics of participant’s menstrual cycle, previous gynecologic surgery, 
etc.).  See Section 5.
As part of the gynecological history and to ensure the participant is eligible for study 
participation, the investigator or qualified designee will confirm that the participant has 
cyclic (secondary dysmenorrhea) AND non-cyclic, moderate to severe endometriosis-related 
pelvic pain, using an NRS (0-10 anchored with 0 [no pain] and 10 [extremely severe pain]). 
The participant’s rating of her pain during her last 2 menstrual cycles must be an overall 
score of ≥5 to be eligible for participation in the study.  
Pregnancy history (including gravidity and parity), including number of previous pregnancies
and number of live births should be collected for all subjects at Visit 1 and reported on the
appropriate eCRF. 
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior
medication taken by the participant before screening. See Section 6.5 – Concomitant Therapy 
and refer to eCRF entry guidelines.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
 
 
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8.1.7
Rescue Medication (Naproxen Sodium) Dispensing and Instructions for Use
Naproxen sodium rescue medication (275 mg tablets) will be dispensed to each participant at 
Visits 2 through 6, inclusive.  The investigator or qualified designee will instruct the 
participant on the proper use of the rescue medication according to local guidance.  
Participants should be reminded that they should not take additional pain medication for ERP 
and that the naproxen sodium tablets provided by the Sponsor should be used only for ERP 
and not for other ailments during the course of the study.
Overdoses must be reported to the Sponsor (See Sections 8.5 and 10.3.1). 
8.1.8
Rescue Medication Accountability
The use of naproxen sodium rescue medication will be reviewed at each study visit and 
during the telephone follow-up. An eDiary report will identify if a participant has taken an 
overdose of naproxen sodium based on the local labelling, and the investigator should follow 
up with the participant and report the overdose as appropriate.
8.1.9
Home Pregnancy Test Dispensing
Starting at Visit 2, participants will be given a urine pregnancy test (UPT) to take home. 
Additional UPTs for home use will be dispensed to participants as needed.
8.1.10
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.
Any participant who is screened more than once will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 8.10.1.
8.1.11
Placebo Dispensing (for Run-In Period)
All participants will be dispensed single-blind, placebo run-in medication. 
8.1.12
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
 
 
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A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.13
Study Intervention Administration
The distribution of study intervention will be witnessed by the investigator and/or qualified 
designee at the study visits. Participants will receive either MK-7264 45 mg or placebo 
matched to 45 mg MK-7264. Participants should be instructed to take 1 tablet from the bottle 
bid.
Participants will be provided with enough study intervention to last between study site visits.
Study intervention should begin on the day of treatment randomization and will be
administered at the study site at Visit 4. This first dose of study treatment at Visit 4 should be
administered after the pre-dose PK sample collection and before approximately 11:00 AM. 
As dosing is bid, the next dose should be taken orally in the evening, approximately 12 hours 
later. Subsequent dosing will be performed by the participant (ie, unsupervised at her home) 
bid, approximately 12 hours apart at approximately the same time each day. However, on the 
day of a study site visit, the morning dose should not be taken at home and instead will be 
given as a witnessed dose at the study site after the pre-dose PK sample collection, and 
before approximately 11:00 AM. Participants should be contacted (eg, by phone or text) and 
reminded not to take their study intervention before a study site visit that includes pre-dose 
PK collection.
Participants who vomit after dosing or miss a dose should be instructed to continue with the 
next scheduled dose.  
8.1.13.1
Timing of Dose Administration
Study intervention (ie, MK-7264 or matching placebo) will be administered orally, bid, 
approximately 12 hours apart for approximately 8 weeks (ie, two menstrual cycles) during 
the double-blind study treatment period.
8.1.14
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Discontinuation visit should be performed (at the time of withdrawal). Any 
AEs that are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4 .
8.1.14.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
 
 
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Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.15
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 drug 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 treatment assignment, the 
investigator or who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical 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 principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
 
 
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system should be used for emergency unblinding in the event that this is required for 
participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.16
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Electronic Patient-reported Outcomes
8.2.1.1
eDiary Dispensing and Instructions
At Visit 2, each participant will be given a handheld electronic device containing the eDiary
and will be properly trained and instructed on its use by the investigator or qualified 
designee. Participants should bring their eDiary device for all study visits, and should be 
contacted and reminded to do so (eg, by phone or text) before each visit. 
Participants will be instructed to enter the daily eDiary information described below 
(Sections 8.2.1.2 through 8.2.1.6) on the evening of Visit 2, and every evening through study 
end. Preferably, this will be done at the same time each day (eg, before bedtime). 
Participants will be instructed to think only about the past 24 hours when completing the 
daily questions.  If a participant forgets to enter the daily information, she will have 24 hours 
to do so.  
Participants will also be asked to complete the daily eDiary entries from the previous day 
during Visit 2 (ie, while at the study site), if Visit 2 occurs more than one day after the last 
day of the previous menstrual bleeding.
If a participant discontinues early from study intervention, but agrees to be followed for the 
remaining study visits, she will be asked to continue completing the daily eDiary entries.  
Completion of the daily questions in the eDiary is expected to take less than 10 minutes. 
Participants will be instructed to complete the EHP-5 and PGIC (Sections 8.2.1.7 and 
8.2.1.8) at the same time they complete their daily eDiary entries on the evenings of the visits 
indicated on the SoA.  If these are forgotten, the participant will have 48 hours to complete 
them starting from the time when the visit is logged in to the eDiary. 
 
 
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Additional information for the site staff can be found on a secure online portal.  Additional 
information for the participants can be found within the eDiary.  
8.2.1.2
Pelvic Pain Severity Numeric Rating Scale
At the end of every day (just before she goes to bed), the participant will enter in her eDiary a 
rating of her worst pain or cramps in her pelvic area in the past 24 hours.  This will be 
measured using a 0-10 NRS anchored with 0 (no pain or cramps) and 10 (extreme pain or 
cramps).
In order to confirm participant eligibility at Visit 3 and 4, study site staff will confirm that the 
participant has reported at least moderate pelvic pain during the SC and the BC as defined by 
average daily pelvic pain (cyclic and non-cyclic) score >5. 
8.2.1.3
Vaginal Bleeding or Non-bleeding Days
At the end of every day (just before she goes to bed), the participant will enter in the eDiary 
whether or not she had any vaginal bleeding during the past 24 hours and the amount of 
bleeding (eg, spotting, light, moderate, or heavy).
In order to confirm participant eligibility at Visit 3 and 4, study site staff will confirm that the 
participant’s menstrual cycles before Visit 3 (SC) and Visit 4 (BC) were 24 to 38 days 
(inclusive) as documented in the eDiary.
8.2.1.4
Use of Rescue Medication (Naproxen sodium)
At the end of every day (just before she goes to bed), the participant will enter in the eDiary 
whether or not she took any of the pain relief tablets (naproxen sodium) provided by the 
study site in the last 24 hours. If yes, she will provide the number of tablets taken and the 
reason for taking them.
8.2.1.5
Use of Pain Relief Medication Other than Rescue Medication
At the end of every day (just before she goes to bed), the participant will enter in the eDiary 
whether or not she took any other pain relief medication (ie, other than the naproxen sodium 
provided by the study site) in the last 24 hours. If yes, she will provide the medication name
(selected from a dropdown menu), dose, when taken, and the reason taken (ie, for ERP, other 
reasons, or ERP and other reasons).  
In order to confirm participant eligibility at Visit 3 and 4, study site staff will confirm that the 
participant has taken only the study provided rescue medication for control of ERP during the 
SC and BC as evidenced in the eDiary. (Short term use (ie, ≤3 days) of other non-opioid pain 
medications for acute conditions other than ERP is permitted.)
 
 
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8.2.1.6
Impact of Pelvic Pain
At the end of every day (just before she goes to bed), the participant will answer questions in 
the eDiary to assess the impact, if any, of pain or cramps in her pelvic area on the following 
items: limitations in paid work/work around the home/school work, limitations in physical 
activities, limitations in leisure or social activities and limitations on sleep.
8.2.1.7
Endometriosis Health Profile-5
The EHP-5 is an endometriosis-specific questionnaire to assess the participant’s health-
related quality of life at the beginning of the run-in period and at the end of TRC2. 
Participants will complete the EHP-5 in the eDiary at approximately the same time in the 
evening as other eDiary entries on the day of the visits outlined in the SoA. The recall period
on the EHP-5 is ‘the last 4 weeks’. It is anticipated to take less than 5 minutes to complete.
8.2.1.8
Patient Global Impression of Change
The PGIC is a 7-point scale collecting a participant’s rating of overall change in her ERP
relative to her condition before initiation of the treatment.
At the end of TRC2, participants will complete the PGIC in the eDiary. The PGIC should be 
completed at approximately the same time in the evening as other eDiary entries on the day 
of the visit outlined in the SoA. It is anticipated to take less than 5 minutes to complete.
8.2.2
eDiary Compliance
Daily eDiary entries will be uploaded automatically into a secure online portal managed by 
the eDiary vendor. Sites will have access to reports within an automated database compiled 
from uploaded eDiary data which will be used to identify non-compliant subjects. Sites will 
not be able to view subject eDiary responses directly to prevent unblinding of site personnel.
Sites will monitor participant compliance in completing the following daily eDiary entries: 

Pelvic pain score, 

Vaginal bleeding,

Rescue medication intake, 

Intake of pain relief medication other than the naproxen sodium provided by the 
Sponsor, and

Impact of pelvic pain.  
Participants must respond to each one of the daily eDiary questions in order to be considered 
compliant for a given day. Sites will review the compliance reports regularly and before
every in clinic or telephone visit after Visit 2 to identify participants who have been non-
compliant with the protocol. Participants who have been non-compliant with eDiary entry for 
1 day should be contacted immediately. In order to confirm participant eligibility at Visit 3 
and 4, study site staff will confirm that the participant has demonstrated compliance with 
>75% of daily eDiary entries (Section 5.1).
 
 
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Additionally, participants should be contacted any time that the reports indicate that the 
participant has used pain relief medication other than the rescue medication. 
Sites are not required to continue to monitor eDiary compliance after a participant has 
discontinued study intervention. 
The site is expected to make every reasonable effort to contact the participant (repeated calls, 
emails, text messages, etc.) to provide appropriate counseling. Site personnel must document 
any contact or attempted contact on a Subject Contact Log to be maintained at the site. 
Supplemental study visits may be scheduled for subject re-training. 
8.2.3
Collect eDiary
The eDiary will be collected from the participant at her last study visit.  Additional details 
will be provided in a separate document.  
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits) can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
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 
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.
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.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
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, 
 
 
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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.
8.3.3
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 Visit 1 to ensure the participant meets study 
Inclusion Criteria (see Section 5.1).  
8.3.4
Gynecological Examination
A gynecological examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements). The examination will include speculum 
insertion and a bimanual examination. Only abnormal findings should be recorded on eCRFs, 
either as medical history or AEs.
8.3.5
Breast Examination
A breast examination will be conducted by an investigator or medically qualified designee 
(consistent with local requirements). Only abnormal findings should be recorded on eCRFs, 
either as medical history or AEs.
8.3.6
Vital Signs
Vital signs will be measured in a sitting position after 5 minutes rest and will include oral or 
tympanic temperature (in centigrade), systolic and diastolic blood pressure (mm Hg), and 
heart rate (beats per minute). 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 Visit 1 will be recorded as 
AEs in the eCRF.
8.3.7
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.
8.3.8
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.
 
 
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•
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 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 7 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.

The use of local laboratories is allowed in cases where safety follow-up is considered to 
be time-sensitive.
8.3.8.1
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. Details regarding this 
process will be provided in a separate document.  
8.3.9
Pregnancy Testing
Urine and/or serum pregnancy testing will be performed at the investigator site as indicated 
in the SoA. 
If at any time during the study, the participant’s menstrual cycle is 2 weeks later than 
expected, she will be instructed to perform a UPT at home and contact the clinic to schedule 
a visit as soon as possible. A clinic visit should be scheduled regardless of the outcome of the 
UPT.  The Sponsor will be consulted as soon as possible. See Section 8.1.9.
 
 
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8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
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 AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered drug-related.
After the post-treatment telephone contact conducted 14 days following cessation of double-
blind study intervention, if the investigator becomes aware of any AEs (serious or non-
serious) assessed as related to the rescue medication (naproxen sodium), they must be 
reported to the Sponsor.
Investigators are not obligated to actively seek AE or SAE 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.
 
 
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All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Table 3
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
Timeframe to Report 
Event and Follow-up 
Information to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
-
drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report 
outcome
Within 24 hours of 
learning of event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential 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 5 calendar 
days of learning of 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs. 
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
In this study, an overdose of blinded medication is any daily dose higher than 2 tablets. For 
naproxen sodium, investigator/site personnel are to consult the local approved naproxen 
sodium label for guidance on the definition of overdose.
No specific information is available on the treatment of overdose of MK-7624. Oral doses of 
up to 1800 mg bid for 14 days were explored in earlier clinical studies without any untoward 
clinical effects (see MK-7264 IB). Overdose should be treated according to the participant’s 
clinical signs and symptoms.
Refer to the local label for information regarding treatment of an overdose of naproxen 
sodium.  
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
 
 
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8.6
Pharmacokinetics
The date and time for the last dose of study treatment taken before the study visit on which
the PK sample was collected should be recorded in the eCRF. In addition, the date and time
of the PK sample collection should also be recorded in the eCRF.
8.6.1
Blood Collection for Plasma MK-7264
Blood samples will be collected at several visits during the study for determination of MK-
7264 as outlined in the SoA. 
Visit 4 (randomization): The first sample will be collected pre-dose of study intervention. A 
second sample will be collected 2 hours after the first dose of study intervention. 
Visit 5 and 6: Samples will be collected pre-dose of study intervention at the specified study 
site visits (ie, the morning dose of study intervention will be taken after the PK sample is 
collected). 
Discontinuation visit: The blood sample may be collected at any time. 
Note:  If a Discontinuation visit occurs after Visit 6 (PK sample collection), an additional 
blood sample for PK does not need to be collected. 
MK-7264 plasma concentrations will be determined using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay.
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for Genetic Analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
 
 
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the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover DNA for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8. Since all study visits will be scheduled around the participant’s menses (Visit 
1:  ~1 to 3 weeks before menses; subsequent visits:  ~1 day after end of menses), site staff 
will need to be in close contact with the participants before Visit 1 and between other clinic 
visits to monitor the timing of the participant’s menses.
8.10.1
Screening
The interval from Visit 1 to Visit 3 will constitute the screening period of approximately 8 
weeks. If a participant meets initial entry criteria at Visit 1, she will return to the site for Visit 
2 when she will begin using the eDiary and will be provided naproxen sodium rescue 
medication to use as instructed.
Potential participants will be evaluated at Screening to determine if they fulfill the entry 
requirements as set forth in Section 5.1 and 5.2 – Inclusion and Exclusion Criteria. 
Screening procedures, such as safety labs, may be repeated once at an unscheduled visit if 
results are inconsistent with the participant’s clinical status or recent results. The time period 
between Visit 1 and V2, may be extended due to the need to repeat screening assessments or 
timing of menses.
If any participant fails to meet the study entry criteria, screening procedures may be repeated 
based on investigator judgment after initial screening, and after consultation with the 
Sponsor. Participants may only be rescreened once. However, participants will not be 
permitted to rescreen if inclusion criteria for the overall pelvic pain score on the NRS was not 
met at Visit 1.
8.10.2
Placebo Run-In
Participants will return for Visit 3 on the first non-menstrual day after the SC menses. If the 
participant meets Visit 3 eligibility criteria, she will enter a single-blind, placebo run-in 
 
 
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period of approximately 4 weeks (ie, the duration of BC). The run-in period will end on the 
last day of menses of the BC, and the participant will return to the site the next day for Visit 
4 (randomization).
8.10.3
Treatment Period
Participants who meet eligibility criteria at Visit 4 will enter the treatment period of 
approximately 8 weeks, consisting of 2 menstrual cycles (ie, TRC1 and TRC2). The 
treatment period will start on the first non-menstrual day after the BC menses. The 
participant will return to the site for Visit 5 the day after the last day of the TRC1 menses. 
The participant will return to the site for Visit 6 the day after the last day of the TRC2 
menses. 
8.10.4
Post-Treatment Period
After TRC2, all participants will have 1 additional cycle (~4 weeks) of pain score evaluation 
only with rescue medication use (if needed). The PTC will start on the first non-menstrual 
day after the TRC2 menses. During this time, participants will continue to record information 
in the daily eDiary. Participants will be contacted by telephone approximately 2 weeks after 
Visit 6 for safety follow up. The participant will return to the site for the final visit (Visit 7), 
the day after the last day of the last menses.
8.10.5
Discontinued Participants Continuing to be Monitored in the Study
If a participant is discontinued from the study intervention early, the Discontinuation Visit 
assessments are to be performed as indicated in the SoA. 
It is intended that all randomized participants should be followed through completion of the 
study, regardless of premature discontinuation of treatment, unless the participant withdraws 
consent from any study follow-up. Thus, participants who discontinue from study 
intervention before completion of the study should continue to be monitored after the 
Discontinuation Visit to obtain relevant information through the end of the study.
After the Discontinuation Visit, a telephone contact will be conducted 14 days following 
cessation of double-blind study intervention during which all reportable safety events as 
outlined in Section 8.4, Table 3 will be collected. After the 14 day telephone contact, only 
drug-related SAEs will be collected; in addition, if the investigator becomes aware of any 
AEs (serious or non-serious) assessed as related to the rescue medication (naproxen sodium), 
they must be reported to the Sponsor.
Study site visits (or telephone contacts if scheduling of site visits is not possible) should 
occur at timepoints that correspond to each remaining study visit on the SoA. Only safety 
events as specified in the paragraph above and concomitant medication information will be 
collected at these visits.  In addition, participants will be asked to continue to provide daily 
eDiary entries after discontinuation of study intervention; however, if a participant does not 
agree to continue using the eDiary, she will still be followed for collection of safety events as 
specified above and concomitant medication information. 
 
 
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Concomitant therapies specifically prohibited (see Table 1) while the participant was on 
study intervention are no longer prohibited after discontinuation of study intervention.  
For these participants who have discontinued study intervention early, sites will be instructed 
to exert diligent efforts to continue to contact them. To enable sites to reach participants, the
participants should provide primary and secondary contact information (eg, home phone,
work phone, mobile phone). Sites must document the outcome of the telephone contact(s), to 
demonstrate diligent efforts have been made. If a participant does not agree to be contacted
for follow-up for each of the remaining visits (as described in Section 7.1 – Discontinuation
of Study Intervention), the participant should be encouraged to accept a telephone contact at
least at the final visit date (ie, Visit 7). 
Additionally, the ICF will explain the importance of continued data collection from
participants, including the use of continued contact by phone.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9).  
Changes to exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, but prior to unblinding/final database lock, will be documented in a supplemental 
statistical analysis plan (sSAP) and referenced in the Clinical Study Report (CSR) for the 
study.  Post hoc exploratory analyses will be clearly identified in the CSR. Separate analysis 
plans (ie, separate documents from the sSAP) will be developed to detail other planned 
analyses including those specific to the analysis of PK data and participant-reported 
outcomes.
 
 
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9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Sections 9.2-9.12. 
Study Design Overview
A Phase 2a, Proof of Concept, Randomized, Double-blind, 
Placebo-controlled Clinical Trial, to Evaluate the Efficacy and 
Safety of MK-7264 in Women with Moderate to Severe 
Endometriosis-related Pain
Treatment Assignment
Participants will be randomized in a 1:1 ratio to MK-7264 or
placebo. Randomization will be stratified according to the 
following factors: moderate pelvic pain (score of ≥5 to ˂8 on the 
NRS in the eDiary at baseline cycle) or severe pelvic pain (score 
of ≥8 on the NRS in the eDiary at baseline cycle).
Analysis Populations
Efficacy: Full Analysis Set (FAS) population. 
Safety: All Participants as Treated (APaT) population.
Primary Endpoint
Efficacy:
Average daily pelvic pain scores (cyclic and non-cyclic) during
TRC2.
Safety:
•
The proportion of participants with adverse events (AEs)
•
The proportion of participants with an AE which leads to 
discontinuation
Statistical Methods for 
Key Efficacy Analyses
The primary analysis approach will be conducted utilizing the 
longitudinal analysis of covariance (ANCOVA) model. In this 
model, the response vector consists of the change from baseline 
in the average daily pelvic pain score during TRC1 and TRC2. 
The model will include factors for average pelvic pain scores at 
baseline cycle, stratum, treatment, cycle, interaction of stratum-
by-cycle, and the interaction of treatment-by-cycle as covariates. 
The model will use all available daily scores for calculating 
average pain scores during TRC1 and TRC2. The least squares 
(LS) mean change from baseline with the associated standard 
errors (SEs) will be displayed for each treatment group. 
Estimated treatment differences (MK-7264 − placebo) along with 
corresponding 95% CIs will also be presented.
Statistical Methods for 
Key Safety Analyses
The analysis of safety endpoints will follow a tiered approach. 
The tiers differ with respect to the analyses that will be 
performed. Tier 1 safety endpoints will be subject to inferential 
testing for statistical significance with p-values and 95% CIs 
provided for between-group comparisons. Tier 2 safety 
endpoints will be evaluated via point estimates and 95% CIs for 
between-group comparisons. Tier 3 safety endpoints will be 
evaluated via point estimates only.
 
 
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Interim Analyses (IA)
This study is designed as a group sequential trial with one interim 
analysis and a final analysis. The interim analysis will be planned
for the primary endpoint when 84 participants have been enrolled 
and completed TRC2 (ie, 60% of the participants who are 
expected to complete TRC2). A non-binding futility criterion will 
be used based on the futility boundary using an O’Brien-Fleming
like beta error spending function (Hwang, Shih, deCani gamma = 
-4), and the results will be reviewed by a SiDMC.
At the IA, if the one-sided p-value is ≥  0.340, which is equivalent 
to observe that the treatment difference (MK-7264 - placebo) in 
change from baseline in average daily pelvic pain scores during 
TRC2 is greater than  -0.180 point (given the assumed Standard 
Deviation [SD]), the study enrollment may be terminated in 
support of an overall conclusion of futility. 
No interim analyses for safety will be planned for this protocol.
Multiplicity
No adjustment will be made for multiplicity.
Sample Size and Power 166 participants (83 in each group) will be randomized in this 
study, and the expected drop-out rate is 15%. Then 140 evaluable 
participants (70 participants in each group) will provide 84% 
power to detect a difference of 1 point between MK-7264 and 
placebo during TRC2, in change from baseline of the average 
daily pelvic pain score in the NRS, with one IA conducted when 
84 participants have been enrolled and completed TRC2 or 60% 
of the participants who are expected to complete TRC2. This 
power calculation is based on a two-sided test with Type I error 
0.05.
The sensitivity assessment of the power on the assumptions of 
dropout rate and SD are provided in Section 9.9. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee of the Sponsor.
The study will be conducted as a double-blind study under in-house blinding procedures. The 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  
Blinding issues related to the planned interim analyses are described in Section 9.7.  
 
 
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9.3
Hypotheses/Estimation
The primary hypothesis for this study is stated in Section 3. 
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary Efficacy Endpoint

Average daily pelvic pain scores (cyclic and non-cyclic) during TRC2
Secondary Efficacy Endpoints

Average daily cyclic pelvic pain scores during TRC2

Average daily non-cyclic pelvic pain scores during TRC2
Exploratory Efficacy Endpoints

Average daily use of naproxen sodium rescue medication by number of tablets taken 
for daily pelvic pain (cyclic and non-cyclic, combined and separately) during TRC2

Proportion of participants with at least 1-point (2, or 3) reduction in average daily 
pelvic pain score (cyclic and non-cyclic, combined and separately) as compared to 
baseline

Proportion of participants with at least 1-point (2, or 3) reduction in average daily 
pelvic pain score (cyclic and non-cyclic, combined and separately) as compared to 
baseline, and no increase in the average daily use of rescue medication by number of 
tablets

Proportion of participants with at least 1-point (2, or 3) reduction in average daily 
pelvic pain score (cyclic and non-cyclic, combined and separately) as compared to 
baseline, no increase in the average daily use of rescue medication by number of 
tablets, and no use of concomitant pain medication 

Proportion of participants with at least 1-point (2, or 3) reduction in average daily 
pelvic pain score (cyclic and non-cyclic, combined and separately) as compared to 
baseline, no increase in the average daily use of rescue medication by number of 
tablets, and no use of concomitant pain medication for ERP

Average daily pelvic pain scores (cyclic and non-cyclic) during PTC

Average daily pelvic pain scores (cyclic and non-cyclic) during TRC1
 
 
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
Number of days with no impact (score=0) of endometriosis-related pain at TRC2 on 
each of the following items, separately: work/school, physical activities, leisure/social 
activities, and sleep.

Patient’s Global Impression of Change ratings at TRC2

Endometriosis Health Profile-5 at TRC2
9.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 8.4. The analysis of safety 
results is described in Section 9.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, vital signs, and body weight. 
The a priori safety endpoint(s) of interest are: Taste related AEs (including dysgeusia, 
ageusia, and hypogeusia).
9.4.3
Pharmacokinetic Endpoints
Plasma pharmacokinetic parameters, Cmax and AUC, will be estimated using the population 
model developed using Phase 1 and Phase 2 data.
An exploratory analysis may be conducted to understand the pharmacokinetic and efficacy 
relationship.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all randomized participants 
who have received at least one dose of double-blind study treatment and had at least one day 
of eDiary entry during the treatment cycle post randomization.
The modified Full Analysis Set (mFAS) population will be used as a supportive population 
for primary and secondary efficacy endpoints. The mFAS population consists of all 
randomized participants who have received at least one dose of double-blind study treatment, 
and had at least 10 days of eDiary entries in each of the treatment cycles post randomization.
The completer population will be used as a supportive population for primary and secondary 
efficacy endpoints, and will be used for the planned interim analysis. The completer
population consists of all randomized participants who have completed the TRC2.
The Per-Protocol (PP) population will be used as another supportive population for primary 
and secondary efficacy endpoints. The PP population excludes participants from FAS due to 
important deviations from the protocol that may substantially affect the results of the 
 
 
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primary/secondary efficacy endpoint(s). Potential deviations that may result in the exclusion 
of a participant from the Per-Protocol population include:

Compliance with <75% of eDiary daily entries

No daily pelvic pain scores during TRC2
The final determination on protocol deviations will be made prior to the final unblinding of 
the database.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least one dose of study 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population.  
This will be the treatment group to which they are randomized except for participants who 
take incorrect study treatment for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study treatment actually received. 
The evaluable PK population for PK data analysis is defined as all participants with one 
measurable PK sample. 
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary
objectives.  Methods related to exploratory objectives will be described in the supplemental 
SAP.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. The primary analysis will be based on the FAS population, and supportive 
analyses will be based on the mFAS, Completer population and PP population.
The primary efficacy endpoint is the average daily pelvic pain score during TRC2. The 
variable of change from baseline in the average daily pelvic pain score will be used in the 
analysis of the primary endpoint. The primary analysis approach will be conducted utilizing 
the longitudinal analysis of covariance (ANCOVA) model. In this model, the response vector 
consists of the change from baseline in the average daily pelvic pain scores during TRC1 and 
TRC2. The model will include factors for average pelvic pain scores at baseline cycle, 
stratum, treatment, cycle, interaction of stratum-by-cycle, and the interaction of treatment-by-
cycle as covariates. The model will use all available daily scores for calculating average pain 
scores during TRC1 and TRC2. The least-squares (LS) mean change from baseline at TRC2 
with the associated standard errors (SEs) will be displayed for each treatment group; and the 
estimated treatment differences (MK-7264 − placebo) along with corresponding 95% CIs 
will also be presented.
 
 
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The average daily pelvic pain score during TRC1 will be analyzed from the same model, and 
the LS mean (SEs, and 95% CIs) will be presented in the same way.
The secondary endpoints will be analyzed in the same way as the primary endpoint.
Table 4 summarizes the key analyses strategies of the primary and secondary efficacy 
endpoints.
 
 
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Table 4
Statistical Methods for Efficacy Endpoints
Endpoint/Variable
(During TRC2)
Approach
Statistical 
Method
Analysis 
Population
Missing 
Data 
Approach
Primary
Average daily pelvic pain scores 
during TRC2
P
Longitudinal 
ANCOVA
FAS
Observed 
data only
S
Longitudinal 
ANCOVA
mFAS/Completer 
Population/PP
Observed 
data only
S
Longitudinal 
ANCOVA
FAS
Jump to 
reference 
imputation
Secondary
Average daily cyclic pelvic pain 
scores during TRC2
P
Longitudinal 
ANCOVA
FAS
Observed 
data only
S
Longitudinal 
ANCOVA
mFAS/Completer 
Population/PP
Observed 
data only
S
Longitudinal 
ANCOVA
FAS
Jump to 
reference 
imputation
Average daily non-cyclic pelvic pain 
scores during TRC2
P
Longitudinal 
ANCOVA
FAS
Observed 
data only
S
Longitudinal 
ANCOVA
mFAS/Completer 
Population/PP
Observed 
data only
S
Longitudinal 
ANCOVA
FAS
Jump to 
reference 
imputation
ANCOVA = Analysis of covariance; FAS = Full Analysis Set; mFAS=modified Full Analysis Set; PP = Per 
Protocol 
P = Primary; S = Supportive.
For the continuous endpoints for the exploratory objectives, similar statistical approaches
will be used as described above for the primary endpoint. For the proportions in the 
exploratory endpoints, they will be analyzed by logistic-regression models comparing 
MK-7264 with placebo, including average pelvic pain scores at baseline cycle, stratum, 
treatment, cycle, interaction of stratum-by-cycle, and the interaction of treatment-by- cycle as 
covariates.
 
 
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Additionally, change from baseline in average daily pelvic pain score (cyclic and non-cyclic, 
combined and separately) on days with rescue medication versus days without use rescue 
medication will also be summarized.
Handling of Missing Data
Sensitivity analyses will be conducted to incorporate methods for handling missing data due 
to participant who discontinue the trial. The missing data will be imputed based on jump-to-
reference method, that is, the missing scores in each treatment group will be imputed from
the placebo group. The multiple-imputation (MI) approach will be used and the details will 
be documented in sSAP.
9.6.2
Statistical Methods for Safety Analyses
The APaT population will be used for all safety analyses. Safety and tolerability will be 
assessed by clinical review of all relevant parameters including AEs, laboratory values, vital 
signs, and body weight.
The analysis of safety results will follow a tiered approach (Table 5). The tiers differ with 
respect to the analyses that will be performed. Tier 1 safety endpoints will be subject to 
inferential testing for statistical significance with p-values and 95% CIs provided for 
between-group comparisons. Tier 2 safety endpoints will be evaluated via point estimates 
and 95% CIs for between-group comparisons. Tier 3 safety endpoints will be evaluated via 
point estimates only.
Tier 1 Events
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance 
with p-values and 95% confidence intervals to be provided for between-treatment differences 
in the proportion of participants with events; these analyses will be performed using the 
Miettinen and Nurminen (M&N) method (1985), an unconditional, asymptotic method. For 
this protocol, Taste-related AEs (including dysgeusia, ageusia, and hypogeusia, as well as 
other related terms) are considered Tier 1 events.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events (also via the M&N 
method (1985).
Membership in Tier 2 requires that at least 4 participants in any treatment group exhibit the 
event. The threshold of at least 4 events was chosen because the 95% confidence interval for 
the between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
for Tier 2 events may be provided without adjustment for multiplicity, the confidence 
 
 
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intervals should be regarded as a helpful descriptive measure to be used in review, not a 
formal method for assessing the statistical significance of the between-group differences in 
adverse events and safety parameters that meet predefined limits of change.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a drug 
related AE, a serious AE, an AE which is both drug-related and serious, and discontinuation 
due to an AE will be considered Tier 2 endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Table 5
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint 
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Taste related AE (including dysgeusia, 
ageusia, and hypogeusia)
X
X
X
Tier 2
Any AE 
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any discontinuation due to AE
X
X
Any discontinuation due to Serious AE
X
X
Any discontinuation due to Drug-Related AE
X
X
Any discontinuation due to Serious Drug-
Related AE
X
X
Specific AEs (incidence ≥ 4 participants in 
one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs, or PDLCs 1 (incidence 
< 4 participants in both treatment groups)
Change from Baseline Results (Lab data, Vital 
Signs and Body Weight)
X
X
1
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Note: AE = Adverse Event; SOC=System Organ Class; PDLC=predefined limit of change; X = results will be provided.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and body 
weights, summary statistics for baseline, on-treatment, and change from baseline values will 
be provided by treatment group in table format.
 
 
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the summary statistics. No statistical hypothesis tests will be performed on these 
characteristics. 
Demographics and baseline characteristics include age, race, ethnicity, body weight, height, 
BMI (weight/height2 in kg/m2), medical history, gynecological history, and prior and 
concomitant medications. All variables will be summarized by treatment group either by 
descriptive statistics or categorical tables. 
The number and percentage of participants screened and randomized, the primary reasons for 
screening failure, and the primary reasons for discontinuation will be tabulated. The number 
of participants who were treated and completed the clinical trial will also be tabulated.
9.7
Interim Analyses
Treatment-level results and/or participant-level data from the interim analysis will be 
provided by the unblinded statistician to the standing internal Data Monitoring Committee 
(siDMC) which consists of SPONSOR personnel. Limited additional SPONSOR personnel 
may be unblinded to the treatment level results of the interim analysis, if required, in order to 
act on the recommendations of the siDMC. The extent to which individuals are unblinded 
with respect to results of interim analyses will be documented by the unblinded statistician.
The processes by which recommendations and decisions are reached and communicated are 
documented in the siDMC charter for the SPONSOR. The protocol-specific siDMC charter 
will be referenced in the CSR. Prior to final study unblinding, individuals who have been 
unblinded at any level will not be involved in any discussions regarding modifications to the 
protocol, statistical methods, identification of protocol deviations, or data validation efforts 
after the interim analyses.
This study is planned to have one interim analysis for futility and a final analysis. The 
interim analysis will be planned for the primary endpoint when 84 participants have been 
enrolled and completed TRC2 (60% of the participants who are expected to complete TRC2). 
The Completer Population (see Section 9.5.1) will be used for the assessment of evidence for
futility. A non-binding futility criterion will be used based on the futility boundary using 
O’Brien-Fleming like beta error spending function (Hwang, Shih, deCani gamma = -4). This 
is a conservative approach which will spend 2.8% beta error (Type II error) at the IA and the 
results will be reviewed by the SiDMC. During the futility analysis the enrollment of 
participants will continue.
At the IA, if the one-sided p-value is ≥  0.340, which is equivalent to observing that the 
treatment difference (MK-7264 - placebo) in change from baseline in average daily pelvic 
pain scores during TRC2 is greater than  -0.180 point (Table 6), the study enrollment may be 
 
 
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terminated in support of an overall conclusion of futility. The criterion and the boundary 
properties for the IA are given in Table 6.
Table 6
Boundary Properties for Planned Interim Analysis
Analysis
Value
Futility
IA: 84‡ participants or 
60% of the participants 
who are expected to 
complete TRC2
Z
-0.413
Nominal p-value
0.340
delta at bound§§
-0.180
P(Cross) if delta=0§
0.660
P(Cross) if delta=-1#
0.030
‡
The number of 84 participants is 60% of the 140 participants who are expected to 
complete TRC2, which can provide power 84% for this study. 
§§
The difference in change from baseline between MK-7264 and placebo.
§
The probability of crossing the futility bound when the true difference is 0 (null 
hypothesis).
#
The probability of crossing the futility bound when the true difference is -1 (assumed 
true difference for power calculation).
No Interim analyses for safety will be planned for this protocol.
9.8
Multiplicity
No adjustment will be made for multiplicity.
9.9
Sample Size and Power Calculations
166 participants (83 in each group) will be randomized in this study, and the expected drop-
out rate is 15%. Then 140 evaluable participants (70 participants in each group) will provide 
84% power to detect a difference of 1 point between MK-7264 and placebo during TRC2, in 
change from baseline of the average daily pelvic pain score in the NRS, with one IA 
conducted when 84 participants have been enrolled and completed TRC2 or 60% of the 
participants who are expected to complete TRC2. This power calculation is based on a two-
sided test with Type I error 0.05. The drop-out rate is from previous trials in chronic cough of 
MK-7264, and there is limited data to estimate the drop-out rate for ERP. Table 7 provides 
the power calculations for different assumptions of drop-out rate with the randomized 
participants.
 
 
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Table 7
Power Calculation Based on Different Dropout Rates
Number of 
Randomized 
Participants
Dropout Rate
Number of 
Evaluable 
Participants
Power
166
10%
149
86%
12%
146
85%
15% (expected)
140
84%
20%
132
82%
The assumption of the 1 point difference between MK-7264 and placebo, and the common 
standard deviation (SD) of 2 units are based on a publication by Diamond [Diamond, M. P., 
et al 2013]. Table 8 provides the power calculations for different assumptions of SD with the 
sample size. 
Table 8
Power Calculation for Different Assumptions of SD with 140 Evaluable Subjects 
Difference
SD
power
1
2.5
66%
1
2
84%
1
1.5
98%
1
1
100%
9.10
Subgroup Analyses
Analysis for the primary and secondary efficacy endpoints will be provided for the following 
subgroups of baseline factors:

Age category (18 – 30, 31 – 49 years).

Pain intensity: NRS in the eDiary moderate (score: ≥ 5 to ˂8) and severe (score: ≥8) 
at baseline. 

Geographic region (US versus ex-US)
Additional subgroup analysis will be provided for change from baseline in average daily use 
of rescue medication by geographic region (US versus ex-US).
 
 
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9.11
Compliance (Medication Adherence)
For each participant, percent compliance will be calculated using the following formula:
%
100
Therapy
on 
Be
Should
  
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 


A day within the study will be considered an “On-Therapy” day if the participant takes all 
required medication. When a participant takes less than or more than the required medication 
on a day, that day is not considered an “On-Therapy” day.
For participants who are followed for the entire study period, the “Number of Days Should 
be on Therapy” is the number of days from the first scheduled treatment day to the last 
scheduled treatment day. For participants who discontinue from the study, the “Number of 
Days Should be on Therapy” is the number of days from the first scheduled treatment day to 
the last dose day.
Summary statistics will be provided on percent compliance for the APaT population. 
9.12
Extent of Exposure
The duration of treatment for each participant will be evaluated by calculating the number of 
days on therapy. Exposure to study intervention will be summarized using descriptive 
statistics (ie, mean, SD, median, minimum, and maximum) for the APaT population.
 
 
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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.
B. Publication and Authorship
 
 
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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 (Institutiona 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.
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 
 
 
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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.
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 
 
 
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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 report form 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
Committees Structure
10.1.4.1
Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate Standing Internal 
Data Monitoring Committee (siDMC) will monitor the interim data from this study. The 
siDMC is comprised of members of Sponsor Senior Management, none of whom are directly 
associated with the conduct of this study. The siDMC will monitor the study at an 
appropriate frequency (Section 9.7 [Interim Analyses]) for evidence of futility, as described 
in the detailed monitoring guidelines. The siDMC will determine whether the study should 
continue according to the protocol.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
 
 
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If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
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. 
10.1.7
Compliance with Law, Audit, and Debarmen
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 good clinical practice); 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. 
 
 
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Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including 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.
 
 
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor 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 9 will be performed by the central laboratory.
•
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be 
entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
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 9
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
eGFR will be 
calculated with each 
serum creatinine
measurement (using 
the CKD EPI 
formula
[http://mdrd.com/]
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 (all crystals will be characterized)
Other Screening 
Tests
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)
 
 
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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, device, 
diagnostic agent, or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, 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, or are 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.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
 
 
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•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
 
 
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f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
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.
 
 
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Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
 
 
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-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
 
 
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•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
 
 
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•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
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 after menarche and until becoming postmenopausal unless 
permanently sterile. All participants in this study are WOCBP and must follow the 
contraception requirements below.
•
This includes women with tubal infertility from endometriosis. 
•
Exception:  Women who have had a documented bilateral salpingectomy may participate 
in the study, but do not have to follow protocol-specified contraception requirements. 
Note:  Documentation of bilateral salpingectomy can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview.
10.5.2
Contraception Requirements
A woman is eligible to participate in the study if she meets one of the following criteria:
•
Is heterosexually abstinent; 
Note: Sexual abstinence is defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
OR
•
Is heterosexually active and agrees to use two of the following barrier contraception 
methods consistently and correctly during the protocol-defined time frame in Section 5.1: 
male condom, female condom, cervical cap, diaphragm, sponge, or spermicide. 
Note:  Hormonal contraception except for sporadic use of emergency 
contraception is not permitted during the study. Male and female condoms should 
not be used at the same time. 
OR
•
Has undergone bilateral tubal sterilization;
OR 
•
Has a vasectomized partner.
Note: Partner must be the sole male sexual partner of the WOCBP and the absence of 
sperm has been confirmed. If not, a double barrier method of contraception must be 
used.
 
 
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10.5.3
Pregnancy Testing
Study participants should only be included after a negative highly sensitive urine and serum 
pregnancy test at Visit 1 and at Visit 4 (randomization). In between these visits, urine 
pregnancy testing will be performed at Visit 2 and 3. After randomization, additional 
pregnancy testing will be performed as indicated on the SoA (Section 1.3). At visits in which 
only a urine pregnancy test is indicated on the SoA, a serum pregnancy test will also be 
required when a pregnancy is suspected or when a urine pregnancy test is positive, unless 
pregnancy has already been confirmed by ultrasound. 
If any menstrual cycle is 2 weeks later than expected, the participant must perform a urine 
pregnancy test at home and contact the clinic to schedule a visit as soon as possible. The 
Sponsor must be consulted.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues 
that is a sign of a normal or abnormal process or of a condition or disease. A 
biomarker may be used to see how well the body responds to a treatment for a 
disease or condition. 
b. Pharmacogenomics: The investigation of variations of DNA and RNA 
characteristics as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will 
be used in various experiments to understand:

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the 
body

Other pathways drugs/vaccines may interact with

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how 
individuals respond to drugs/vaccines, enhance our understanding of human disease 
and ultimately improve public health through development of novel treatments 
targeted to populations with the greatest need. All specimens will be used by the 
Sponsor or those working for or with the Sponsor.
3.
Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
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 
 
 
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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 
treatment 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.
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.
 
 
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6.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that 
their biospecimens not be used for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main 
study. If medical records for the main study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com). Subsequently, the participant's 
specimens will be flagged in the biorepository and restricted to main study use only. 
If specimens were collected from study participants specifically for future biomedical 
research, these specimens will be removed from the biorepository and destroyed. 
Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if 
the investigator is no longer required by regulatory authorities to retain the main 
study records) or the specimens have been completely anonymized, there will no 
longer be a link between the participant’s personal information and their specimens. 
In this situation, the request for withdrawal of consent and/or destruction cannot be 
processed.
7.
Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored 
for longer if a regulatory or governmental authority has active questions that are 
being answered. In this special circumstance, specimens will be stored until these 
questions have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped 
to the Sponsor-designated biorepository. If a central laboratory is not utilized in a 
particular study, the study site will ship directly to the Sponsor-designated 
biorepository. The specimens will be stored under strict supervision in a limited 
access facility which 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.
 
 
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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.
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/ 
 
 
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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: Abbreviations
Abbreviation
Expanded Term
AE
Adverse event 
ANCOVA
Analysis of covariance
APaT
All participants as treated
ATP
Adenosine triphosphate
AUC50
Area under the curve required to achieve 50% of the maximal response
bid
Twice daily
BC
Baseline Cycle
BMI
Body mass index
BPS
Bladder pain syndrome
CHC
Combined hormonal contraceptive
CRF
Case Report Form 
CSR
Clinical Study Report
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram 
ECI
Events of clinical interest
eCRF
Electronic Case Report Form
EDC
Electronic data collection 
eDiary
Electronic diary
EHP-5
Endometriosis Health Profile-5
EMA
European Medicines Agency
ePRO
Electronic patient reported outcome
ERP
Endometriosis-related pain
FAS
Full analysis set
GCP
Good Clinical Practice 
GnRH
Gonadotropin-releasing hormone
hCG
Human chorionic gonadotropin
IB
Investigator’s Brochure 
IA
Interim analysis
IC
Interstitial cystitis
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board 
IRT
Interactive response technology
IUD
Intrauterine device
LS
Least squares
MI
Multiple imputation
NRS
Numeric rating scale
NSAID
Nonsteroidal anti-inflammatory drug
OA
Osteoarthritis
PGIC
Patient Global Impression of Change
PK
Pharmacokinetic
PoC
Proof of concept
PP
Per-protocol
PPI
Proton pump inhibitor
PTC
Post-treatment Cycle
SAE
Serious adverse event 
 
 
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Abbreviation
Expanded Term
SAP
Statistical analysis plan
SC
Screening Cycle
SD
Standard deviation
SE
Standard error
SiDMC
Standing Internal Data Monitoring Committee
SoA
Schedule of activities
sSAP
Supplemental statistical analysis plan
TRC1
Treatment Cycle 1
TRC2
Treatment Cycle 2
UPT
Urine pregnancy test
WOCBP
Woman/women of childbearing potential 
 
 
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11
REFERENCES
[Anaf, V., et al 2002]
Anaf V, Simon P, El Nakadi I, Fayt I, 
Simonart T, Buxant F, et al. Hyperalgesia, 
nerve infiltration and nerve growth factor 
expression in deep adenomyotic nodules, 
peritoneal and ovarian endometriosis. Hum 
Reprod. 2002;17(7):1895-900.
04VMBQ
[Berlanda, N., et al 2016]
Berlanda N, Somigliana E, Vigano P, 
Vercellini P. Safety of medical treatments for 
endometriosis. Expert Opin Drug Saf. 2016 
Jan;15(1):21-30.
04RNJ0
[Brown, J. 2014]
Brown J, Farquhar C. Endometriosis: an 
overview of Cochrane Reviews. Cochrane 
Database Syst Rev. 2014 Mar 
10;(3):CD009590.
04VM4Q
[Davenport, A., et al 2017]
Davenport A, Brauer N, Rotgeri A, Rottmann 
A, Koch M, Zollner TM, et al. [O-017] P2X3 -
A Highly Innovative Target for the Non-
Hormonal Treatment of 
Endometriosis[abstract]. Abstract of the 2017 
ASCO Annual meeting; 2017 Mar 16; 
Chicago, IL:ASCO; 2017. P.1.
04S0V8
[Diamond, M. P., et al 2013]
Diamond MP, Carr B, Dmowski WP, Koltun 
W, O'Brien C, Jiang P, et al. Elagolix 
treatment for endometriosis-associated pain: 
results from a phase 2, randomized, double-
blind, placebo-controlled study. Reprod Sci. 
2013:1-9. [Epub ahead of print].
04SJF0
[Ding, S., et al 2017]
Ding S, Zhu L, Tian Y, Zhu T, Huang X, 
Zhang X. P2X3 receptor involvement in 
endometriosis pain via ERK signaling 
pathway. PLoS One. 2017 Sep 
12;12(9):e0184647.
04S05X
[Dunselman, G. A. J, et al 
2014]
Dunselman GAJ, Vermeulen N, Becker C, 
Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. 
ESHRE guideline: management of women 
with endometriosis. Hum Reprod. 
2014;29(3):400-12.
04VM9S
 
 
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[Fritz, M. A. 2011]
Fritz MA, Speroff L. Clinical gynecologic 
endocrinology and infertility. 8th ed. 
Philadelphia: Lippincott Williams & Wilkins: 
c2011. Chapter 29, Endometriosis; p.1121-
1248.
04RZ8J
[Fuldeore, M. J. 2017]
Fuldeore MJ, Soliman AM. Prevalence and 
Symptomatic Burden of Diagnosed 
Endometriosis in the United States: National 
Estimates from a Cross-Sectional Survey of 
59,411 Women. Gynecol Obstet Invest. 
2017;82(5):453-461.
04RK80
[Guidice, L. C. 2010]
Guidice LC. Endometriosis. N Engl J Med 
2010;362:2389-98.
04RK7C
[Harada, T., et al 2008]
Harada T, Momoeda M, Taketani Y, Hoshiai 
H, Terakawa N. Low-dose oral contraceptive 
pill for dysmenorrhea associated with 
endometriosis: a placebo-controlled, double-
blind, randomized trial. Fertil Steril. 2008 
Nov;90(5):1583-8.
04RPL8
[Howard, F. M. 2009]
Howard FM. Endometriosis and mechanisms 
of pelvic pain. J Minim Invasive Gynecol. 
2009 Sep-Oct;16(5):540-50.
04RK78
[Leyland, N., et al 2010]
Leyland N, Casper R, Laberge P, Singh SS; 
SOGC. Endometriosis: diagnosis and 
management. J Obstet Gynaecol Can. 2010 
Jul;32(7 Suppl 2):S1-3.
04VMC8
[Martinez, B., et al 2013]
Martinez B, Canser E, Gredilla E, Alonso E, 
Gilsanz F. Management of patients with 
chronic pelvic pain associated with 
endometriosis refractory to conventional 
treatment. Pain Pract. 2013;13(1):53-8.
04WCM2
[Morotti, M., et al 2014]
Morotti M, Vincent K, Brawn J, Zondervan 
KT, Becker CM. Peripheral changes in 
endometriosis-associated pain. Hum Reprod 
Update. 2014;20(5):717-36.
04VMCD
[North, R. A. 2004]
North RA. P2X3 receptors and peripheral pain 
mechanisms. J Physiol. 2004 Jan 15;554(Pt 
2):301-8.
04JRR8
 
 
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[Parazzini, F., et al 2017]
Parazzini F, Esposito G, Tozzi L, Noli S, 
Bianchi S. Epidemiology of endometriosis and 
its comorbidities. Eur J Obstet Gynecol 
Reprod Biol. 2017 Feb;209:3-7.
04RK7D
[Practice Committee of the 
American Society for 
Reproductive Medc 2014]
Practice Committee of the American Society 
for Reproductive Medicine. Treatment of 
pelvic pain associated with endometriosis: a 
committee opinion. Fertil Steril. 2014 
Apr;101(4):927-35.
04RNHX
[Schleedoorn, M. J., et al 
2016]
Schleedoorn MJ, Nelen WL, Dunselman GA, 
Vermeulen N; EndoKey Group. Selection  of 
key recommendations for the management of 
women with endometriosis by an international 
panel of patients and professionals. Hum 
Reprod. 2016 Jun;31(6):1208-18.
04RK82
[Taylor, H. S., et al 2017]
Taylor HS, Giudice LC, Lessey BA, Abrao 
MS, Kotarski J, Archer DF, et al. Treatment of 
endometriosis-associated pain with elagolix, 
an oral GnRH antagonist. N Engl J Med. 2017 
Jul 6;377(1):28-40.
04VM4V
[Tokushige, N., et al 2006]
Tokushige N, Markham R, Russell P, Fraser 
IS. Nerve fibres in peritoneal endometriosis. 
Hum Reprod. 2006 Nov;21(11):3001-7.
04RK7R
 
 
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Supplemental Statistical Analysis Plan (sSAP)
Protocol Title: A Phase 2a, Proof of Concept, Randomized, Double-blind, 
Placebo-controlled Clinical Trial, to Evaluate the Efficacy and Safety of MK-
7264 in Women with Moderate to Severe Endometriosis-related Pain
 
 
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TABLE OF CONTENTS
1. INTRODUCTION........................................................................................................4
2. SUMMARY OF CHANGES.......................................................................................4
3. ANALYTICAL AND METHODOLOGICAL DETAILS .......................................4
3.1 STATISTICAL ANALYSIS PLAN SUMMARY .........................................4
3.2 RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING .................6
3.3 HYPOTHESES/ESTIMATION .....................................................................6
3.4 ANALYSIS ENDPOINTS .............................................................................6
3.4.1
Efficacy Endpoints..............................................................................6
3.4.2
Safety Endpoints.................................................................................7
3.4.3
Pharmacokinetic Endpoints ................................................................7
3.5 ANALYSIS POPULATIONS ........................................................................7
3.5.1
Efficacy Analysis Populations............................................................7
3.5.2
Safety Analysis Populations ...............................................................8
3.6 STATISTICAL METHODS...........................................................................9
3.6.1
Statistical Methods for Efficacy Analyses..........................................9
3.6.2
Statistical Methods for Safety Analyses...........................................14
3.6.3
Summaries of Baseline Characteristics, Demographics, 
and Other Analyses.................................................................................16
3.7 INTERIM ANALYSES................................................................................16
3.8 MULTIPLICITY ..........................................................................................17
3.9 SAMPLE SIZE AND POWER CALCULATIONS.....................................17
3.10
SUBGROUP ANALYSES AND EFFECT OF BASELINE
FACTORS ....................................................................................................18
3.11
COMPLIANCE (MEDICATION ADHERENCE) ................................19
3.12
EXTENT OF EXPOSURE.....................................................................19
4. REFERENCES...........................................................................................................20
 
 
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LIST OF TABLES
Table 1
Statistical Methods for Efficacy Endpoints ..................................................10
Table 2
Analysis Strategy for Safety Parameters ......................................................15
Table 3
Boundary Properties for Planned Interim Analysis......................................17
Table 4
Power Calculation Based on Different Dropout Rates.................................18
Table 5
Power Calculation for Different Assumptions of SD with 140 Evaluable 
Subjects......................................................................................................................18
 
 
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1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis 
plan that are not “principal” in nature and result from information that was not available at 
the time of protocol finalization.     
2. SUMMARY OF CHANGES
This document is the first version of the sSAP.
3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Sections 3.2-3.12.
Study Design Overview
A Phase 2a, Proof of Concept, Randomized, Double-blind, 
Placebo-controlled Clinical Trial, to Evaluate the Efficacy and 
Safety of MK-7264 in Women with Moderate to Severe 
Endometriosis-related Pain
Treatment Assignment
Participants will be randomized in a 1:1 ratio to MK-7264 or 
placebo. Randomization will be stratified according to the 
following factors: moderate pelvic pain (score of ≥5 to ˂8 on 
the NRS in the eDiary at baseline cycle) or severe pelvic pain 
(score of ≥8 on the NRS in the eDiary at baseline cycle).
Analysis Populations
Efficacy: Full Analysis Set (FAS) population. 
Safety: All Participants as Treated (APaT) population.
Primary Endpoint
Efficacy:
Average daily pelvic pain scores (cyclic and non-cyclic) during 
TRC2.
Safety:
•
The proportion of participants with adverse events (AEs)
•
The proportion of participants with an AE which leads to 
discontinuation
Statistical Methods for 
Key Efficacy Analyses
The primary analysis approach will be conducted utilizing the 
longitudinal analysis of covariance (ANCOVA) model. In this
model, the response vector consists of the change from baseline 
in the average daily pelvic pain score during Treatment Cycle 1 
(TRC1) and Treatment Cycle 2 (TRC2). The model will include 
factors for average pelvic pain scores at baseline cycle, stratum, 
treatment, cycle, interaction of stratum-by-cycle, and the 
interaction of treatment-by-cycle as covariates. The model will 
use all available daily scores for calculating average pain scores 
during TRC1 and TRC2. The least squares (LS) mean change 
 
 
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from baseline with the associated standard errors (SEs) will be 
displayed for each treatment group. Estimated treatment 
differences (MK-7264 − placebo) along with corresponding 95% 
CIs will also be presented.
Statistical Methods for 
Key Safety Analyses
The analysis of safety endpoints will follow a tiered approach. 
The tiers differ with respect to the analyses that will be 
performed. Tier 1 safety endpoints will be subject to inferential 
testing for statistical significance with p-values and 95% CIs 
provided for between-group comparisons. Tier 2 safety 
endpoints will be evaluated via point estimates and 95% CIs for 
between-group comparisons. Tier 3 safety endpoints will be 
evaluated via point estimates only.
Interim Analyses (IA)
This study is designed as a group sequential trial with one interim 
analysis and a final analysis. The interim analysis will be planned 
for the primary endpoint when 84 participants have been enrolled 
and completed TRC2 (ie, 60% of the participants who are 
expected to complete TRC2). A non-binding futility criterion will 
be used based on the futility boundary using an O’Brien-Fleming
like beta error spending function (Hwang, Shih, deCani gamma = 
-4), and the results will be reviewed by a SiDMC.
At the IA, if the one-sided p-value is ≥0.340, which is equivalent 
to observe that the treatment difference (MK-7264 - placebo) in 
change from baseline in average daily pelvic pain scores during 
TRC2 is greater than -0.180 point (given the assumed Standard 
Deviation [SD]), the study enrollment may be terminated in 
support of an overall conclusion of futility. 
No interim analyses for safety will be planned for this protocol.
Multiplicity
No adjustment will be made for multiplicity.
Sample Size and Power 166 participants (83 in each group) will be randomized in this 
study, and the expected drop-out rate is 15%. Then 140 evaluable 
participants (70 participants in each group) will provide 84% 
power to detect a difference of 1 point between MK-7264 and 
placebo during TRC2, in change from baseline of the average 
daily pelvic pain score in the NRS, with one IA conducted when 
84 participants have been enrolled and completed TRC2 or 60% 
of the participants who are expected to complete TRC2. This 
power calculation is based on a two-sided test with Type I error 
0.05.
The sensitivity assessment of the power on the assumptions of 
dropout rate and SD are provided in Section 3.9. 
 
 
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3.2
RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee of the Sponsor.
The study will be conducted as a double-blind study under in-house blinding procedures. The 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  
Blinding issues related to the planned interim analyses are described in Section 3.7.   
3.3
HYPOTHESES/ESTIMATION
The primary hypothesis for this study is stated in Section 3 of Protocol.
3.4
ANALYSIS ENDPOINTS
3.4.1
Efficacy Endpoints
Primary Efficacy Endpoint

Average daily pelvic pain scores (cyclic and non-cyclic) during TRC2
Secondary Efficacy Endpoints

Average daily cyclic pelvic pain scores during TRC2

Average daily non-cyclic pelvic pain scores during TRC2
Exploratory Efficacy Endpoints

Average daily use of naproxen sodium rescue medication by number of tablets taken 
for daily pelvic pain (cyclic and non-cyclic, combined and separately) during TRC2

Proportion of participants with at least 1-point (2, or 3) reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline
during TRC2

Proportion of participants with at least 1-point (2, or 3) reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline
during TRC2, and no increase in the average daily use of rescue medication by number 
of tablets

Proportion of participants with at least 1-point (2, or 3) reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline
 
 
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during TRC2, no increase in the average daily use of rescue medication by number of 
tablets, and no use of concomitant pain medication 

Proportion of participants with at least 1-point (2, or 3) reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline
during TRC2, no increase in the average daily use of rescue medication by number of 
tablets, and no use of concomitant pain medication for ERP

Average daily pelvic pain scores (cyclic and non-cyclic, combined and separately) 
during PTC

Average daily pelvic pain scores (cyclic and non-cyclic, combined and separately) 
during TRC1

Number of days with no impact (score=0) of endometriosis-related pain at TRC2 on 
each of the following items, separately: work/school, physical activities, leisure/social 
activities, and sleep. 

Patient’s Global Impression of Change ratings at TRC2

Endometriosis Health Profile-5 at TRC2
3.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 8.4. The analysis of safety 
results is described in Section 3.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, vital signs, and body weight. 
The a priori safety endpoint(s) of interest are: Taste related AEs (including dysgeusia, ageusia, 
and hypogeusia).
3.4.3
Pharmacokinetic Endpoints
Plasma pharmacokinetic parameters, Cmax and AUC, will be estimated using the population 
model developed using Phase 1 and Phase 2 data.
An exploratory analysis may be conducted to understand the pharmacokinetic and efficacy 
relationship.
3.5
ANALYSIS POPULATIONS
3.5.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all randomized participants 
who have received at least one dose of double-blind study treatment and had at least one day 
of eDiary entry during the treatment cycle post randomization.
 
 
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The modified Full Analysis Set (mFAS) population will be used as a supportive population 
for primary and secondary efficacy endpoints. The mFAS population consists of all 
randomized participants who have received at least one dose of double-blind study treatment, 
and had at least 10 days of eDiary entries in each of the treatment cycles post randomization.
The completer population will be used as a supportive population for primary and secondary 
efficacy endpoints, and will be used for the planned interim analysis. The completer 
population consists of all randomized participants who have completed the TRC2.
The Per-Protocol (PP) population will be used as another supportive population for primary 
and secondary efficacy endpoints. The PP population excludes participants from FAS due to 
important deviations from the protocol that may substantially affect the results of the 
primary/secondary efficacy endpoint(s). Potential deviations that may result in the exclusion 
of a participant from the Per-Protocol population include:

Compliance with <75% of eDiary daily entries

No daily pelvic pain scores during TRC2
For each participant, percent eDiary compliance will be calculated using the following 
formula:
The number of days with eDiary daily entries (numerator) is the number of days with eDiary 
daily entries during overall trial period (i.e., from the date of Visit 2 to one day before the 
date of Visit 7/Discontinuation) and the number of expected days with eDiary daily entries 
(denominator) is the number of days during overall trial period (i.e., from the date of Visit 2 
to one day before the date of Visit 7/Discontinuation).
The final determination on protocol deviations will be made prior to the final unblinding of 
the database.
3.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least one dose of study 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population.  
This will be the treatment group to which they are randomized except for participants who 
take incorrect study treatment for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study treatment actually received. 
At least one laboratory, vital sign, weight, or height measurement obtained subsequent to at 
least one dose of study treatment is required for inclusion in the analysis of the respective 
safety parameter. To assess change from baseline, a baseline measurement is also required.
 
 
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The evaluable PK population for PK data analysis is defined as all participants with one 
measurable PK sample.
3.6
STATISTICAL METHODS
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in Section 3.6.1.
3.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. The primary analysis will be based on the FAS population, and supportive 
analyses will be based on the mFAS, Completer population and PP population.
The efficacy analyses will be performed based on the available data during 5 cycles, defined 
as below:

Screening Cycle (SC): 
o
Starts the first non-bleeding day of the SC (i.e., 1 day after the last day of the 
menses before Visit 2) and ends the last bleeding day of SC. 

Baseline Cycle (BC) placebo run-in period:
o
Starts on the first non-bleeding day of the BC (i.e., 1 day after the last
bleeding day of the SC) and ends the last bleeding day of BC.

TRC1 after randomization:
o
Starts on Day 1(i.e., the first study medication intervention) and ends the last 
bleeding day of TRC1.

TRC2:
o
Starts on the first non-bleeding day of TRC2 (i.e.,1 day after the last bleeding 
day of the TRC1) and ends the last bleeding day of TRC2.

Post-Treatment Cycle (PTC) after the participant has stopped taking study 
intervention:  
o
Starts on the first non-bleeding day of PTC (i.e.1 day after the last bleeding 
day of the TRC 2) or the day after the last dose of study medication, 
whichever is last and ends the last bleeding day of PTC.
Primary Efficacy Analysis
The primary efficacy endpoint is the average daily pelvic pain score during TRC2. The 
variable of change from baseline in the average daily pelvic pain score will be used in the 
analysis of the primary endpoint. The primary analysis approach will be conducted utilizing 
the longitudinal analysis of covariance (ANCOVA) model. In this model, the response vector 
consists of the change from baseline in the average daily pelvic pain scores during TRC1 and 
 
 
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TRC2. The model will include factors for average pelvic pain scores at baseline cycle, 
stratum, treatment, cycle, interaction of stratum-by-cycle, and the interaction of treatment-by-
cycle as covariates. The model will use all available daily scores for calculating average pain 
scores during TRC1 and TRC2. The least-squares (LS) mean change from baseline at TRC2 
with the associated standard errors (SEs) will be displayed for each treatment group; and the 
estimated treatment differences (MK-7264 − placebo) along with corresponding 95% CIs 
will also be presented.
Secondary Efficacy Analyses
The secondary endpoints will be analyzed in the same way as the primary endpoint.
Table 1 summarizes the key analyses strategies of the primary and secondary efficacy 
endpoints.
Table 1
Statistical Methods for Efficacy Endpoints
Endpoint/Variable
(During TRC2)
Approach
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary
Average daily pelvic pain 
scores during TRC2
P
Longitudinal 
ANCOVA
FAS
Observed data 
only
S
Longitudinal 
ANCOVA
mFAS/Completer 
Population/PP
Observed data 
only
S
Longitudinal 
ANCOVA
FAS
Jump to 
reference 
imputation
Secondary
Average daily cyclic pelvic 
pain scores during TRC2
P
Longitudinal 
ANCOVA
FAS
Observed data 
only
S
Longitudinal 
ANCOVA
mFAS/Completer 
Population/PP
Observed data 
only
S
Longitudinal 
ANCOVA
FAS
Jump to 
reference 
imputation
Average daily non-cyclic 
pelvic pain scores during 
TRC2
P
Longitudinal 
ANCOVA
FAS
Observed data 
only
S
Longitudinal 
ANCOVA
mFAS/Completer 
Population/PP
Observed data 
only
S
Longitudinal 
ANCOVA
FAS
Jump to 
reference 
imputation
ANCOVA = Analysis of covariance; FAS = Full Analysis Set; mFAS=modified Full Analysis Set; PP = Per 
Protocol 
P = Primary; S = Supportive.
 
 
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Exploratory Efficacy Analyses

For the continuous endpoints for the exploratory objectives, similar statistical 
approaches will be used as described above for the primary endpoint. Average daily 
use of naproxen sodium rescue medication in terms of number of tablets taken for 
daily pelvic pain (cyclic and non-cyclic, combined and separately) as compared to 
baseline during TRC2:
From the longitudinal ANCOVA model, the response vector consists of the change 
from baseline in the average daily use of naproxen sodium rescue medication during 
TRC1and TRC2. The model will include factors for average daily use of naproxen 
sodium rescue medication at baseline cycle, stratum, treatment, cycle, interaction of 
stratum-by-cycle, and the interaction of treatment-by- cycle as covariates.

Average daily pelvic pain scores (cyclic and non-cyclic, combined and separately) as 
compared to the Screening Cycle during PTC:
From the longitudinal ANCOVA model, the response vector consists of the change 
from screening cycle in the average daily pelvic pain scores during BC, TRC1, TRC2, 
and PTC. The model will include factors for average pelvic pain scores at screening 
cycle, stratum, treatment, cycle, interaction of stratum-by-cycle, and the interaction of 
treatment-by- cycle as covariates. The LS mean (SEs, and 95% CIs) will be 
presented.

Average daily pelvic pain scores (cyclic and non-cyclic, combined and separately) as 
compared to baseline during TRC1:
The average daily pelvic pain score during TRC1 will be analyzed from the same 
model (including response vector and covariates) for the primary endpoint, and the 
LS mean (SEs, and 95% CIs) will be presented in the same way.
For the proportions in the following exploratory endpoints, they will be analyzed by logistic-
regression models comparing MK-7264 with placebo, including average pelvic pain scores at 
baseline cycle, stratum, treatment, cycle, interaction of stratum-by-cycle, and the interaction 
of treatment-by- cycle as covariates.

Proportion of participants with at least 1-point (2, or 3) reduction in average daily 
pelvic pain score (cyclic and non-cyclic, combined and separately) as compared to 
baseline during TRC2.

Proportion of participants with at least 1-point (2, or 3) reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline
during TRC2, and no increase in the average daily use of rescue medication by number 
of tablets. 

Proportion of participants with at least 1-point (2, or 3) reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline
 
 
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during TRC2, no increase in the average daily use of rescue medication by number of 
tablets, and no use of concomitant pain medication.

Proportion of participants with at least 1-point (2, or 3) reduction in average daily pelvic 
pain score (cyclic and non-cyclic, combined and separately) as compared to baseline
during TRC2, no increase in the average daily use of rescue medication by number of 
tablets, and no use of concomitant pain medication for ERP.
The following PRO exploratory endpoints will be analyzed using available data.

Endometriosis Health Profile (EHP)-5: 
The EHP-5 is an endometriosis-specific questionnaire to assess the participant’s 
health-related quality of life. Participants will respond by selecting one of these five 
categorical responses- “never”, “rarely”, “sometimes”, “often”, “always”-” at the 
beginning of the run-in period (Visit 3) and at the end of TRC 2 (Visit 6) on 5 items 
from the core questionnaire. The EHP-5 responses will be summarized in terms of 
frequencies and percentages in the cross-classification table for each of 5 items.

The Patient’s Global Impression of Change (PGIC) ratings:
The PGIC is a 7-point scale collecting a participant’s rating of overall change in her 
ERP relative to her condition before initiation of the treatment. Participants rate their 
change as “much better”, “better”, “a little better”, “the same,” “a little worse”, 
“worse”, or “much worse”. Proportion of subjects with improvements (either “much 
better” or “better” or “a little better” on the PGIC scale) at TRC2 will be analyzed using 
the stratified Miettinen and Nurminen method (1985) [1].

Impact score of pelvic pain:
Fraction of days with no impact (score=0) of endometriosis-related pain (ERP) during
BC and TRC2 will be summarized on each of work/school, physical activities, 
leisure/social activities, and sleep items.
Additionally, change from baseline in average daily pelvic pain score (cyclic and non-cyclic, 
combined and separately) during TRC2 on days with rescue medication versus days without 
use rescue medication will also be summarized.
Handling of Missing Data
Sensitivity analyses will be conducted to incorporate methods for handling missing data (i.e., 
no eDiary entry for either TRC1 or TRC2). The missing data will be imputed based on jump-
to-reference method, that is, the missing scores after dropout time in treatment group will be 
imputed from the placebo group. 
The longitudinal data analysis (LDA) method assumes that data are missing at random 
(MAR). In this study, it is expected that missing at random and missing completely at 
random (MAR/MCAR) mechanisms will underlie most of the missingness, and the 
proportion of data missing not at random (MNAR), driven solely by unobserved values of the 
 
 
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study endpoints, will be small. The multiple imputation (MI) approach will be used to assess 
the robustness of the primary analysis approaches.
Jump-to-reference (J2R) Multiple-imputation Analysis
J2R imputation falls under the category of pattern mixture models known as reference-based 
imputation (RBI). The RBI approach uses different imputation models for missing data in 
different treatment groups. In J2R, missing data in the control group are imputed under the 
MAR assumption, while missing data in the treatment groups are imputed under a MNAR 
assumption using the control group profile for time points after withdrawal.
The following steps will be used to implement the J2R multiple-imputation analysis. 
1) A parameter-estimation model is fitted using PROC MCMC. All of the covariates 
included in the primary analysis will be used for the parameter-estimation model. For 
the MCMC procedure, an initial random seed = 72642730 will be used. N = 500 sets
pseudo-independent samples of the model parameters will be drawn from the joint 
posterior distribution.
2) The imputation model is built, where, for each pattern of withdrawal, a predicted 
value model is created using the parameters estimated in Step 1. The random seed for 
the imputations is 72642730. For subjects in the control (reference) group, the 
predicted means are calculated under MAR assumption; for subjects in the other 
treatment arm, the predicted means are calculated under MNAR using the jump-to-
reference approach, that is, the mean profile is based on the same treatment arm 
before withdrawal and ‘jumps’ to the mean profile based on the reference arm after 
withdrawal. A complete dataset will be generated using the imputation model for 
each set of the N = 500 parameters obtained in Step 1. 
3) For each of the imputed complete datasets, an ANCOVA model will be used for the 
change from baseline values at last time point. The model will include the same 
covariates as in the primary analysis model. The treatment difference across the 500 
datasets will then be combined using PROC MIANALYZE, i.e., using Rubin’s rule 
for multiple imputation (Rubin, 1987) to provide the final results.
To get correct the variance for the jump-to-reference imputation method, a pattern mixture 
model approximation will also be used. Based on the definition, the jump-to-reference 
imputation will have a mean treatment difference of zero between treatment and control for 
those who dropped out in the treatment arm. Therefore, the overall mean treatment difference 
for jump-to-reference becomes
ߠ௃ଶோൌሺߨ௧ߤ௧
ௗ൅ሺ1 െߨ௧ሻߤ௧
௣ሻെߤ௧
௣ൌߨ௧ሺߤ௧
ௗെߤ௧
௣ሻ
where ߨ௧is the proportion of completers (i.e., subjects with non-missing response at t) in the 
drug group, t is the last time point, and ߤ௧
ௗand ߤ௧
௣are the mean effects for drug and control, 
respectively. It can be estimated from the primary analysis model as ߠ෡ܬ2ܴൌߨෝݐሺߤෝݐ
݀െߤෝݐ
݌ሻ. 
The variance can be approximated by, 
var൫θ෠୎ଶୖ൯ൌπෝ୲
ଶvarሺμො୲
ୢെμො୲
୮ሻ൅൫μො୲
ୢെμො୲
୮൯
ଶπෝ୲ሺ1 െπෝ୲ሻ/n
where n is sample size in the drug treatment arm. The first term can be estimated from the 
primary analysis model. 


';/


3%

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3.6.2
Statistical Methods for Safety Analyses
The APaT population will be used for all safety analyses. Safety and tolerability will be 
assessed by clinical review of all relevant parameters including AEs, laboratory values, vital 
signs, and body weight.
The analysis of safety results will follow a tiered approach (Table 2). The tiers differ with 
respect to the analyses that will be performed. Tier 1 safety endpoints will be subject to 
inferential testing for statistical significance with p-values and 95% CIs provided for 
between-group comparisons. Tier 2 safety endpoints will be evaluated via point estimates 
and 95% CIs for between-group comparisons. Tier 3 safety endpoints will be evaluated via 
point estimates only.
Tier 1 Events
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance 
with p-values and 95% confidence intervals to be provided for between-treatment differences 
in the proportion of participants with events; these analyses will be performed using the 
Miettinen and Nurminen (M&N) method (1985), an unconditional, asymptotic method. For 
this protocol, Taste-related AEs (including dysgeusia, ageusia, and hypogeusia, as well as 
other related terms) are considered Tier 1 events. 
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events (also via the M&N 
method (1985).
Membership in Tier 2 requires that at least 4 participants in any treatment group exhibit the 
event. The threshold of at least 4 events was chosen because the 95% confidence interval for 
the between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
for Tier 2 events may be provided without adjustment for multiplicity, the confidence 
intervals should be regarded as a helpful descriptive measure to be used in review, not a 
formal method for assessing the statistical significance of the between-group differences in 
adverse events and safety parameters that meet predefined limits of change.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a drug 
related AE, a serious AE, an AE which is both drug-related and serious, and discontinuation 
due to an AE will be considered Tier 2 endpoints. 
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
 
 
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Table 2
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint 
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Taste related AE (including dysgeusia, 
ageusia, and hypogeusia)
X
X
X
Tier 2
Any AE 
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any discontinuation due to AE
X
X
Any discontinuation due to Serious AE
X
X
Any discontinuation due to Drug-Related AE
X
X
Any discontinuation due to Serious Drug-
Related AE
X
X
Specific AEs (incidence ≥ 4 participants in 
one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs, or PDLCs 1 (incidence 
< 4 participants in both treatment groups)
Change from Baseline Results (Lab data, Vital 
Signs and Body Weight)
X
X
1
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Note: AE = Adverse Event; SOC=System Organ Class; PDLC=predefined limit of change; X = results will be provided.
The safety lab parameters, vital signs, height and weight will be analyzed based on available 
data during 5 periods defined as below:

Screening Period: 
o
Starts at the time the subject signs the ICF (Visit 1) and ends the last bleeding 
day of the SC. 

Run-In Period:
o
Starts on the first non-bleeding day of the BC (i.e. 1 day after the last bleeding
day of the SC) and ends prior to the time of witnessed dose on Day 1.

TRC1 after randomization:
o
Starts on Day 1 at the time of witnessed dose and ends the last bleeding day of 
TRC1.

TRC2:
o
Starts on the first non-bleeding day of TRC2 (i.e.1 day after the last bleeding 
day of the TRC1), and ends the last bleeding day of TRC2 or on the day of 
last dose of study medication, whichever is last.
 
 
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
PTC after the participant has stopped taking study intervention:  
o
Starts on the first non-bleeding day of PTC (i.e.1 day after the last bleeding 
day of the TRC 2) or the day after the last dose of study medication,
whichever is last and ends on the day of Visit 7.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and body 
weights, summary statistics for baseline, on-treatment, and change from baseline values will 
be provided by treatment group in table format.
3.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the summary statistics. No statistical hypothesis tests will be performed on these 
characteristics. 
Demographics and baseline characteristics include age, race, ethnicity, body weight, height, 
BMI (weight/height2 in kg/m2), medical history, gynecological history, and prior and 
concomitant medications. All variables will be summarized by treatment group either by 
descriptive statistics or categorical tables. 
The number and percentage of participants screened and randomized, the primary reasons for 
screening failure, and the primary reasons for discontinuation will be tabulated. The number 
of participants who were treated and completed the clinical trial will also be tabulated.
3.7 INTERIM ANALYSES
Treatment-level results and/or participant-level data from the interim analysis will be 
provided by the unblinded statistician to the standing internal Data Monitoring Committee 
(siDMC) which consists of SPONSOR personnel. Limited additional SPONSOR personnel 
may be unblinded to the treatment level results of the interim analysis, if required, in order to 
act on the recommendations of the siDMC. The extent to which individuals are unblinded 
with respect to results of interim analyses will be documented by the unblinded statistician.
The processes by which recommendations and decisions are reached and communicated are 
documented in the siDMC charter for the SPONSOR. The protocol-specific siDMC charter 
will be referenced in the CSR. Prior to final study unblinding, individuals who have been 
unblinded at any level will not be involved in any discussions regarding modifications to the 
protocol, statistical methods, identification of protocol deviations, or data validation efforts 
after the interim analyses.
This study is planned to have one interim analysis for futility and a final analysis. The 
interim analysis will be planned for the primary endpoint when 84 participants have been 
enrolled and completed TRC2 (60% of the participants who are expected to complete TRC2). 
The Completer Population (see Section 3.5.1) will be used for the assessment of evidence for
futility. A non-binding futility criterion will be used based on the futility boundary using 
 
 
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O’Brien-Fleming like beta error spending function (Hwang, Shih, deCani gamma = -4). This 
is a conservative approach which will spend 2.8% beta error (Type II error) at the IA and the 
results will be reviewed by the SiDMC. During the futility analysis the enrollment of 
participants will continue.
At the IA, if the one-sided p-value is ≥ 0.340, which is equivalent to observing that the 
treatment difference (MK-7264 - placebo) in change from baseline in average daily pelvic 
pain scores during TRC2 is greater than  -0.180 point (Table 3), the study enrollment may be 
terminated in support of an overall conclusion of futility. The criterion and the boundary 
properties for the IA are given in Table 3.
Table 3
Boundary Properties for Planned Interim Analysis
Analysis
Value
Futility
IA: 84‡ participants or 60% of 
the participants who are 
expected to complete TRC2
Z
-0.413
Nominal p-value
0.340
delta at bound§§
-0.180
P(Cross) if delta=0§
0.660
P(Cross) if delta=-1#
0.030
‡
The number of 84 participants is 60% of the 140 participants who are expected to complete 
TRC2, which can provide power 84% for this study. 
§§
The difference in change from baseline between MK-7264 and placebo.
§
The probability of crossing the futility bound when the true difference is 0 (null hypothesis).
#
The probability of crossing the futility bound when the true difference is -1 (assumed true 
difference for power calculation).
No Interim analyses for safety will be planned for this protocol.
3.8 MULTIPLICITY
No adjustment will be made for multiplicity
3.9
SAMPLE SIZE AND POWER CALCULATIONS
166 participants (83 in each group) will be randomized in this study, and the expected drop-
out rate is 15%. Then 140 evaluable participants (70 participants in each group) will provide 
84% power to detect a difference of 1 point between MK-7264 and placebo during TRC2, in 
change from baseline of the average daily pelvic pain score in the NRS, with one IA 
conducted when 84 participants have been enrolled and completed TRC2 or 60% of the 
participants who are expected to complete TRC2. This power calculation is based on a two-
sided test with Type I error 0.05. The drop-out rate is from previous trials in chronic cough of 
MK-7264, and there is limited data to estimate the drop-out rate for ERP. Table 4 provides 
the power calculations for different assumptions of drop-out rate with the randomized 
participants.
 
 
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Table 4
Power Calculation Based on Different Dropout Rates 
Number of 
Randomized 
Participants
Dropout Rate
Number of 
Evaluable 
Participants
Power
166
10%
149
86%
12%
146
85%
15% (expected)
140
84%
20%
132
82%
The assumption of the 1 point difference between MK-7264 and placebo, and the common 
standard deviation (SD) of 2 units are based on a publication by Diamond [2]. Table 5
provides the power calculations for different assumptions of SD with the sample size. 
Table 5
Power Calculation for Different Assumptions of SD with 140 Evaluable Subjects 
Difference
SD
power
1
2.5
66%
1
2
84%
1
1.5
98%
1
1
100%
3.10 SUBGROUP ANALYSES AND EFFECT OF BASELINE FACTORS
Analysis for the primary and secondary efficacy endpoints will be provided for the following 
subgroups of baseline factors:

Age category (18 – 30, 31 – 49 years).

Pain intensity: NRS in the eDiary moderate (score: ≥ 5 to ˂8) and severe (score: ≥8) 
at baseline. 

Geographic region (US versus ex-US)
Additional subgroup analysis will be provided for change from baseline in average daily use 
of rescue medication by geographic region (US versus ex-US).
 
 
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3.11 COMPLIANCE (MEDICATION ADHERENCE)
For each participant, percent compliance will be calculated using the following formula:
%
100
Therapy
on 
Be
Should
  
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 


A day within the study will be considered an “On-Therapy” day if the participant takes all 
required medication. When a participant takes less than or more than the required medication 
on a day, that day is not considered an “On-Therapy” day.
For participants who are followed for the entire study period, the “Number of Days Should 
be on Therapy” is the number of days from the first scheduled treatment day to the last 
scheduled treatment day. For participants who discontinue from the study, the “Number of 
Days Should be on Therapy” is the number of days from the first scheduled treatment day to 
the last dose day.
Summary statistics will be provided on percent compliance for the APaT population. 
3.12 EXTENT OF EXPOSURE
The duration of treatment for each participant will be evaluated by calculating the number of 
days on therapy. Exposure to study intervention will be summarized using descriptive 
statistics (ie, mean, SD, median, minimum, and maximum) for the APaT population.
 
 
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4. REFERENCES 
[1]
Miettinen O, Nurminen M. Comparative analysis of two rates. 
Statistics in Medicine 1985;4:213-26.
03P76P
[2]
Diamond MP, Carr B, Dmowski WP, Koltun W, O'Brien C, Jiang P, 
et al. Elagolix treatment for endometriosis-associated pain: results 
from a phase 2, randomized, double-blind, placebo-controlled study. 
Reprod Sci. 2013:1-9. [Epub ahead of print].
04SJF0
 
 
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