Conditions: Human Immunodeficiency Virus AIDS Virus
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 17
Healthy volunteers: no

Brief summary:
This study will evaluate the anti-retroviral activity of MK-8527 in HIV-1 infected, ART-naïve participants. The primary hypothesis is that MK-8527 has superior anti-retroviral activity compared to placebo, as measured by change from baseline in plasma HIV-1 ribonucleic acid (RNA) at 168 hours postdose.

Detailed description:
Up to five panels (Panels A-E) of 6 participants each will be enrolled in a sequential manner. In each panel, participants will receive a single dose of MK-8527 up to 50 mg. Historical data from previous single does studies will be used for placebo (control) comparisons.

Arms:
arm 1: Single oral dose of 10 mg MK-8527 capsule after an 8-hour fast arm 2: Single oral dose of 3 mg MK-8527 capsule after an 8-hour fast arm 3: Single oral dose of 1 mg MK-8527 capsule after an 8-hour fast. Dose level determined by results of previous panels. arm 4: Single oral dose of ≤50 mg MK-8527 capsule after an 8-hour fast. Dose level determined by results of previous panels. arm 5: Single oral dose of ≤50 mg MK-8527 capsule after an 8-hour fast. Dose level determined by results of previous panels.

Interventions: intervention 1: MK-8527
Intervention descriptions: intervention 1: Single oral capsule

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03615183 
Document Date: 
07-JUN-2018
A Single-Dose Clinical Trial to Study the Safety, Tolerability,
Pharmacokinetics, and Anti-Retroviral Activity of MK-8527 
Monotherapy in Anti-Retroviral Therapy (ART)-Naïve, HIV-1 
Infected Participants


PRODUCT: MK-8527 
1
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-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 Single-Dose Clinical Trial to Study the Safety, Tolerability, 
Pharmacokinetics, and Anti-Retroviral Activity of MK-8527 Monotherapy in Anti-Retroviral 
Therapy (ART)-Naïve, HIV-1 Infected Participants
Protocol Number: 002-00
Compound Number: MK-8527
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):
EudraCT
2018-001861-18
Approval Date:  07-JUN-2018
 
 
04Y8GH


PRODUCT: MK-8527 
2
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
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
 
 
04Y8GH


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CCI


PRODUCT: MK-8527 
4
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
5.3.2.1
Caffeine Restrictions..........................................................................37
5.3.2.2
Alcohol Restrictions...........................................................................37
5.3.2.3
Tobacco Restrictions..........................................................................37
Activity Restrictions ....................................................................................37
5.3.3
Contraception and Pregnancy Testing .........................................................38
5.3.4
5.3.4.1
Contraception.....................................................................................38
5.3.4.2
Pregnancy Testing..............................................................................38
5.4
Screen Failures.....................................................................................................38
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................39
6.2
Preparation/Handling/Storage/Accountability .................................................41
Dose Preparation..........................................................................................41
6.2.1
Handling, Storage, and Accountability........................................................41
6.2.2
6.3
Measures to Minimize Bias: Randomization and Blinding..............................42
Intervention Assignment..............................................................................42
6.3.1
Stratification.................................................................................................42
6.3.2
Blinding........................................................................................................42
6.3.3
6.4
Study Intervention Compliance..........................................................................42
6.5
Concomitant Therapy..........................................................................................42
Rescue Medications and Supportive Care ...................................................43
6.5.1
6.6
Dose Modification (Escalation/Titration/Other)...............................................43
6.7
Intervention After the End of the Study............................................................44
6.8
Clinical Supplies Disclosure................................................................................44
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................44
7.1
Discontinuation of Study Intervention...............................................................44
7.2
Participant Withdrawal From the Study...........................................................45
7.3
Lost to Follow-up .................................................................................................45
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................46
8.1
Administrative and General Procedures ...........................................................47
Informed Consent.........................................................................................47
8.1.1
8.1.1.1
General Informed Consent.................................................................47
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................47
Inclusion/Exclusion Criteria ........................................................................47
8.1.2
Participant Identification Card.....................................................................48
8.1.3
Medical History ...........................................................................................48
8.1.4
 
 
04Y8GH


PRODUCT: MK-8527 
5
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
Prior and Concomitant Medications Review ...............................................48
8.1.5
8.1.5.1
Prior Medications...............................................................................48
8.1.5.2
Concomitant Medications ..................................................................48
Assignment of Screening Number...............................................................48
8.1.6
Assignment of Treatment/Randomization Number.....................................48
8.1.7
Study Intervention Administration ..............................................................48
8.1.8
8.1.8.1
Timing of Dose Administration.........................................................49
Discontinuation and Withdrawal .................................................................49
8.1.9
8.1.9.1
Withdrawal From Future Biomedical Research ................................49
Participant Blinding/Unblinding..................................................................49
8.1.10
Domiciling ...................................................................................................50
8.1.11
Calibration of Equipment.............................................................................50
8.1.12
8.2
Efficacy/Immunogenicity Assessments ..............................................................50
8.3
Safety Assessments...............................................................................................50
Physical Examinations.................................................................................50
8.3.1
Vital Signs....................................................................................................51
8.3.2
8.3.2.1
Resting Vital Signs ............................................................................51
8.3.2.2
Orthostatic Vital Signs.......................................................................51
Electrocardiograms ......................................................................................51
8.3.3
Clinical Safety Laboratory Assessments .....................................................52
8.3.4
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................53
Time Period and Frequency for Collecting AE, SAE, and Other 
8.4.1
Reportable Safety Event Information ..........................................................53
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......55
8.4.2
Follow-up of AE, SAE, and Other Reportable Safety Event Information...55
8.4.3
Regulatory Reporting Requirements for SAE .............................................55
8.4.4
Pregnancy and Exposure During Breastfeeding ..........................................55
8.4.5
Events of Clinical Interest (ECIs) ................................................................56
8.4.6
8.5
Treatment of Overdose........................................................................................56
8.6
Pharmacokinetics.................................................................................................57
Blood Collection for Plasma MK-8527 and PBMC MK-8527-TP .............57
8.6.1
8.7
Pharmacodynamics..............................................................................................57
8.8
Future Biomedical Research Sample Collection...............................................57
8.9
Planned Genetic Analysis Sample Collection ....................................................57
8.10
Biomarkers ...........................................................................................................57
8.11
Health Economics Medical Resource Utilization and Health Economics.......58
8.12
Visit Requirements...............................................................................................58
 
 
04Y8GH


PRODUCT: MK-8527 
6
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
Screening......................................................................................................58
8.12.1
Treatment Period Visit.................................................................................58
8.12.2
8.12.2.1
Predose Procedures (All Panels)........................................................58
8.12.2.2
Treatment Procedures (All Panels) ....................................................58
Discontinued Participants Continuing to be Monitored in the Study ..........59
8.12.3
Poststudy......................................................................................................59
8.12.4
Critical Procedures Based on Study Objectives: Timing of Procedure .......59
8.12.5
Study Design/Dosing/Procedures Modifications Permitted Within 
8.12.6
Protocol Parameters .....................................................................................60
9
STATISTICAL ANALYSIS PLAN .............................................................................62
9.1
Statistical Analysis Plan Summary.....................................................................62
9.2
Responsibility for Analyses .................................................................................63
9.3
Hypotheses/Estimation ........................................................................................63
9.4
Analysis Endpoints...............................................................................................63
9.5
Analysis Populations............................................................................................64
9.6
Statistical Methods...............................................................................................64
9.7
Interim Analyses ..................................................................................................66
9.8
Multiplicity ...........................................................................................................66
9.9
Sample Size and Power Calculations .................................................................66
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................67
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........67
Code of Conduct for Clinical Trials.............................................................67
10.1.1
Financial Disclosure.....................................................................................69
10.1.2
Data Protection.............................................................................................69
10.1.3
10.1.3.1
Confidentiality of Data ......................................................................70
10.1.3.2
Confidentiality of Participant Records...............................................70
10.1.3.3
Confidentiality of IRB/IEC Information............................................70
Publication Policy........................................................................................70
10.1.4
Compliance with Study Registration and Results Posting Requirements ...71
10.1.5
Compliance with Law, Audit, and Debarmen .............................................71
10.1.6
Data Quality Assurance ...............................................................................72
10.1.7
Source Documents .......................................................................................73
10.1.8
Study and Site Closure.................................................................................73
10.1.9
10.2
Appendix 2: Clinical Laboratory Tests..............................................................74
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................75
Definition of AE ..........................................................................................75
10.3.1
 
 
04Y8GH


PRODUCT: MK-8527 
7
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
Definition of SAE ........................................................................................76
10.3.2
Additional Events Reported.........................................................................77
10.3.3
Recording AE and SAE ...............................................................................78
10.3.4
Reporting of AE, SAE, and Other Reportable Safety Events to the 
10.3.5
Sponsor ........................................................................................................79
10.4
Appendix 4: Contraceptive Guidance and Pregnancy Testing........................80
10.5
Appendix 5: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................81
10.6
Appendix 6: Country-specific Requirements ....................................................86
10.7
Appendix 7: 12-Lead Electrocardiogram Abnormality Criteria ....................87
10.8
Appendix 10.8: Algorithm for Assessing Out of Range Laboratory Values ..89
10.9
Appendix 9: Approximate Blood/Tissue Volumes Drawn/Collected by 
Trial Visit and by Sample Types ........................................................................90
10.10 Appendix 10: Abbreviations ...............................................................................91
11
REFERENCES...............................................................................................................92
 
 
04Y8GH


PRODUCT: MK-8527 
8
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
LIST OF TABLES
Table 1
Dose Escalation Scheme for MK-8527............................................................14
Table 2
MK-8527 Total Exposure (AUC) and Exposure Multiples After Different 
Doses in Toxicology Studies in Animals.........................................................20
Table 3
Preliminary Summary Geometric Mean (Geometric % CV) MK-8527 
Plasma Pharmacokinetic Parameter Values Following Administration of 
Single Oral Doses of MK-8527 to Healthy Fasted Male Participants .............21
Table 4
Preliminary Summary Geometric Mean (Geometric % CV) MK-8527-TP 
PBMC Pharmacokinetic Parameter Values Following Administration of 
Single Oral Doses of MK-8527 to Healthy Fasted Male Participants .............22
Table 5
Study Interventions ..........................................................................................40
Table 6
Sample Allocation Schedule............................................................................42
Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................54
Table 8
PK/PD Blood Collection Window...................................................................60
Table 9
Protocol-required Safety Laboratory Assessments..........................................74
 
 
04Y8GH


PRODUCT: MK-8527 
9
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
LIST OF FIGURES
No table of figures entries found.
 
 
04Y8GH


PRODUCT: MK-8527 
10
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Single-Dose Clinical Trial to Study the Safety, Tolerability, 
Pharmacokinetics, and Anti-Retroviral Activity of MK-8527 Monotherapy in Anti-Retroviral 
Therapy (ART)-Naïve, HIV-1 Infected Participants
Short Title: MK-8527 Single Dose Trial in HIV-1 Infected Participants
Acronym:
Hypotheses, Objectives, and Endpoints:
Study Population: Treatment naïve HIV-1 infected participants
Primary Objectives
Primary Endpoints
- To evaluate the antiretroviral activity of 
MK-8527 in HIV-1 infected participants 
relative to placebo.
Hypothesis: At a dose that is sufficiently safe 
and generally well tolerated, MK-8527 has 
superior antiretroviral activity compared to 
placebo, as measured by change from 
baseline in plasma HIV-1 RNA (log10 
copies/mL) at 168 hours postdose. That is, 
the true mean difference in the plasma HIV -
1 RNA reduction from baseline between 
MK-8527 and placebo is at least 1.0 log10 
copies/mL.
- Plasma HIV-1 RNA (log10 copies/mL) 
reduction from baseline
- To evaluate the safety and tolerability of 
MK-8527 in HIV-1 infected participants.
- AEs, laboratory tests, vital signs (VS), 
ECGs
 
 
04Y8GH


PRODUCT: MK-8527 
11
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
Secondary Objectives
Secondary Endpoints
- To evaluate the intracellular PK of MK-
8527-TP in PBMC after administration of 
single oral doses to HIV-1 infected 
participants.
Hypothesis: At a dose that is sufficiently safe 
and generally well tolerated, the true GM 
C168hr MK-8527-TP in PBMC is at least 0.2 
pmol/106 cells
- MK-8527-TP AUC0-168, AUC0-last, 
AUC0-inf, Tmax, Cmax, C168hr, and 
apparent terminal t1/2 in PBMC.
- To evaluate plasma PK of MK-8527 after 
administration of single oral doses to HIV-1 
infected participants.
- MK-8527 plasma AUC0-168, AUC0-last, 
AUC0-inf, Tmax, Cmax, C168hr, and 
apparent terminal t1/2.
- To evaluate the PK-PD association of 
plasma MK-8527 and intracellular MK-
8527-TP with viral load reduction.
- PK (MK-8527-TP in PBMC, MK-8527 
plasma)/PD (Plasma HIV-1 RNA) 
correlation
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
- To evaluate the relationship between dose 
and antiretroviral activity of MK-8527.
- Dose-response (Plasma HIV-1 RNA) 
relationship
-  To evaluate the potential for long term 
exposure of PBMC MK-8527-TP at 
potentially efficacious levels
- PBMC MK-8527-TP C336H, C672H
- To explore the relationship between genetic 
variation and response to the treatment 
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
 
 
04Y8GH


PRODUCT: MK-8527 
12
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of HIV-1 Infection
Population
HIV-1 Infected Participants
Study Type
Interventional
Intervention Model
Sequential
This is a single-site study.
Type of Control
Historical control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 11 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 30 participants will be allocated.
 
 
04Y8GH


PRODUCT: MK-8527 
13
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
Panel A
MK-8527
10 mg
Once
Oral
Single Dose
Experimental
Panel B
MK-8527
25 mg
Once
Oral
Single Dose
Experimental
Panel C
MK-8527
≤50 mg
Once
Oral
Single Dose
Experimental
Panel D
MK-8527
≤50 mg
Once
Oral
Single Dose
Experimental
Panel E
MK-8527
≤50 mg
Once
Oral
Single Dose
Experimental
Abbreviations:
Total 
Number
30 participants (5 panels of 6 participants each).
Duration of 
Participation
Each participant will participate in the study for approximately 8 weeks from 
the time the participant signs the Informed Consent Form (ICF) through the 
final contact. After a screening phase of ~4 weeks, each participant will receive
assigned intervention. After drug administration, each participant will be 
followed for 28 days.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.
 
 
04Y8GH


PRODUCT: MK-8527 
14
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
1.2
Schema
The study design is depicted in Table 1.
Table 1
Dose Escalation Scheme for MK-8527
Panela
Dose of MK-8527b
A
10 mg
B
25 mg
Cc
≤50 mg
Dc
≤50 mg 
Ec
≤50 mg 
a   In each panel, 6 participants will receive a single dose of MK-8527.
b  The decision to proceed to the next panel will be made following review of safety 
and viral load data out to at least Day 8 (i.e., 7 days post-dose) from the preceding 
panel.
c A decision to enroll Panel C and the dose to be administered will be based on the 
results of safety, PK and viral load data out to at least Day 8 in Panels A and B.
Enrollment of Panels D and E and the doses to be administered will be based on the 
results of safety, PK, and viral load data from all prior panels.
 
 
04Y8GH


PRODUCT: MK-8527
15
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
1.3
Schedule of Activities (SoA)
All Panelsa
Pre-
trial
Treatment
Post-
study Notes
Scheduled Hour, Day, Week, etc.
Screen-
ing 1
Pre-
dose
0
0.25 0.5 1
2
3
4
6
8
12 24 48 72 96 120 144 168 192 240 336 504 672
l
Post-
studyk
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Inclusion/Exclusion Criteria
X
X
Recheck 
clinical 
status before 
1st dose of 
study
intervention
Participant Identification Card
X
Medical History (includes 
substance usage)
X
Substances: 
Drugs, 
alcohol, 
tobacco, and 
caffeine
Prior/Concomitant Medication 
Review
    X---------------------------------------------------------------------------------------------------------------------------X
Intervention Allocation 
X
Clinic Procedures and Assessments
MK-8527 Administration
X
Standard Mealsc
X--------------X
Safety Procedures
Full physical examination
X
X
X
X
X
Height
X
Weight
X
X
Vital Signs (heart rate, blood 
pressure)
X
Xm
X
X
X
X
Vital Signs (respiratory rate, body 
temperature)
X
X
X
X
X
X
 
 
04Y8GH


PRODUCT: MK-8527
16
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
All Panelsa
Pre-
trial
Treatment
Post-
study Notes
Scheduled Hour, Day, Week, etc.
Screen-
ing 1
Pre-
dose
0
0.25 0.5 1
2
3
4
6
8
12 24 48 72 96 120 144 168 192 240 336 504 672
l
Post-
studyk
Orthostatic Vital Signs (heart rate, 
blood pressure)
X
X
X
X
X
X
12-lead ECG
X
Xm
X
X
X
X
Urine/Serum β-Human Chorionic 
Gonadotropin (β-hCG; WOCBP 
only)e
X
Xd
Serum Follicle Stimulating 
Hormone (FSH) -  (WONCBP 
only)f
X
HIV, hepatitis B and C screen (per 
site SOP)
X
Urine Drug Screen (per site SOP)g
X
X
Hematology, Urinalysis, Chemistry
X
Xd
X
X
X
AE/SAE review
     X--------------------------------------------------------------------------------------------------------------------------X
Pharmacokinetics
Blood for Plasma MK-8527 Assayh
X
X X X X X X X X X X X X
X
Blood for MK-8527 PBMC Assayi
X
X
X X
X
X
X
X
X
X
X
X
X
Pharmacodynamics
Blood for HIV RNA, viral 
resistancej
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
CD-4 cell count
X
Biomarkers
Blood (DNA) for Genetic Analysisb
X
Collected 
from 
randomized 
participants 
only – See 
Section 8.8
and 8.9.
 
 
04Y8GH


PRODUCT: MK-8527
17
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
All Panelsa
Pre-
trial
Treatment
Post-
study Notes
Scheduled Hour, Day, Week, etc.
Screen-
ing 1
Pre-
dose
0
0.25 0.5 1
2
3
4
6
8
12 24 48 72 96 120 144 168 192 240 336 504 672
l
Post-
studyk
a. Panels will be conducted sequentially with review of data from prior panel before proceeding. Panel B and C will occur after completion and review of safety, 
pharmacokinetic, and viral dynamic data from Panels A and B, respectively. Panel D and E will occur after completion and review of safety, pharmacokinetic, 
and viral dynamic data from prior panels. 
b. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at 
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 (FBR) if the participant signs the FBR consent. If the planned genetic 
analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
c. Standardized meals will be provided at ~4 and ~10 hours post-dose. A snack will be offered at ~ 7 and 13 hours post-dose. After the 24 hour postdose 
procedures have been completed, subsequent meal and snacks will be unrestricted in terms of caloric content, composition and timing.
d. Can be conducted on admission (within 24 hours before dosing).
e. For female participants of childbearing potential only. Urine pregnancy test can be performed at predose.
f. For postmenopausal women only.
g. Screening UDS is mandatory; any additional UDS are conducted per site SOP.
h. Leftover plasma samples will be stored for future biomedical research at the end of the study, if the participant signs theFuture Biomedical Research consent.
i. For all panels, PBMC samples may be collected up to the post-trial visit regardless of initiation of ART.
j. For all panels, blood for HIV-1 viral RNA and viral resistance may be collected up to the post-trial visit if a participant does not start ART.
k. The post-trial visit will occur approximately 28 days following administration of the study drug. Follow up for any clinical or laboratory adverse experiences 
should occur by phone or in person if the post-trial visit occurs prior to 28 days following the last dose of study drug. For confirmation of viral load return to 
baseline, additional data from viral load samples collected during routine follow-up visits may be transmitted to the sponsor for those participants who do not 
begin ART and who provide appropriate informed consent.
l. The 672 hour sample may be collected at the post-trial  visit.
m. Predose ECGs and VS (heart rate and blood pressure) will be obtained in triplicate approximately 1-2 minutes apart within 3 hours prior to dosing MK-8527.
 
 
04Y8GH


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PRODUCT: MK-8527
23
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS     
Study Population: Treatment naïve HIV-1 infected participants
Objectives
Endpoints
Primary
•
To evaluate the antiretroviral activity of 
MK-8527 in HIV-1 infected participants
relative to placebo.
Hypothesis: At a dose that is sufficiently 
safe and generally well tolerated, MK-
8527 has superior antiretroviral activity 
compared to placebo, as measured by 
change from baseline in plasma HIV-1 
RNA (log10 copies/mL) at 168 hours 
postdose. That is, the true mean 
difference in the plasma HIV -1 RNA 
reduction from baseline between MK-
8527 and placebo is at least 1.0 log10 
copies/mL.
•
Plasma HIV-1 RNA (log10 copies/mL)
reduction from baseline

To evaluate the safety and tolerability of 
MK-8527 in HIV-1 infected participants.

AEs, laboratory tests, vital signs (VS), 
ECGs
Secondary
•
To evaluate the intracellular PK of MK-
8527-TP in PBMC after administration of 
single oral doses to HIV-1 infected 
participants.
Hypothesis: At a dose that is sufficiently 
safe and generally well tolerated, the true
GM C168hr MK-8527-TP in PBMC is at 
least 0.2 pmol/106 cells
•
MK-8527-TP AUC0-168, AUC0-last,
AUC0-inf, Tmax, Cmax, C168hr, and 
apparent terminal t1/2 in PBMC.
•
To evaluate plasma PK of MK-8527 after 
administration of single oral doses to 
HIV-1 infected participants.
•
MK-8527 plasma AUC0-168, AUC0-
last, AUC0-inf, Tmax, Cmax, C168hr, 
and apparent terminal t1/2.
•
To evaluate the PK-PD association of 
plasma MK-8527 and intracellular MK-
8527-TP with viral load reduction.
•
PK (MK-8527-TP in PBMC, MK-8527 
plasma)/PD (Plasma HIV-1 RNA) 
correlation
 
 
04Y8GH


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PRODUCT: MK-8527
27
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
For the PK assessment, active MK-8527-TP in PBMCs may be determined for up to 28 days 
following single dose administration. Plasma concentrations of unchanged MK-8527 will be 
determined for up to 7 days. These will enable determination of attainment of predicted 
target required for significant viral load reduction on a weekly dosing regimen and exposures 
below the safety margins established from the monkey NOAEL.
This study will establish whether achieving the efficacy target is associated with a 
commensurate VL reduction worthy of continued clinical development. Hence, assessment of 
this primary pharmacokinetic parameter will be conducted 7 days after administration of the 
MK-8527 dose. Additional assessments beyond 7 days (e.g., 14, 21 or 28 days) may also be 
performed.
4.2.1.3
Viral Pharmacodynamic Endpoints
A pharmacodynamic (PD) endpoint of a >1.0 log10 suppression of HIV-1 RNA from 
baseline on Day 7, relative to historical placebo data, will be used. A 70% posterior 
probability of achieving the target viral load reduction for at least one dose level that also 
exhibits an acceptable safety and tolerability profile will satisfy the primary 
pharmacodynamic hypothesis. The 70% posterior probability was chosen as a reasonable 
level of certainty in the results to ensure that the appropriate dose(s) that can achieve the PD
target is taken into subsequent studies in the patient population with a reasonable chance of 
achieving the desired therapeutic effect in VL reduction. This target is consistent with 
previous observations with NRTI drugs which have produced VL reduction of 0.5log 10 as 
well as results with some newer compounds which have demonstrated potential to lower VL
below 1.0log10, and also with past feedback from regulatory agencies that limit NRTI 
monotherapy studies to 7-10 days in duration. A decrease of this magnitude supports 
potential activity with long term administration in the target population.
Participants with a baseline HIV-1 RNA load of at least 5,000 copies/mL will be enrolled to 
ensure an adequate dynamic range by which changes in HIV RNA can be quantified. 
Periodic blood samples will be collected to assess MK-8527 associated changes in absolute 
VL over time and will be compared relative to historical placebo data.  Based on the long 
half-life of MK-8527-TP, changes in VL may be assessed through 28 days for participants
who do not initiate follow-on ART. For these participants, any VL data that are further 
collected as part of routine follow-up may be transmitted to the Sponsor, provided the 
participant gave appropriate consent. These extra data would only be reviewed to determine 
when the participant’s VL returned to baseline to provide an exploratory and preliminary 
understanding of the long term effect of MK-8527. 
Evaluation of VL data from other HIV monotherapy studies has indicated that results are 
consistent between trials and that on average, participants receiving placebo do not exhibit a 
change from baseline that differs from the anticipated within-participant variability in VL. 
Furthermore, given the overall favorable safety profile of MK-8527 in preclinical and clinical 
testing to date, the need for a placebo control to minimize investigator and participant bias 
with respect to adverse experiences was deemed not necessary. 
 
 
04Y8GH


PRODUCT: MK-8527
28
PROTOCOL/AMENDMENT NO.: 002-00
MK-8527-002-00-FINAL PROTOCOL
07-JUN-2018
Additionally, the kinetics of VL reduction vs. dose and exposure will also be determined.
4.2.1.4
Planned Exploratory Biomarker Research
4.2.1.4.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples 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.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 5.
 
 
04Y8GH


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PRODUCT: MK-8527
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made to end the study following this review period, the study end will be defined as the date 
of the Sponsor decision and this end of study date supersedes the definitions outlined above.
The Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics 
Committee(s) [IRB(s)/IEC(s)] will be apprised of the maximum duration of the study beyond 
the last participant out and the justification for keeping the study open.
Clinical Criteria for Early Study Termination
4.4.1
There are no prespecified criteria for terminating the study early.
A primary objective of this early Phase 1 study is to identify the maximum safe and well-
tolerated dose and/or dosing regimen that achieve PK, PD, and/or biologic targets in humans 
based on preclinical or early clinical data. Therefore, it is possible that study participants may 
not receive all doses specified in the protocol if this objective is achieved at lesser dose levels 
in this study. This would not be defined as early termination of the study, but rather an earlier 
than anticipated achievement of the study objective(s). If a finding (e.g., PK, PD, efficacy, 
biologic targets, etc.) from another preclinical or clinical study using the study
intervention(s), comparator(s), drug(s) of the same class, or methodology(ies) used in this 
study results in the study(s) or program being stopped for non-safety reasons, this also does 
not meet the definition of early study termination.
Early study termination is defined as a permanent discontinuation of the study due to 
unanticipated concerns of safety to the study participants arising from clinical or preclinical 
studies with the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study.
Enrollment of the trial will be halted in the following circumstances:
1. One participant reports a serious AE with a potential causal relationship to the study 
drug or two (2) participants per panel report severe AEs with a potential causal 
relationship to study drug.
2. Three (3) or more of the enrolled participants experience the same AE requiring 
withdrawal from the study, or the same severe AE assessed as having a potential 
causal relationship to study drug.
3. Two (2) participants experience severe but not life threatening AEs or severe 
clinically significant laboratory abnormalities that are similar in nature. 
4. One (1) serious AE/laboratory abnormality is reported that is life threatening, results 
in persistent or significant disability/incapacity, results in or prolongs an existing 
inpatient hospitalization, or is another important medical event OR participant death 
thought to be potentially related to the investigational product.
5. Two (2) or more of the enrolled participants experience confirmed QTcF > 500 ms or 
QTcF change from baseline > 60 ms in a given panel with a potential causal 
relationship to study drug.
 
 
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If one of the above circumstances occurs, enrollment and dosing will be halted, and an
internal safety review will be conducted prior to making a decision about terminating the
study. The safety of participants will be assessed on an ongoing basis, and while conditions 
that could warrant early trial termination are not limited to those noted above, these criteria 
are meant to pre-specify circumstances under which the trial may be terminated early. In the
event that the trial is interrupted or safety data suggest that the benefit-to-risk assessment has
been meaningfully altered and must be reassessed, the Regulatory Authority will be notified.
5
STUDY POPULATION
Male/Female participants with HIV-1 infection who are 18 to 60 years (inclusive) will be 
enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Other than HIV infection, is in good health based on medical history, physical 
examination, VS measurements performed at the prestudy (screening) visit and/or 
prior to administration of the single dose of study drug.
2. Is documented HIV-1 positive as determined by a positive ELISA or QT-PCR with
confirmation (e.g., Western Blot).
3. Was diagnosed with HIV-1 infection ≥ 3 months prior to screening or perform the 
French 2008 HAS Algorithm to confirm chronic HIV.
4. Has a screening plasma HIV-1 RNA ≥5,000 copies/mL within 30 days prior to the
treatment phase of this study.
5. Has a screening plasma CD4+ T-cell count of >200/mm3.
6. Is ART-naïve which is defined as having never received any antiretroviral agent OR
the following:
≤30 consecutive days of an investigational antiretroviral agent, excluding an NRTI,
OR
≤60 consecutive days of combination ART not including an NRTI
7. Has not received an investigational agent or marketed ART within 30 days of study
drug administration.
 
 
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8. Is willing to receive no other ART for the monitoring period of this study.
9. Has no evidence at screening for mutations conferring resistance to NRTIs (including 
but not limited to M184V, M184I) as previously defined.
10. Has the following laboratory values at screening: direct bilirubin ≤ 1.0 mg/dL, AST 
(SGOT) and ALT (SGPT) ≤2 x upper limit of normal.
Demographics
11. Is from 18 years to 60 years of age inclusive, at the time of signing the informed 
consent.
12. Has a Body Mass Index (BMI) ≤35 kg/m2, inclusive. See Section 8.1 for criteria on 
rounding to the nearest whole number. BMI = weight (kg)/height (m)2.
13. Is Male or Female with the following requirements:
Male Participants
a.
If the male participant has a female partner(s) of childbearing potential, he must agree 
to use a medically acceptable method of contraception during the study and for 120 
days after the last dose of study drug. If their partner is pregnant, males must agree to 
use a condom and no additional method of contraception is required for the pregnant 
partner.
NOTE: Spermicides alone are not an acceptable method of contraception. Their 
partner must additionally be using one of the following methods: hormonal 
contraception, intra-uterine device, diaphragm with spermicide, cervical cap with 
spermicide.
Female Participants
b. If the participant is a female with reproductive potential, she must demonstrate a 
serum β-human chorionic gonadotropin (β-hCG) level consistent with the nongravid 
state at the prestudy (screening) visit and agree to use (and/or have their partner use) 
2 acceptable methods of birth control beginning at the prestudy (screening) visit, 
throughout the study (including washout intervals between treatment periods/panels) 
and until 28 days after the last dose of study drug. Acceptable methods of birth 
control are defined in Section 5.3.4.1.
c.
If the participant is a postmenopausal female: she is without menses for at least 1 year 
and have a documented follicle stimulating hormone (FSH) level in the 
postmenopausal range at prestudy (screening).
AND/OR
 
 
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d. If the participant is a surgically sterile female: she is status posthysterectomy, or 
oophorectomy.
These procedures must be confirmed with medical records. In the absence of 
documentation, hysterectomy may be confirmed by pelvic exam or if necessary by 
ultrasound; oophorectomy may be confirmed by hormone levels, particularly FSH in 
the post-menopausal range. Information must be captured appropriately within the 
site's source documents.
Informed Consent
14. Provides written informed consent/assent for the study. The participant may also 
provide consent/assent for future biomedical research. However, the participant may 
participate in the main study without participating in future biomedical research.
Additional Categories
15. Is willing to comply with the trial restrictions (see Section 5.3 for a complete 
summary of trial restrictions).
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological (outside of HIV-1 infection), renal, respiratory, 
genitourinary, or major neurological (including stroke and chronic seizures) 
abnormalities or diseases. Participants with a remote history of uncomplicated medical 
events (eg, uncomplicated kidney stones, as defined as spontaneous passage and no 
recurrence in the last 5 years, or childhood asthma) may be enrolled in the study at the 
discretion of the investigator.
2. Is mentally or legally incapacitated at the time of the prestudy (screening) visit or 
expected during the conduct of the study or has a history of clinically significant 
psychiatric disorder over the last 5 years. Participants who have had situational 
depression may be enrolled in the study at the discretion of the investigator.
3. Has a history of cancer (malignancy). Exception: participants, who, in the opinion of the 
study investigator, are highly unlikely to sustain a recurrence for the duration of the 
study.
4. Has an estimated creatinine clearance (CrCl) ≤ 90 mL/min based on the Cockcroft-Gault 
(CG) Equation.
 
 
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Cockcroft-Gault Equation: 
ClCr = (140-age[yr])(body wt [kg])
(72)(serum creat [mg/dL])
[When creatinine is measured in micromole/litre, use this formula]
ClCr = (140-age[yr])(body wt[kg])
(72)(serum creatinine [micromol/L] x 0.0113)
For females, multiple the result by 0.85.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl.
Participants who have a measured CrCl of up to 10% below 90 mL/min may be enrolled in 
the study at the discretion of the investigator.
5. Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic 
allergic reaction) to prescription or non-prescription drugs or food.
6. Is positive for hepatitis B surface antigen.
7. Has a history of chronic hepatitis C unless there has been documented cure and/or 
participant with a positive serologic test for HCV has a negative HCV VL.
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
9. Is unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 
half-lives) prior to administration of the initial dose of study drug, throughout the study, 
until the poststudy visit. There may be certain medications that are permitted (see Section 
6.5).
Prior/Concurrent Clinical Study Experience
10. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
 
 
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Diagnostic Assessments
11. Has a clinically significant abnormality on the ECG performed at the prestudy 
(screening) visit and/or prior to administration of the initial dose of study drug. Appendix 
7 provides a table of the 12-Lead ECG Abnormality Criteria.
Other Exclusions 
12. Is under the age of legal consent.
13. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
14. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
15. Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict 
smoking to ≤10 cigarettes per day.
16. Has a positive urine drug screen (except for cannabis) at screening and/or predose;
rechecks are allowed.
17. Presents any concern to the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
18. 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
Meals and Dietary Restrictions
5.3.1
5.3.1.1
Diet Restrictions
Participants will fast from all food and drinks, except water, for at least 8 hours prior to trial
drug administration (and laboratory safety tests). Participants will fast from all food and 
drinks except water between trial drug administration and the first scheduled meal. Meals and
snack(s) will be provided by the site at timepoints indicated in the trial flowchart.
During the domiciled period, participants will fast from all food and drinks except water 
between meals and snacks. The caloric content and composition of meals will be the same for 
all participants. After the 24-hour postdose procedures have been completed, subsequent 
meals and snacks will be unrestricted in caloric content, composition and timing.
 
 
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Water will be provided during trial drug administration. Water will be restricted 1 hour prior
to and 1 hour after trial drug administration.
Instructions on whether to take MK-8527 with or without food and/or drink may be modified
during the trial based on newly available data.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study, and until the poststudy visit.
Participants also will refrain from the consumption of all fruit juices 24 hours prior to and 
after study drug administration. On all other days during the study, consumption of fruits and 
fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is allowed.
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy and poststudy visits and from 12 hours prior to 
and after study drug administration. At all other times, caffeinated beverages or xanthine-
containing products will be limited to no more than 6 units per day (1 unit = 120 mg of 
caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy and 
poststudy visits and from 24 hours prior to and after study drug administration. At all other 
times, alcohol consumption is limited to no more than approximately 3 alcoholic beverages 
or equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine 
[118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Smoking (and/or the use of nicotine/nicotine-containing products) should be restricted to ≤10 
cigarettes per day and participants will be required to follow the smoking restrictions defined 
by the CRU while on site.
Activity Restrictions
5.3.3
Participants will avoid unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the prestudy (screening) visit until the poststudy visit.
 
 
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Contraception and Pregnancy Testing
5.3.4
5.3.4.1
Contraception
Women of childbearing potential can be enrolled. However, a highly effective method of
contraception must be used with a failure rate of <1%. Acceptable methods of birth control
(to be used during the period as specified in Section 5.1.2) are the following: intrauterine
device (IUD without local hormone release), and vasectomy of partner having occurred >3
months prior to screening with a confirmatory negative sperm count. Surgical sterilization of 
the male partner or the female participant must be documented with medical records. Oral 
contraceptives are not allowed as a method of birth control in this trial.
Participants must be completely informed of the unknown risks of pregnancy and agree not 
to become pregnant during the time they are participating in this trial.
Male participants with female partner(s) of child-bearing potential must agree to use a 
medically acceptable method of contraception during the trial and for 90 days after the last 
dos e of trial drug. Males should use a condom. Female partners must additionally use one of 
the following methods if they are not pregnant: hormonal contraception, intra-uterine device,
diaphragm, or cervical cap. If their partner is pregnant, males must agree to use a condom
and no additional method of contraception is required for the pregnant partner. Male 
participants must also agree to not donate sperm during the study and for a period of 90 days 
after the last dose of study drug.
If there is any question that a participant will not be reliable in the use of appropriate
contraceptive methods, he/she should not be entered into the trial.
5.3.4.2
Pregnancy Testing
Female participants of childbearing potential will be tested for serum -human chorionic
gonadotropin (hCG) at pretrial. Serum or urine -hCG will be tested at predose and at the last
trial visit. In the case of a positive or borderline serum β-hCG pregnancy test at the pretrial
visit, the participant must not enter the trial; in the case of a positive or borderline serum or 
urine β-hCG pregnancy test during the trial, the pregnancy test should be repeated and 
confirmed positive. If the pregnancy has been confirmed the participant must be discontinued 
from the trial immediately and the pregnancy must be reported to the Sponsor as outlined in 
Section 8.4.5.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information may be 
included, as outlined in the electronic case report forms (eCRF) entry guidelines. Minimal 
information may include demography, screen failure details, eligibility criteria, and any AEs 
or SAEs meeting reporting requirements.
 
 
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5.5
Participant Replacement Strategy
If a participant discontinues from study intervention or withdraws from the study, a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number. The study site should 
contact the Sponsor for the replacement participant’s treatment/randomization number.
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  will be packaged to support enrollment and replacement participants as 
required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies. Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
 
 
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The study intervention(s) to be used in this study are outlined in Table 5.  
Table 5
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
Panel A
Experimental
MK-8527
Drug
Capsule
10 mg
1 mg
0.5 mg
10 mg
Oral
Single 
Dose
Experimental
IMP
Sponsor
Panel B
Experimental
MK-8527
Drug
Capsule
10 mg
1 mg
0.5 mg
25 mg
Oral
Single 
Dose
Experimental
IMP
Sponsor
Panel C
Experimental
MK-8527
Drug
Capsule
10 mg
1 mg
0.5 mg
≤50 mg
Oral
Single 
Dose
Experimental
IMP
Sponsor
Panel D
Experimental
MK-8527
Drug
Capsule
10 mg
1 mg
0.5 mg
≤50 mg
Oral
Single 
Dose
Experimental
IMP
Sponsor
Panel E
Experimental
MK-8527
Drug
Capsule
10 mg
1 mg
0.5 mg
≤50 mg
Oral
Single 
Dose
Experimental
IMP
Sponsor
All supplies indicated in Table 5 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 8.1.8 for details regarding administration of the study intervention.
 
 
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6.2
Preparation/Handling/Storage/Accountability
Dose Preparation
6.2.1
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.
Handling, Storage, and Accountability
6.2.2
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
Intervention Assignment
6.3.1
Participants in this study will be assigned to panel and treatment according to an allocation 
schedule.  A sample allocation schedule is shown in Table 6.
Table 6
Sample Allocation Schedule
Panel
N
Dose of MK-8527a
A
6
10 mg
B
6
25 mg
Cb
6
≤50 mg
Db
6
≤50 mg 
Eb
6
≤50 mg 
a  Doses may be adjusted downward following review of safety and viral load data from preceding panels.
b A decision to enroll Panel C and the dose to be administered will be based on the results of safety, PK and 
viral load data out to at least Day 8 in Panels A and B. Enrollment of Panels D and E and the doses to be 
administered will be based on the results of safety, PK, and viral load data from all prior panels.
Stratification
6.3.2
No stratification based on age, sex, or other characteristics will be used in this study.
Blinding
6.3.3
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of   
starting the study, he/she may be included in the study if the investigator can rationalize that 
the specific use of a prior medication is not clinically relevant within the context of the study.
 
 
04Y8GH


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PRODUCT: MK-8527 
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Dose escalation decisions will be based on key safety data including VS, 12-lead ECGs, 
laboratory safety tests, and AEs from the previous dose levels up to at least 168 hours. Dose 
escalation in subsequent panels will also include review of PK data from previous panels.
See Section 4.3. If, as judged by the Sponsor and investigator, the safety and tolerability data 
do not justify dose escalation, the dose will not be increased as planned. Instead, participants 
may:
● receive the same dose level to further explore safety and tolerability at that level;
● receive a lower dose of the study treatment;
● receive the same or lower dose as a divided dose; or
● receive a lower dose with or without food.
Or, dosing may be stopped. Participant discontinuation criteria are outlined in Section 7.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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 
8.1.9, or if available, a protocol clarification letter.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
 
 
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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 has a confirmed positive serum pregnancy test.
•
The participant has a positive UDS at any time during the course of the study, confirmed 
upon rechecks.
For participants who are discontinued from study intervention, all applicable discontinuation 
activities will be performed according to Section 8.1.9, or if available, a protocol clarification 
letter.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
Participants may withdraw from the study at any time for any reason. If a participant 
withdraws from the study, they will no longer receive study intervention or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study,as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
 
 
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•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Study File Binder (or equivalent).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed approximately 499.5 mL (see Appendix 9).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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8.1
Administrative and General Procedures
Informed Consent
8.1.1
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical study or future biomedical research .If there are changes to the participant’s status 
during the study (eg, health or age of majority requirements), the investigator or 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 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 sub study. A copy of the 
informed consent will be given to the participant.
Inclusion/Exclusion Criteria
8.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
 
 
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Participant Identification Card
8.1.3
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
Medical History
8.1.4
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
8.1.5
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
Assignment of Screening Number
8.1.6
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 intervention allocation.Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Assignment of Treatment/Randomization Number
8.1.7
All eligible participants will be allocated, by non-random assignment, and will receive a 
treatment number. The treatment number identifies the participant for all procedures 
occurring after treatment allocation. Once a treatment number is assigned to a participant, it 
can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 treatment number.
Study Intervention Administration
8.1.8
Administration of study medication will be witnessed by the investigator and/or study staff.
 
 
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8.1.8.1
Timing of Dose Administration
All doses of MK-8527 will be given in the morning at approximately the same time in each 
treatment panel. In each panel, participants will receive a single dose of MK-8527 as a 
capsule.
Discontinuation and Withdrawal
8.1.9
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a post-study visit (approximately 28 days 
after the last dose of study intervention is given) to have the applicable procedures 
conducted. However, the investigator may decide to perform the poststudy procedures at the 
time of discontinuation or as soon as possible after discontinuation. If the poststudy visit 
occurs prior to 28 days after the last dose of study intervention is given, the investigator 
should perform a follow-up telephone call 28 days after the last dose of study intervention to 
determine if any AEs have occurred since the post-study clinic visit. Any AEs that are 
present at the time of discontinuation/withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
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. 
Participant Blinding/Unblinding
8.1.10
This is an open-label study; there is no blinding for this study.
 
 
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Domiciling
8.1.11
Participants will report to the clinical research unit (CRU) the evening prior to the scheduled 
day of study intervention administration for each treatment period and remain in the unit until 
24 hours postdose. At the discretion of the investigator, participants may be requested to 
remain in the CRU longer.
Calibration of Equipment
8.1.12
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/Immunogenicity Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 9.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
8.3.1
A complete physical examination will be conducted per institutional standard. Height and 
weight will also be measured and recorded. The pre-dose physical examination may be 
performed within 24 hour prior to dosing.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index (BMI)
Body Mass Index equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1-0.4 round down and 0.5-0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
 
 
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Vital Signs
8.3.2
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed. The same 
method must be used for all measurements for each individual participant and should be the 
same for all participants.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a semi-recumbent position for approximately 10 minutes
prior to having VS measurements obtained. Semi-recumbent VS will include heart rate (HR)
and blood pressure (BP). The correct size of the BP cuff and the correct positioning on the
participants' arm is essential to increase the accuracy of BP measurements.
At pre-dose in each Panel, HR and BP will be triplicate measurements obtained 
approximately 1-2 minutes apart within 3 hours of dosing MK-8527. The mean of these 
measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed). Post-dose VS measurements will be single 
measurements.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and BP) will also be obtained. Participants should be semi-recumbent for 
approximately 10 minutes and then stand upright for approximately 2 minutes prior to
measurement of orthostatic VS.
Electrocardiograms
8.3.3
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semirecumbent for at least 10 minutes prior to each 
electrocardiogram (ECG) measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin marker pen to ensure reproducible electrode placement.
Predose ECGs in each panel will be obtained in triplicate at least 1-2 minutes apart within 3
hours prior to dosing MK-8527. The mean of these measurements will be used as the 
baseline to calculate change from baseline for safety evaluations (and for rechecks, if 
needed).  Post-dose ECG measurements will be single measurements.
 
 
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During each treatment panel, if a participant demonstrates an increase in QTc interval ≥60 
msec compared with mean predose baseline measurement, the ECG will be repeated twice 
within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent the 
value at that time point. If the mean QTc interval increase from baseline for any postdose 
time point is ≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs 
every 15 minutes for at least 1 hour or until the QTc is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study cardiologist 
may be appropriate and the Sponsor should be notified.
If the QTc interval is 500 msec, the reading should be repeated. If confirmed prolonged, the 
Sponsor should be notified and the ECGs should be reviewed by a cardiologist. The 
participant should be telemetry-monitored (until the QTc is <500 msec) or should be 
considered for transfer to a location where closer monitoring and definitive care (e.g., a 
cardiac or intensive care unit) is available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
A study cardiologist will be consulted by the Principal Investigator as needed to review ECG 
tracings with abnormalities.
Clinical Safety Laboratory Assessments
8.3.4
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator 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).
 
 
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•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events (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, who is a qualified physician, and any designees are responsible for 
detecting, assessing, 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.
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
8.4.1
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 for 
randomized participants only if the event is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment, or a procedure.
From the time of treatment allocation/randomization through 28 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 any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered drug-related.
Investigators are not obligated to actively seek 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.
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 7.
 
 
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation 
(Randomized 
participants only)
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.
For vaccine studies only:
-any death until 
participant completion of 
study
(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 24 
hours of 
learning of 
event
 
 
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Method of Detecting AEs, SAEs, and Other Reportable Safety Events
8.4.2
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.
Follow-up of AE, SAE, and Other Reportable Safety Event Information
8.4.3
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.
Regulatory Reporting Requirements for SAE
8.4.4
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.
Pregnancy and Exposure During Breastfeeding
8.4.5
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), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
 
 
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All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECIs)
8.4.6
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include: 
a.
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.
b. An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
The participant has taken (accidentally or intentionally) any drug administered as part of the 
protocol that exceeds the dose as prescribed by the protocol. It is up to the investigator or the 
reporting physician to decide whether a dose is to be considered an overdose, in consultation 
with the Sponsor.
 
 
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8.6
Pharmacokinetics
The decision as to which plasma and/or urine samples collected will be assayed for 
evaluation of PK/PD will be collaboratively determined by the Sponsor (e.g., samples at 
lower doses may not be assayed if samples at higher doses reveal undetectable drug 
concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.
Blood Collection for Plasma MK-8527 and PBMC MK-8527-TP
8.6.1
Sample collection, storage, and shipment instructions for plasma and PBMC samples will be 
provided in the operations/laboratory manual.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
provided in the operations/laboratory manual.
8.8
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:

DNA for future research

Leftover main study plasma from MK-8527 assay stored for future research
8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association
between genetic variants in DNA and drug response. This sample will not be collected at the
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does
not approve the collection of the sample for these purposes. If the sample is collected,
leftover extracted DNA will be stored for future biomedical research if the participant signs
the future biomedical research consent. If the planned genetic analysis is not approved, but
future biomedical research is approved and consent is given, this sample will be collected for
the purpose of future biomedical research.
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples
will be provided in the operations/laboratory manual.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
 
 
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8.11
Health Economics Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
Screening
8.12.1
Approximately 4 weeks prior to treatment allocation, potential participants will be evaluated 
to determine that they fulfill the entry requirements as set forth in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to treatment allocation if there are Day -1 
procedures planned per protocol.
Treatment Period Visit
8.12.2
8.12.2.1
Predose Procedures (All Panels)
Prior to each treatment, the clinical and laboratory safety data, viral load data, and PK data
from the previous dose level/treatment panel will be reviewed by the Investigator and the 
Clinical Team and a mutual decision on whether to advance to the next dose level will be
made. No dose escalation will occur without agreement of the Investigator and the Sponsor.
Participants will report to the CRU the day prior to the scheduled day of administration of the
study drug or time specified by the investigator. Participants will fast from all food and drink,
except for water, for a minimum of 8 hours prior to study drug administration and prior to
obtaining samples for laboratory safety tests (refer to Section 5.3).
After the Day 1 predose procedures have been completed, participants will be assigned a 
unique allocation number associated with a specific treatment sequence as defined by a 
computer-generated allocation schedule. For details on procedures, please refer to the SoA 
(Section 1.3), Procedures (Section 8) and/or corresponding appendices.
8.12.2.2
Treatment Procedures (All Panels)
Procedures for study drug administration and postdose procedures are listed in the SoA, 
Section 1.3 of this protocol.
Participants will be administered a single dose of MK-8527 in the morning. The exact clock 
time of dosing should be recorded.
 
 
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Discontinued Participants Continuing to be Monitored in the Study
8.12.3
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all study procedures specified in the SoA may be completed at the discretion of the 
investigator and with Sponsor agreement. The subset of study procedures completed will be 
communicated in a protocol clarification letter.
Poststudy
8.12.4
Participants will be required to return to clinic approximately 28 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 28 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
28 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
Critical Procedures Based on Study Objectives: Timing of Procedure
8.12.5
For this study, the VL and PBMC blood sample for MK-8527 are the critical procedures.
At any postdose time point, the PBMC blood sample for MK-8527 needs to be collected as 
close to the exact time point as possible. All other procedures should be completed as close 
to the prescribed/scheduled time as possible. Study procedures can be performed prior or 
after the prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
PK Collection (MK-8527 plasma and MK-8527-TP PBMC) and PD collection (viral 
load) as outlined in Table 8.
 
 
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Table 8
PK/PD Blood Collection Window
Blood PK/PD Collection
PK/PD Collection Window
0 – 1.0 hr
5 min
1 - <2hr
10 min
2 - <24 hr
15 min
24 - <48 hr
1 hr
48 - 168 hr
2 hr
>168 - <672 hr
24 hr
672 hr
48 hr
•
Predose standard safety evaluations: VS and ECG at 3 hrs; laboratory safety tests, urine 
drug screen and physical exam at 24 hrs
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
exam
a.
<24 hr postdose may be obtained within 15 min of the theoretical sampling time
b. 24 hr - <48 hr postdose may be obtained within 1 hr of the theoretical sampling time
c.
48 hr – 168 hr postdose may be obtained within 2 hr of the theoretical sampling time
d.
>168 - <672 hr postdose may be obtained within 24 hr of the theoretical sampling 
time
e.
672 hr postdose may be obtained within 48 hr of the theoretical sampling time
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
8.12.6
Parameters
This is a Phase 1 assessment of MK-8527 in humans, and the PK, PD, and safety profiles of 
the compound are still being elucidated. This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of Phase 1 clinical studies. Modifications to the 
dose, dosing regimen, and/or clinical or laboratory procedures currently outlined may be 
required to achieve the scientific goals of the study objectives and/or to ensure appropriate 
safety monitoring of the study participants.
 
 
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As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed that 
that tested in Protocol 001.

Repeat of or decrease in the dose of the study intervention administered in any given 
panel

Entire panel(s) may be omitted

Adjustment of the dosing interval (e.g., divided doses [BID to QD, QD to BID, TID, 
or vice versa])

Instructions to take study intervention with or without food or drink may also be 
modified based on newly available data

Modification of the PK/pharmacodynamic sample timing, processing and shipping 
details based on newly available data
The PK/PD sampling scheme currently outlined in the protocol may be modified during the 
study based on newly available PK or PD data (e.g., to obtain data closer to the time of peak 
plasma concentrations). If indicated, these collected samples may also be assayed in an 
exploratory manner for metabolites and/or additional PD markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or PD analyses. The total 
blood volume withdrawn from any single participant will not exceed the maximum allowable 
volume during his/her participation in the entire study (Section 8).
The timing of procedures for assessment of safety procedures (e.g., VS, ECGs, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study file and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
 
 
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9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
the Statistical Analysis Plan (SAP) (Sections 9.2-9.9).
Statistical Methods
Primary Objective (Safety): Incidence of AEs will be descriptively summarized. Summary 
statistics and plots will be generated for the change from baseline values in the VS, ECG
parameter values, and selected laboratory safety parameter values for participants, as deemed 
clinically appropriate. Depending on the safety parameter, the difference from baseline will 
either be computed on the original scale (raw change from baseline) or on the log scale and 
back-transformed for reporting (percent change from baseline). Summary statistics for the 
raw laboratory safety tests, ECGs, and/or VS may also be computed, as deemed clinically 
appropriate.
Primary Objective (Pharmacodynamics): The log10 plasma HIV-RNA (copies/mL)
measurements from participants in all panels will be pooled and analyzed based on a 
longitudinal data analysis model containing fixed effects for dose level, time (pre-dose, 168 
hrs post-dose) and dose level by time interaction, and a random effect for participant. The 
change from baseline for each dose level at 168 hours post-baseline will be estimated from 
this model. A posterior distribution for the true mean change from baseline at 168 hours will 
be generated for each dose level using flat priors under a normal likelihood assumption. 
Historical placebo data from recent monotherapy studies in HIV-1 participants (MK-0518 
Protocol 004, MK-1439 Protocol 005, MK-6186 Protocol 007, and MK-1972 Protocol 003) 
will be separately analyzed based on a longitudinal data analysis model containing fixed 
effects for study and time (pre-dose, 168 hours post-dose), and a random effect for 
participant. The change from baseline for placebo at 168 hours post-baseline will be 
estimated from this model, and a posterior distribution for the true mean change from 
baseline at 168 hours will be generated using flat priors under a normal likelihood 
assumption. Using the posterior distributions for each dose level and placebo, the posterior 
distribution of the true mean difference between each dose level and placebo will be 
generated, and the posterior probability that the true mean difference in the log10 plasma 
HIV-1 RNA reduction from baseline between MK-8527 and placebo is at least 1.0 log10 
copies/mL will be calculated. A 70% posterior probability for at least one dose level that also 
exhibits an acceptable safety and tolerability profile will satisfy the primary 
pharmacodynamics hypothesis. For each dose level, the posterior probability that the true 
mean log10 plasma HIV-1 RNA reduction from baseline is at least 1.0 log10 copies/mL will 
also be calculated.
 
 
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9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacodynamic Department and Translational 
Pharmacology Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
9.3
Hypotheses/Estimation
Primary
At a dose that is sufficiently safe and generally well tolerated, MK-8527 has superior
antiretroviral activity compared to placebo, as measured by change from baseline in plasma
HIV-1 RNA (log10 copies/mL) at 168 hours postdose. That is, the true mean difference in 
the plasma HIV-1 RNA reduction from baseline between MK-8527 and placebo is at least 
1.0 log10 copies/mL.
Secondary
At a dose that is sufficiently safe and generally well tolerated, the true GM C168hr MK-
8527-TP in PBMC is at least 0.2 pmol/106 cells.
9.4
Analysis Endpoints
Primary Pharmacodynamic
The primary pharmacodynamic variables in this study include plasma HIV -1 RNA pre-dose
and 4, 24, 96, 120, 144, 168, 240, 336, 504 and 672 hours post-dose.
Primary Safety
The primary safety endpoints in this study include all types of AEs, in addition to laboratory 
safety assessments, ECGs, and VS.
Secondary Endpoints
The secondary endpoints in this study include AUC0-168hr, Tmax, Cmax, C168hr, apparent 
terminal t1/2 for both MK-8527 plasma and MK-8527-TP in PBMC following single oral 
administration of MK-8527 on Day 1.
 
 
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9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Participants as Treated (ASasT) – The population includes all participants who received 
at least one dose of the investigational drug. This population will be used for assessments of 
safety and tolerability.
Per-Protocol (PP) – The population includes the subset of participants who comply with the
protocol sufficiently to ensure that generated data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Compliance covers such 
considerations as exposure to treatment, availability of measurements and absence of major 
protocol deviations. Major protocol deviations will be identified to the extent possible prior 
to unblinding by individuals responsible for data collection/compliance, and its analysis and
interpretation. Any participants or data values excluded from analysis will be identified, 
along with their reason for exclusion, in the CSR. At the end of the study, all participants
who are compliant with the study procedure as aforementioned and have available data from 
at least one treatment will be included in the primary analysis dataset. This population will be 
used for the primary PD, secondary PK and exploratory PK and PD analyses.
9.6
Statistical Methods
Primary (Safety)
Incidence of AEs will be descriptively summarized. Summary statistics and plots will be 
generated for the change from baseline values in the VS, ECG parameter values, and selected 
laboratory safety parameter values for participants, as deemed clinically appropriate. 
Depending on the safety parameter, the difference from baseline will either be computed on 
the original scale (raw change from baseline) or on the log scale and backtransformed for 
reporting (percent change from baseline). Summary statistics for the raw laboratory safety 
tests, ECGs, and/or VS may also be computed, as deemed clinically appropriate.
Primary (Pharmacodynamics)
The log10 plasma HIV-RNA (copies/mL) measurements from participants in all panels will 
be pooled and analyzed based on a longitudinal data analysis (LDA) model containing fixed
effects for dose level, time (pre-dose, 168 hrs post-dose) and dose level by time interaction,
and a random effect for participant. The response vector consists of the baseline and 168 
hours post-baseline values. Time is treated as a categorical variable so that no restriction is
imposed on the trajectory of means over time. The change from baseline for each dose level 
at 168 hours post-baseline will be estimated from this model. A posterior distribution for the 
true mean change from baseline at 168 hours will be generated for each dose level using flat 
priors under a normal likelihood assumption. 
 
 
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Historical placebo data from recent monotherapy studies in HIV-1 participants (MK-0518 
Protocol 004, MK-1439 Protocol 005, MK-6186 Protocol 007, and MK-1972 Protocol 003) 
will be separately analyzed based on a longitudinal data analysis model containing fixed 
effects for study and time (pre-dose, 168 hrs post-dose), and a random effect for participant. 
The change from baseline for placebo at 168 hours post-baseline will be estimated from this 
model, and a posterior distribution for the true mean change from baseline at 168 hours will 
be generated using flat priors under a normal likelihood assumption. Using the posterior 
distributions for each dose level and placebo, the posterior distribution of the true mean 
difference between each dose level and placebo will be generated, and the posterior 
probability that the true mean difference in the log10 plasma HIV-1 RNA reduction from 
baseline between MK-8527 and placebo is at least 1.0 log10 copies/mL will be calculated. 
A 70% posterior probability for at least one dose level that also exhibits an acceptable safety
and tolerability profile will satisfy the primary pharmacodynamics hypothesis. For each dose 
level, the posterior probability that the true mean log10 plasma HIV-1 RNA reduction from 
baseline is at least 1.0 log10 copies/mL will also be calculated. To address the exploratory 
objective related to antiretroviral activity at 672 hours post-baseline, a similar analysis will 
be performed using VL measurements at baseline and 672 hours post-baseline. Similar 
exploratory analyses may be performed at timepoints earlier than 168 hours post-baseline.
Secondary (Pharmacokinetic)
Values of MK-8527 plasma and intracellular MK-8527-TP in PBMC pharmacokinetic 
parameters C168hr, C336hr, C672hr, AUC0-168hr, AUC0-last, AUC0-inf, and Cmax from 
participants in all panels will be pooled. Each PK parameter will be analyzed separately for 
plasma and PBMC. The PK log transformed and analyzed based on a linear model containing 
a fixed effect for dose level. The 95% confidence intervals for the means will be constructed 
on the natural log scale and will reference the t-distribution. Exponentiating the means will 
yield estimates for the population geometric means on the original scale. The secondary 
hypothesis will be evaluated by calculating the posterior probability that the true GM C168hr 
MK-8527-TP in PBMC is at least 0.2 pmol/106 cells for each dose level using flat priors 
under a normal likelihood assumption. The secondary hypothesis will be supported for any 
dose for which the posterior probability is greater than 70%.  Data will be examined for 
departures from the assumptions of the statistical model(s) as appropriate; e.g.,
heteroscedasticity, nonnormality of the error terms. Distribution-free methods may be used if 
a serious departure from the assumptions of the model(s) is observed, or suitable data
transformation may be applied.
Individual values will be listed for each MK-8527 plasma and intracellular MK-8527-TP in
PBMC PK parameter (C168hr, C240hr, C336hr, C540hr, C672hr, AUC0-168hr, AUC0-last,
AUC0-inf, Cmax, Tmax, and apparent terminal t1/2) by dose level, and the following (non-
model-based) descriptive statistics will be provided: N (number of participants with non-
missing data), arithmetic mean, standard deviation, arithmetic percent CV (calculated as 100 
x standard deviation/arithmetic mean), median, minimum, maximum, geometric mean, and 
geometric percent CV (calculated as 100 x sqrt(exp(s2) -1), where s2 is the observed 
variance on the natural log-scale).
 
 
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Secondary and Exploratory (Pharmacokinetic/Pharmacodynamic)
The PK-PD and dose-PD association of MK-8527 will be explored. Graphs to visualize the 
association of the reduction in log10 plasma HIV-1 RNA levels with various plasma and 
intracellular MK-8527-TP in PBMC parameters (e.g., C168hr, C672hr, AUC0-168hr, AUC0-
last, AUC0-inf, and Cmax) and dose will be generated. Exploratory linear and/or non-linear 
model fits may be considered, as appropriate. Exposure levels and doses that result in various 
proportions of the population (e.g., 80%, 90%) that have at least 1.0 log10 reduction from 
baseline in plasma HIV-1 RNA levels with high confidence may be estimated.
The duration of antiretroviral suppression after a single dose of MK-8527 will be evaluated 
with individual plots across time.
9.7
Interim Analyses
No interim analysis is planned in this study.
9.8
Multiplicity
Since there is only one primary pharmacodynamic hypothesis, no multiplicity adjustment 
will be made.
9.9
Sample Size and Power Calculations
Pharmacodynamic (Primary): If the true SDs of the log10 reduction from baseline in plasma
HIV-RNA at 168 hours postdose are 0.3, 0.4, or 0.5 for this study, there is ~80% power to 
yield at least 70% posterior probability if the true mean log10 reduction is at least 1.11, 1.12, 
or 1.13 log10 with N=6 participants in a panel.
PK
Pharmacokinetic (Secondary): If the true SDs of the C168hr triphosphate in PBMC are 0.25, 
0.35, or 0.45 for this study, there is ~80% power to yield at least 70% posterior probability if 
the true mean C168 are at least 0.27, 0.27, or 0.28 pmol/10^6 cells with N=6 participants in a 
panel.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Code of Conduct for Clinical Trials
10.1.1
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (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.
 
 
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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 
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.
Financial Disclosure
10.1.2
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.
Data Protection
10.1.3
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF 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.
Publication Policy
10.1.4
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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Compliance with Study Registration and Results Posting Requirements
10.1.5
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. 
Compliance with Law, Audit, and Debarmen
10.1.6
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. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
 
 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
10.1.7
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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Source Documents
10.1.8
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.
Study and Site Closure
10.1.9
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 local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 9
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose [fasting]
Calcium
Alkaline 
phosphatase
Gamma GT
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
•
Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines) 
•
Serum/Urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)
•
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)
NOTES: Laboratory safety tests will be performed after at least an 8-hour fast. Pre-dose laboratory
procedures can be conducted up to 24 hours prior to dosing.
Investigators 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
Definition of AE
10.3.1
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.”
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.7 for protocol-specific exceptions.
Definition of SAE
10.3.2
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.
 
 
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d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events Reported
10.3.3
Additional events which 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
 
 
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Recording AE and SAE
10.3.4
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.
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.
Assessment of causality
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
 
 
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Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
10.3.5
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Contraceptive Guidance and Pregnancy Testing
This appendix is not applicable to this study.
 
 
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10.5
Appendix 5: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
1.
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. 
2.
Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
3.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
4.
DNA: Deoxyribonucleic acid.
5.
RNA: Ribonucleic acid.
6.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 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.
 
 
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7.
Summary of Procedures for Future Biomedical Research.
1.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
2.
Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
3.
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.
4.
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.
5.
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.
 
 
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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.
6.
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.
7.
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.
 
 
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8.
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.
9.
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.
10.
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.
11.
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.
12.
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.
 
 
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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.
13.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
14.
References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.
Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.
Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.6
Appendix 6: Country-specific Requirements
This appendix is not applicable to this study.
 
 
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10.7
Appendix 7: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR <40 
bpm
Junctional Rhythm with HR <40 
bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With Left Anterior 
Hemiblock (LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior 
Hemiblock (LPHB)
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms  + Increase of 15 ms; 
or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
Incomplete Right BBB (ICRBBB) 
(QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 ms
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
 
 
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale or 
P Pulmonale
Definite Evidence of P Mitrale or P 
Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH Plus 
Strain Pattern
Voltage Criteria  for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1; ms=milliseconds, mm=millimeter
 
 
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10.8
Appendix 10.8: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The participant may be excluded from the study;
2. The participant may be included in the study if the abnormal value(s) is not clinically 
significant (NCS) (the investigator must annotate the laboratory value “NCS” on the 
laboratory safety test source document).
3. The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
4. The abnormal test may be repeated (refer to items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may enter the 
study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
 
 
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10.9
Appendix 9: Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit 
and by Sample Types
Panels A, B, C, D, E
Pre-trial
Treatment Periods
Post-trial
Total Collections
mL 
Per 
Collection
Total mL/ 
Test
Laboratory safety tests‡
1
3
1
5
13
65
Serum β-Human Chorionic
Gonadotropin 
(β-hCG)/FSH
1
0
0
1
5
5
HIV/Hepatitis Screen
1
0
0
1
5
5
Blood for Planned Genetic 
Analysis
1
0
0
1
8.5
8.5
Blood for PBMC
0
12
0
12
16
192
Blood for MK-8527
0
14
0
14
3
42
Blood for HIV RNA, viral
resistance §
1
13
0
14
13
182%
Approx. Total Blood Volume Per Participant for Panels A - E† 499.5 mL
† If additional safety analysis is necessary, additional blood (up to 50 mL) may be obtained.  Note: never to exceed 50 
mL
‡ Blood for CD4 cell count are included in the Laboratory Safety blood draw volume.
    § For all panels blood for HIV-1 viral RNA and viral resistance may be collected up to the post-trial visit if participants 
do not start ART.
An additional 4 mLs of blood may be drawn at 168 hours post-dose if ultra-deep sequencing is needed.
 
 
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
AE
Adverse experiences
ART
Anti-retroviral therapy
BSEP
Bile salt export pump
BMI
Body Mass Index
CRF
Case Report Form 
CRU
Clinical research unit
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram 
ECI
Event of clinical interest
eCRF
Electronic Case Report Form
EDC
Electronic data collection 
EM
Exposure multiple
EMA
European Medicines Agency
FBR
Future Biomedical Research
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
GM
Geometric mean
GMR
Geometric mean ratio
HED
Human equivalent dose
HIV-1
Human immunodeficiency virus type-1
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IRB
Institutional Review Board 
NOAEL
No observed adverse effect level 
NRTI
Nucleoside reverse transcriptase inhibitor
NRTTI
Nucleoside reverse transcriptase translocation inhibitor
OAT1
Organic anion transporter 1
OAT3
Organic anion transporter 3
OATP1B1
Organic anion transporting polypeptide 1B1
OCT2
Organic cation transporter 2
PD
pharmacodynamics
PK
Pharmacokinetic
POC
Proof-of-concept
QP2
Department of quantitative pharmacology and pharmacometrics
RNA
Ribonucleic acid
SAD
Single ascending dose
SAE
Serious adverse event 
SoA
Schedule of activities
SUSAR
Suspected unexpected serious adverse reaction
TP
Triphosphate
UDS
Urine drug screen
VL
Viral load
WOCBP
Woman/women of childbearing potential 
 
 
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REFERENCES
[European 
Medicines 
Agency 2016]
European Medicines Agency. Guideline on the clinical 
development of medicinal products for the treatment of HIV 
infection (EMEA/CPMP/EWP/633/02 Rev. 3). London: 
European Medicines Agency; 2016. 20 p.
04KB08
[Johnson, V. A., 
et al 2013]
Johnson VA, Calvez V, Gunthard HF, Paredes R, Pillay D, 
Shafer RW, et al. Update of the drug resistance mutations in 
HIV-1: March 2013. Top Antivir Med. 2013 Feb-
Mar;21(1):6-14. Erratum in: Top Antivir Med. 2013 Apr-
May;21(2):46.
04CJW4
 
 
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