Conditions: Human Immunodeficiency Virus
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 20
Healthy volunteers: no

Brief summary:
This is a single-dose clinical study to evaluate the safety, tolerability, pharmacokinetics, and anti-retroviral activity of MK-8527 in antiretroviral therapy (ART)-naïve participants living with human immunodeficiency virus type 1 (HIV-1) infection. The primary hypothesis is that, at a dose that is safe and generally well tolerated, MK-8527 will have antiretroviral activity as measured by a reduction from baseline in plasma HIV-1 ribonucleic acid (RNA) of ≥1.0 log10 copies/mL. A total of 4 arms was initially planned but Arm D was never initiated as the primary objectives were achieved following completion of Arms A to C.

Detailed description:

Arms:
arm 1: Participants receive a single oral dose of MK-8527 1.0 mg. arm 2: Participants receive a single oral dose of MK-8527 0.5 mg. arm 3: Participants receive a single oral dose of MK-8527 0.25 mg.

Interventions: intervention 1: MK-8527
Intervention descriptions: intervention 1: MK-8527 capsule taken by mouth.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT05494736
Document Date:  
    19-JUL-2023
Protocol/Amendment No.: 004-02 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
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (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: 004-02
Compound Number: MK-8527
Sponsor Name: Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not Applicable
EU CT
2023-503682-39-00
EudraCT
Not Applicable
JAPIC-CT
Not Applicable
WHO
Not Applicable
UTN
Not Applicable
IND
Not Applicable
Approval Date: 19 July 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 02
19-JUL-2023
An additional panel was added to allow for the 
evaluation of a lower dose of MK-8527; a 
statement of compliance with European Union 
Clinical Trials Regulations (EU CTR) No 
536/2014 was also added.
Amendment 01
09-FEB-2023
Modifications were made to expand clinical site 
locations, including the European Union.
Original Protocol
27-MAY-2022
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 004-02
Overall Rationale for the Amendment:
To add additional panels that would include lower doses of MK-8527 and to add compliance 
language for European Union Clinical Trial Regulations. (EU CTR) 
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
4.1 Overall 
Design
Updated the study design to make Panel C a 
serial panel following Panel B and to add Panel 
D. The dose for Panels C and D is 0.25 mg of 
MK-8527.
The addition of a fourth panel will allow for the 
continued evaluation of safety, tolerability, and 
antiviral efficacy of MK-8527, in Panels C and 
D. Both panels will explore a dose of 0.25 mg of 
MK-8527.This amendment provides an update 
that Panel C will run following Panel B, and 
clarifies that Panel D will run following Panel C. 
Section Number and 
Name
Description of Change
Brief Rationale
Other Changes in Amendment
Throughout Document
The structure of the protocol has been 
updated.
To comply with current industry regulations 
and guidelines. This restructuring does not 
affect the clinical or regulatory integrity of 
the protocol. All other relevant changes and 
their primary reasons are included for 
completeness.
Throughout Document
Minor administrative, formatting, 
grammatical, and typographical changes 
were made throughout the document.
To improve upon the clarity of the protocol.
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Section Number and 
Name
Description of Change
Brief Rationale
1.1 Synopsis
The Intervention table was updated to 
show the actual dose of 0.5 mg was given 
to Panel B, and to add the 0.25 mg dose of 
MK-8527 for Panel C and the newly-added 
Panel D. 
This update allows for the investigation of 
doses of 0.25 mg in Panels C and D.
1.1 Synopsis
Updated the total number of intervention 
groups and arms from 3 to 4.
This change reflects the addition of Panel D 
to the study design.
1.2 Schema
Updated the Overall Study Diagram and 
Study Schema to make Panel C a serial 
panel following Panel B and to add Panel 
D.
Refer to Section 4.1 rationale
2.2.2 Preclinical and 
Clinical Studies
Added data from the 6- and 9-month 
chronic toxicology studies and oral 
Embryo-Fetal Developmental Toxicity and 
Toxicokinetic studies. Added preclinical 
data related to lymphocyte toxicity and 
MK-8527-TP levels.
The update supports continued clinical 
evaluation of MK-8527. 
2.2.3 Ongoing Clinical 
Studies
Added clinical data from Panels A and B 
from this study.
The update supports continued evaluation
of additional doses of MK-8527. 
4.2 Scientific Rationale for 
Study Design
Updated to include viral load data from 
Panels A and B in this study.
The update supports continued evaluation 
of additional doses of MK-8527.
4.3.1 Starting Dose for This 
Study
Preclinical data updated and new exposure 
multiple was added.
The update supports continued clinical 
evaluation of MK-8527.
4.3.3 Rationale for Dose 
Interval and Study Design
Updated based on new study design.
Refer to Section 4.1 rationale
4.4.1 Clinical Criteria for 
Early Study Termination
Updated based on new study design.
Refer to Section 4.1 rationale
6.1 Study Intervention(s) 
Administered
Updated to show the actual dose of 0.5 mg 
given to Panel B, and to add the 0.25 mg 
dose of MK-8527 for Panel C and the 
newly-added Panel D.
This update allows for the investigation of 
doses of 0.25 mg in Panels C and D.
6.3.1 Intervention 
Assignment
Updated based on new study design.
Refer to Section 4.1 rationale
6.5 Concomitant Therapy
ART start was changed from before Day 
10 to before postdose Day 11.
This change is to correct a typographical 
error.
6.6 Dose Modification 
(Escalation/Titration/Other)
Updated based on new study design.
Refer to Section 4.1 rationale
8.11.6 Study 
Design/Dosing/Procedures 
Modifications Permitted 
Within Protocol Parameters
Removed the statement that Panels B and 
C may be run concurrently or sequentially.
This change reflects an update to the study 
design to run all study panels sequentially.
10.1.1
Code of Conduct 
for Interventional Clinical 
Trials
Added compliance language for European 
Union Clinical Trial Regulations. (EU 
CTR).
This is for the addition of a site in Romania.
10.8 Appendix 8: Blood 
Volume
Added a table for the blood volumes that 
will be collected in Romania
This shows the difference in blood volumes 
collected in Romania compared to South 
Aftica
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................21
2.1
Study Rationale....................................................................................................21
2.2
Background ..........................................................................................................21
2.2.1
Pharmaceutical and Therapeutic Background .............................................21
2.2.2
Preclinical and Clinical Studies ...................................................................22
2.2.3
Ongoing Clinical Studies.............................................................................25
2.3
Benefit/Risk Assessment......................................................................................25
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................26
4
STUDY DESIGN............................................................................................................28
4.1
Overall Design......................................................................................................28
4.2
Scientific Rationale for Study Design.................................................................29
4.2.1
Rationale for Endpoints ...............................................................................30
4.2.1.1
Safety Endpoints................................................................................30
4.2.1.2
Pharmacokinetic Endpoints ...............................................................30
4.2.1.3
Pharmacodynamic Endpoints.............................................................30
4.2.1.4
Planned Exploratory Biomarker Research.........................................31
4.2.1.4.1
Planned Genetic Analysis ........................................................31
4.2.1.5
Future Biomedical Research..............................................................31
4.3
Justification for Dose...........................................................................................32
4.3.1
Starting Dose for This Study........................................................................32
4.3.2
Maximum Dose Exposure for This Study ...................................................32
4.3.3
Rationale for Dose Interval and Study Design ............................................33
4.4
Beginning and End-of-Study Definition ............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................34
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
5.3.1
Meals and Dietary Restrictions....................................................................39
5.3.1.1
Diet Restrictions.................................................................................39
5.3.1.2
Fruit Juice Restrictions ......................................................................40
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................40
5.3.2.1
Caffeine Restrictions..........................................................................40
5.3.2.2
Alcohol Restrictions...........................................................................40
5.3.2.3
Tobacco Restrictions..........................................................................40
5.3.3
Activity Restrictions ....................................................................................41
5.4
Screen Failures.....................................................................................................41
5.5
Participant Replacement Strategy......................................................................41
6
STUDY INTERVENTION............................................................................................42
6.1
Study Intervention(s) Administered...................................................................42
6.2
Preparation/Handling/Storage/Accountability .................................................44
6.2.1
Dose Preparation..........................................................................................44
6.2.2
Handling, Storage, and Accountability........................................................44
6.3
Measures to Minimize Bias: Randomization and Blinding..............................45
6.3.1
Intervention Assignment..............................................................................45
6.3.2
Stratification.................................................................................................45
6.3.3
Blinding........................................................................................................45
6.4
Study Intervention Compliance..........................................................................45
6.5
Concomitant Therapy..........................................................................................46
6.5.1
Rescue Medications and Supportive Care ...................................................46
6.6
Dose Modification (Escalation/Titration/Other)...............................................46
6.6.1
Stopping Rules.............................................................................................47
6.7
Intervention After the End of the Study............................................................48
6.8
Clinical Supplies Disclosure................................................................................48
6.9
Standard Policies..................................................................................................48
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................49
7.1
Discontinuation of Study Intervention...............................................................49
7.2
Participant Withdrawal From the Study...........................................................49
7.3
Lost to Follow-up .................................................................................................49
8
STUDY ASSESSMENTS AND PROCEDURES........................................................50
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent.........................................................................................50
8.1.1.1
General Informed Consent.................................................................51
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................51
8.1.2
Inclusion/Exclusion Criteria ........................................................................51
8.1.3
Participant Identification Card.....................................................................51
8.1.4
Medical History ...........................................................................................52
8.1.5
Prior and Concomitant Medications Review...............................................52
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8.1.5.1
Prior Medications...............................................................................52
8.1.5.2
Concomitant Medications..................................................................52
8.1.6
Assignment of Screening Number...............................................................52
8.1.7
Assignment of Treatment/Randomization Number.....................................52
8.1.8
Study Intervention Administration ..............................................................53
8.1.8.1
Timing of Dose Administration.........................................................53
8.1.9
Discontinuation and Withdrawal .................................................................53
8.1.9.1
Withdrawal From Future Biomedical Research ................................53
8.1.10
Participant Blinding/Unblinding..................................................................54
8.1.11
Domiciling ...................................................................................................54
8.1.12
Calibration of Equipment.............................................................................54
8.2
Efficacy/Immunogenicity Assessments ..............................................................54
8.3
Safety Assessments...............................................................................................54
8.3.1
Physical Examinations.................................................................................54
8.3.2
Vital Signs....................................................................................................55
8.3.2.1
Resting Vital Signs ............................................................................55
8.3.2.2
Orthostatic Vital Signs.......................................................................55
8.3.3
Electrocardiograms ......................................................................................55
8.3.4
Clinical Safety Laboratory Assessments .....................................................57
8.3.5
Pregnancy Testing........................................................................................57
8.3.6
Photograph of Rash......................................................................................58
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................58
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................58
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......60
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...61
8.4.4
Regulatory Reporting Requirements for SAE .............................................61
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................61
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................62
8.4.7
Events of Clinical Interest............................................................................62
8.5
Treatment of Overdose........................................................................................62
8.6
Pharmacokinetics.................................................................................................62
8.6.1
Blood Collection for Plasma MK-8527 and PBMC MK-8527-TP .............63
8.7
Pharmacodynamics..............................................................................................63
8.8
Biomarkers ...........................................................................................................63
8.8.1
Planned Genetic Analysis Sample Collection..............................................63
8.9
Future Biomedical Research Sample Collection...............................................63
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8.10
Health Economics Medical Resource Utilization and Health Economics.......63
8.11
Visit Requirements...............................................................................................64
8.11.1
Screening......................................................................................................64
8.11.2
Treatment Period Visit.................................................................................64
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................64
8.11.4
Poststudy......................................................................................................64
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......64
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................65
9
STATISTICAL ANALYSIS PLAN .............................................................................67
9.1
Statistical Analysis Plan Summary.....................................................................67
9.2
Responsibility for Analyses.................................................................................67
9.3
Hypothesis/Estimation.........................................................................................68
9.4
Analysis Endpoints...............................................................................................68
9.5
Analysis Populations............................................................................................68
9.6
Statistical Methods...............................................................................................69
9.7
Interim Analyses ..................................................................................................70
9.8
Multiplicity ...........................................................................................................70
9.9
Sample Size and Power Calculations .................................................................70
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................71
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........71
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................71
10.1.2
Financial Disclosure.....................................................................................74
10.1.3
Data Protection.............................................................................................75
10.1.3.1
Confidentiality of Data ......................................................................75
10.1.3.2
Confidentiality of Participant Records...............................................75
10.1.3.3
Confidentiality of IRB/IEC Information............................................76
10.1.4
Committees Structure...................................................................................76
10.1.5
Publication Policy........................................................................................76
10.1.6
Compliance with Study Registration and Results Posting Requirements ...76
10.1.7
Compliance with Law, Audit, and Debarment ............................................77
10.1.8
Data Quality Assurance ...............................................................................77
10.1.9
Source Documents .......................................................................................78
10.1.10
Study and Site Closure.................................................................................79
10.2
Appendix 2: Clinical Laboratory Tests..............................................................80
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................82
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10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................82
10.3.2
Definition of AE ..........................................................................................82
10.3.3
Definition of SAE ........................................................................................83
10.3.4
Additional Events Reported.........................................................................84
10.3.5
Recording AE and SAE ...............................................................................84
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................87
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................89
10.5
Appendix 5: Contraceptive Guidance................................................................90
10.5.1
Definitions....................................................................................................90
10.5.2
Contraceptive Requirements........................................................................91
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................92
10.7
Appendix 7: Country-specific Requirements....................................................96
10.8
Appendix 8: Blood Volume Table ......................................................................97
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ....................99
10.10 Appendix 10: Algorithm for Assessing Out of Range laboratory Values.....101
10.11 Appendix 11: Abbreviations .............................................................................102
11
REFERENCES.............................................................................................................105
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LIST OF TABLES
Table 1
Study Schema...............................................................................................15
Table 2
Study Interventions......................................................................................43
Table 3
Sample Allocation Schedule........................................................................45
Table 4
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ............................................................................59
Table 5
Pharmacokinetic (Blood) Collection Windows ...........................................65
Table 6
Protocol-required Safety Laboratory Assessments......................................80
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LIST OF FIGURES
Figure 1
Overall Study Diagram ................................................................................15
Figure 2
Mean lymphocyte Counts After Single Doses of MK-8527 in P001, 
Shown as Percent Change From Baseline...................................................24
Figure 3
Mean Lymphocyte Counts After Multiple Weekly Dosing of MK-8527, 
Shown as Percent Change From Baseline...................................................24
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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: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Study Population: Treatment naïve HIV-1 infected participants
Primary Objective
Primary Endpoint
- To evaluate the antiretroviral activity of 
MK-8527 in HIV-1 infected participants.
- Hypothesis: At a dose that is safe and 
generally well tolerated, MK-8527 has 
antiretroviral activity, as measured by 
change from predose 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 
predose after MK-8527 is at least 1.0 log10 
copies/mL.
- Plasma HIV-RNA (log10 copies/mL) 
reduction from predose
- To evaluate the safety and tolerability of 
MK-8527 in HIV-1 infected participants.
- Adverse events
Secondary Objectives
Secondary Endpoints
- To evaluate the intracellular PK of MK-
8527-TP in PBMC after administration of 
single oral doses of MK-8527 to HIV-1 
infected participants.
- Estimation: The GM C168h MK-8527-TP 
will be estimated
- MK-8527-TP AUC0-168, AUC0-last, 
AUC0-inf, Tmax, Cmax, C168hr, and apparent 
terminal t1/2 in PBMC.
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- To evaluate plasma PK of MK-8527 after 
administration of single oral doses to HIV-1 
infected participants.
- MK-8527 plasma AUC0-last, AUC0-inf, 
Tmax, Cmax, Clast, and apparent terminal t1/2
- To evaluate the PK- pharmacodynamic 
association of intracellular MK-8527-TP 
with viral load reduction.
- PK (MK-8527-TP in PBMC) / 
pharmacodynamic (plasma HIV-1 RNA) 
correlation.
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
HIV infection
Population
HIV-1 Infected Participants
Study Type
Interventional
Intervention Model
Sequential
This is a multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 11 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 26 participants will be allocated in this study.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Panel A
MK-8527
1 mg
1.0 mg
Oral
Single Dose
Test Product
Panel B
MK-8527
0.5 mg
0.5 
Oral
Single Dose
Test Product
Panel C
MK-8527
0.25 mg
0.25 mg
Oral
Single Dose
Test Product
Panel D
MK-8527
0.25 mg
0.25 mg
Oral
Single Dose
Test Product
Total Number of Intervention Groups/Arms
4
Duration of Participation
Each participant will participate in the study 
for approximately 8 weeks from the time 
the participant signs the 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:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study. Regulatory, ethical, and study oversight 
considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1 and Table 1.
Figure 1
Overall Study Diagram
AE=adverse event; ECG=echocardiogram; VS=vital signs.
Table 1
Study Schema
Panela
Dose of MK-8527
A
1.0 mg
Bb
0.5 mg
Cb
0.25 mg
Db
0.25 mg
VL=viral load.
a Panel A will have 8 participants and Panels B, C and D will have 6 participants.  All participants will receive a single 
oral 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 
11 (ie,240 hours postdose) from the preceding panel. 
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1.3
Schedule of Activities
All Panels
Study Period
Screening
Intervention
Poststudyb
Notes
Scheduled Hour
Screeninga
Predose
0
1
4
24
48 
to 
144
168
192 
to 
504
672
Administrative 
Procedures
Informed Consent
X
Sec. 5.1, 8.1.1.1
Informed Consent for 
FBR
X
Sec. 5.1, 8.1.1.2
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion 
Criteria
X
X
X
Sec. 5.1, 5.2, 8.1.2
Medical History 
(includes substance 
usage)
X
Includes collection 
of drug, alcohol, 
tobacco, and 
caffeine use.
Sec. 8.1.4
Prior/Concomitant 
Medication Review
X--------------------------------------------------------------------X
Sec. 5.2, 6.5, 8.1.5
Assignment of 
Screening Number
X
Sec. 8.1.6
Assignment of 
Treatment Number
X
Sec. 8.1.7
MK-8527 
Administration
X
Fast for at least 8 
hours prior to 
administration.
Sec. 8.1.8, 8.1.8.1, 
5.3.1
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All Panels
Study Period
Screening
Intervention
Poststudyb
Notes
Scheduled Hour
Screeninga
Predose
0
1
4
24
48 
to 
144
168
192 
to 
504
672
Domiciling
X------------------X
Report to the CRU 
the evening of 
Day 1
Sec. 8.1.11
Standard Meals
X---Xc
Sec. 5.3.1
Safety Procedures
Full physical 
examination
X
X
X
X
X
Sec. 8.3.1, 8.11.5
Height
X
Sec. 8.3.1
Weight
X
X
Sec. 8.3.1
Vital Signs (HR, BP)
X
X
Xd
X
X
X
Duplicate Predose 
HR and BP, Sec. 
8.3.2
Vital Signs (RR, BT)
X
X
X
X
X
X
Sec. 8.3.2
Orthostatic Vital Signs 
(HR, BP)
X
X
X
X
X
X
Sec. 8.3.2
12-lead ECG
X
X
Xd
X
X
X
Triplicate Predose 
ECG, Sec. 8.3.3
Urine/Serum β-hCG; 
WOCBP only
X
X
X
Sec. 8.3.5, 
Appendix 2 
Serum FSH, 
WONCBP only)
X
Sec .5.1, Appendix 
2 
HIV, hepatitis B and C 
screen (per site SOP)
X
Sec. 5.1, 8.3.4
Appendix 2
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All Panels
Study Period
Screening
Intervention
Poststudyb
Notes
Scheduled Hour
Screeninga
Predose
0
1
4
24
48 
to 
144
168
192 
to 
504
672
UDS (per site SOP)
X
X
Sec 8.3.4, Appendix 
2 Screening UDS is 
mandatory, any 
additional UDS/ are 
conducted per site 
SOP
Hematology, 
Urinalysis, Chemistry
X
X
X
X
X
Sec 8.3.4, Appendix 
2 Collect after 
fasting for at least 8 
hours. 
Sec. 8.3.4, 8.11.5, 
Appendix 2
AE/SAE review
X-------------------------------------------------------------------X
Sec. 8.4
Pharmacokinetics
Blood for Plasma MK-
8527 Assay
X-------------------X
Collect: Predose, 
0.25, 0.5, 1, 2, 3, 4, 
6, 8, 12, 24 hours 
postdose
Sec 8.6.1, 8.11.5, 
Appendix 8
Blood for MK-8527 
PBMC-TP Assaye
X
X----------------------------------------X
Collect: Predose, 4, 
12, 24, 96, 120, 144, 
168, 192, 240, 336, 
504, 672 hours 
postdose
Sec 8.6.1, 8.11.5, 
Appendix 8
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All Panels
Study Period
Screening
Intervention
Poststudyb
Notes
Scheduled Hour
Screeninga
Predose
0
1
4
24
48 
to 
144
168
192 
to 
504
672
Pharmacodynamics
Blood for HIV RNAf
X
X
X---------------------------------------Xg
Collect: Screening, 
predose, 4, 12, 24, 
96, 120, 144, 168, 
192, 240, 336, 504, 
672 hours postdose
Sec 8.7, 8.11.5, 
Appendix 8
Blood for HIV viral 
resistance
X
X
X---------------------------------------Xg
Collect: Screening, 
predose, 4, 12, 24, 
96, 120, 144, 168, 
192, 240, 336, 504, 
672 hours postdose
Sec 8.7, 8.11.5, 
Appendix 8
CD-4 Cell Count
X
X
X
Sec. 5.1, 
Appendix 2
Biomarkers
Blood for Genetic 
Analysish
X
Sec. 8.8.1, 
Appendix 8 Collect 
predose from 
enrolled participants 
only.
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All Panels
Study Period
Screening
Intervention
Poststudyb
Notes
Scheduled Hour
Screeninga
Predose
0
1
4
24
48 
to 
144
168
192 
to 
504
672
AE=adverse event; ART=antiretroviral therapy; BDS=blood drug screen; BP=blood pressure; BT=body temperature; CRU=clinical research unit; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; 
HR=heart rate; ID=identification; IEC=Independent Ethics Committee; IRB=Institutional Review Board; NGS=next generation sequencing; PBMC=peripheral blood 
mononuclear cells;  PK=pharmacokinetics; RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; SOP=standard operating procedure; TP=triphosphate; 
UDS=urine drug screen; VS=vital signs; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential. 
a
Participants will be screened within approximately 4 weeks prior to administration of study drug.
b
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. The 672-hour sample may be collected at the post-trial visit.
c
Standard meals will be provided as follows on the full PK sampling Day 1: lunch at approximately 4-hours postdose, dinner at approximately 10-hours postdose, and 
snacks at approximately 7-hours and 13-hours postdose. After the 24-hour postdose procedures have been completed, subsequent meals and snacks will be unrestricted in 
terms of caloric content, composition and timing.
d
Predose VS (HR and BP) will be collected in duplicate and Predose ECGs will be collected in triplicate within 3 hours prior to dosing MK-8527.
e
For all panels, PBMC samples may be collected up to the post-trial visit regardless of initiation of ART.
f
Analysis of viral resistance is done using NGS or Sanger technique depending on local lab.
g
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. HIV-1 RNA samples will not 
be collected if participants have initiated ART at 336, 504, 672 hours postdose.
h
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant (or their legally acceptable representative) provides documented informed consent for FBR. If the planned 
genetic analyses are not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
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2
INTRODUCTION
2.1
Study Rationale
The purpose of this study is to assess the activity of single doses of MK-8527 in ART-naïve 
HIV-1 infected participants for a planned once weekly dosing regimen. A previous single 
dose trial of MK-8527 in HIV infected participants (MK-8527-002) established robust 
efficacy of 3 mg and 10 mg doses. However, while a single 1 mg dose was highly efficacious 
in three of five participants, two participants did not achieve the efficacy target, possibly due 
to confounding factors. This study is being performed to more definitively establish the 
lowest efficacious dose of MK-8527 as monotherapy, therefore guiding dose selection for 
future studies.
2.2
Background
Refer to the IB for detailed background information on MK-8527.
2.2.1
Pharmaceutical and Therapeutic Background
As treatment for HIV-1 has improved, HIV-1 infection has become a chronic, manageable 
disease, provided patients remain adherent. There is clear medical need for antiretroviral 
agents that are highly effective, more tolerable, and more convenient to administer, both for 
treatment and prophylaxis, with improved tolerability compared to existing treatments. A 
highly potent NRTI with improved tolerability and ease of administration would be a 
valuable addition to the HIV-1 treatment armamentarium.
Current recommendations for treatment of HIV infection call for either a 3-agent regimen 
consisting of 2 NRTIs in combination with either an integrase strand transfer inhibitor, a 
protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor or a two-drug regimen 
that includes one agent with a high resistance barrier [Panel on Antiretroviral Guidelines for 
Adults and Adolescents 2021]. Currently marketed NRTIs in common use include tenofovir 
disoproxil fumarate, tenofovir alafenamide fumarate, lamivudine, emtricitabine, and 
abacavir. While the currently approved NRTIs represent a cornerstone of modern ART, there 
are significant toxicities, including loss of bone mineral density, worsening renal function, 
dyslipidemia, and serious hypersensitivity reactions.
MK-8527 is a novel potent deoxyadenosine analog being developed for the treatment and 
prevention of HIV-1 infection. The mechanism of action of MK-8527 is similar to that of 
islatravir [Michailidis, E., et al 2014], leading to a high potency and a high barrier to 
resistance. 
The parent drug MK-8527 is converted intracellularly to MK-8527 TP, the active moiety, 
which is a potent and specific inhibitor of HIV-1 RT activity in vitro with 
 
 significantly more potent than marketed nucleosides.
 
 
 
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Based on preclinical and clinical data, the pharmacokinetic properties of MK-8527 support 
extended duration dosing of once weekly or longer. 
 
 
 
 
 
2.2.2
Preclinical and Clinical Studies
Preclinical studies to date
MK-8527 was well tolerated in repeat dose studies in rats and monkeys up to 6 and 9 months 
in duration respectively, and no adverse changes were noted up to the highest doses 
evaluated.
 
 
There was no MK-8527˗related maternal or developmental toxicity in the oral EFD study in 
pregnant rats when dosed 
 
 
 
 
 
Overall, nonclinical safety studies support continued clinical development of MK-8527.
Clinical trials to date
Three Phase 1 studies of MK-8527 have been completed. MK-8527-001 was a randomized, 
placebo controlled, alternating panel, double-blind trial evaluating the safety, tolerability, and 
PK of single oral doses of MK-8527 in healthy adult participants. 
 
 
 
 
 
 
 
 
 
 
 
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As detailed in the IB, PK of plasma MK-8527 in P001 was dose proportional over the entire 
single dose range. 
 
There was no clinically meaningful effect of a high-fat meal on MK-8527 PK.
MK-8527-003 was a randomized, placebo-controlled, serial panel, multiple rising dose 
double-blinded study evaluating safety, tolerability and PK of multiple doses of MK-8527 in 
healthy participants. 
 
 
 
 
MK-8527-002 was an open-label, single dose, multiple panel study to evaluate the safety, 
tolerability, antiretroviral activity, and PK of MK-8527 monotherapy in treatment naïve HIV 
1 infected participants. Participants received a single oral dose of 1 mg, 3 mg, or 10 mg of 
MK-8527. All doses were generally well-tolerated, with no SAEs, ECIs, or discontinuations 
due to an AE. Only 2 participants reported a total of 3 AEs (pharyngitis, dizziness, 
insomnia), and the AEs were considered unrelated to study intervention. There were no 
abnormalities in laboratory values, vital signs, or ECGs. PK of both parent and MK-8527-TP 
was generally similar between HIV+-positive participants in P002 and in non-HIV-infected 
study participants in P001.
Single doses of 3 mg and 10 mg were shown to achieve target intracellular MK-8527-TP 
C168hr of 0.2 pmol/106 cells. Single 1 mg doses led to robust declines in viral load in 3 of 
the 5 participants but failed to achieve target reduction in 2 of the 5 participants, 1 of whom 
had no response. Across all 3 Phase 1 studies, MK-8527 was rapidly absorbed with a median 
Tmax of 0.5 to 1 hour. Plasma concentrations decreased in a biphasic manner with an apparent 
terminal half-life of ~ 36 to 81 hours and exposures appeared to increase in an approximately 
dose-proportional manner. The active MK-8527-TP moiety reached intracellular Cmax at a 
median Tmax of 10 to 48 hours and the concentrations in PBMC declined with an apparent 
terminal half-life of ~ 94 to 291 hours across doses.
Refer to the IB for additional information on these Phase 1 studies.
 
 
 
 
 
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As noted in the IB, the profile of MK-8527 includes structural differences with islatravir and 
differences in intracellular anabolites and PK.
 
 
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2.2.3
Ongoing Clinical Studies
This study, MK-8527-004, is a repeat PoC study being conducted to definitively establish the 
lowest efficacious dose of MK-8527 as monotherapy. 
As of 29-JUN-2023, 8 participants in Panel A received 1-mg doses of MK-8527 and 
6 participants in Panel B received 0.5-mg doses of MK-8527. In both panels, the true mean 
reduction in the plasma HIV-1 RNA from predose at 1 week after MK-8527 administration 
was greater than 1.0 log10 copies/mL.  
Safety analysis is preliminary and ongoing. 
 
 
 
 
 
 
 
 
 
 
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine. Additional details regarding 
specific benefits and risks for participants participating in this clinical study may be found in 
the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Study Population: Treatment naïve HIV-1 infected participants
Primary Objective
Primary Endpoint
- To evaluate the antiretroviral activity of 
MK-8527 in HIV-1 infected participants.
- Hypothesis: At a dose that is safe and 
generally well tolerated, MK-8527 has 
antiretroviral activity, as measured by 
change from predose 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 
predose after MK-8527 is at least 1.0 log10 
copies/mL.
- Plasma HIV-RNA (log10 copies/mL) 
reduction from predose
- To evaluate the safety and tolerability of 
MK-8527 in HIV-1 infected participants.
- Adverse events
Secondary Objectives
Secondary Endpoints
- To evaluate the intracellular PK of MK-
8527-TP in PBMC after administration of 
single oral doses of MK-8527 to HIV-1 
infected participants.
- Estimation: The GM C168h MK-8527-TP 
will be estimated
- 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-last, AUC0-inf, 
Tmax, Cmax, Clast, and apparent terminal t1/2
- To evaluate the PK- pharmacodynamic 
association of intracellular MK-8527-TP 
with viral load reduction.
- PK (MK-8527-TP in PBMC) / 
pharmacodynamic (plasma HIV-1 RNA) 
correlation.
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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 explore the relationship between 
genetic variation at response to the 
treatment administration and mechanisms of 
disease. Variation across the human genome 
may be analyzed for association with the 
clinical data collected in this study.
- Germline genetic variation and association 
to clinical data collected in this study
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4
STUDY DESIGN
4.1
Overall Design
This is an open-label, single-dose, multiple panel trial of MK-8527 in participants with HIV-
1 infection. This study will be conducted in conformance with GCP.
A total of up to 4 panels (Panels A to D) will be enrolled. Panel A will consist of up to 8 
participants, and Panels B, C and D will consist of up to 6 participants in each panel. In each 
panel, participants will receive a single oral dose of MK-8527 as outlined in [Table 1] and 
will undergo safety assessments and blood sampling for PK and VL analysis.
In Panel A, 8 participants were administered single 1.0 mg doses of MK-8527. In Panel B, 6 
participants were administered single 0.5 mg doses of MK-8527. Panel C dose selection 0.25
mg MK-8527) follow the review of safety, tolerability, PK, and viral load data from Panels A 
and B through at least 10-days (240 hours) postdose.. Based on analysis of safety and 
antiviral efficacy in Panel C, a repeat of the 0.25 mg dose of MK-8527 may be evaluated in 
Panel D.
All doses of study drug intervention will be administered following at least an 8-hour fast.
Participants will be strongly encouraged to initiate an appropriate ART regimen within ~30 
days of dosing MK-8527. The exact timing and regimen will be decided by the participant in 
consultation with the PI or their physician, but ART initiation should not occur before 10 
days (240 hours) postdose in order to determine efficacy up to this time point. 
All participants will be followed for safety monitoring for approximately 28 days after 
dosing of MK-8527. If participants start ART as planned, after the completion of the 240 
hour procedures, the final blood draw for VL and viral resistance will occur on the day of 
ART initiation (prior to receiving the first dose of ART). If participants do not initiate ART, 
the Investigator may ask to continue regular blood draws for VL changes and viral resistance 
for up to ~28 days postdose. Participants choosing to forgo follow-on ART may also be 
asked if they wish to continue to participate in monitoring of VL and viral resistance beyond 
28 days. Blood for MK8527-TP PBMCs will be collected throughout the study regardless of 
ART initiation.  
If the physician and/or Investigator believe that there is a strong indication to start ART 
before 10 days (240 hours) postdose this should be discussed with the Sponsor prior to 
starting. The initiation of follow-on ART is not a requirement for participation in the study 
and is ultimately a decision of the participant and the primary investigator or the participant’s 
physician; the Sponsor will not source the ART. 
Because this is a Phase 1 assessment of MK-8527 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
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Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This protocol is designed with up to 4 panels and will primarily assess the short-term 
antiretroviral activity of MK-8527 monotherapy in ART-naïve HIV-1 infected participants. 
Data from this study will aid dose selection in future studies. The goals of this study will be 
achieved by enrolling a minimum number of participants using the shortest treatment 
duration possible. This design provides the advantages of progressing through multiple dose 
levels expeditiously while allowing sufficient time intervals to assess durability of effect in 
each panel. The time intervals between dosing allows for careful review of emerging data to 
permit a decision on advancing to the next panel at an appropriate dose to fully explore the 
dose-response profile of the compound. 
The doses to be tested in this study are designed based on findings in the previous MK-8527 
002 study, where 3 mg and 10 mg doses were highly efficacious, but 1 mg doses failed to 
achieve target reductions in viral load in 2 of the 5 participants. Preliminary results from 
Panels A and B of this study demonstrated antiviral efficacy at both the1.0 mg and 0.5 mg
doses of MK-8527. This study will evaluate the efficacy and kinetics by which MK-8527 
reduces HIV-1 RNA VL over time and establish the lowest efficacious monotherapy dose in 
suppressing viral replication.
The study is specifically designed with an emphasis on collecting single dose viral dynamic 
data. This is consistent with HIV study guidelines where the mean change in VL from 
baseline is a primary efficacy measure in dose finding monotherapy studies [European 
Medicines Agency 2016]. Although ARV agents are usually administered in combination to 
minimize the risk for resistance, MK-8527 will be given as monotherapy in order to evaluate 
the effect of this agent alone on HIV-1 VL. Therefore, only treatment naïve participants will 
be enrolled in this study in keeping with regulatory guidelines [European Medicines Agency 
2016]. Since only a single dose will be administered and the half-life of the active MK-8527-
TP anabolite is ~4-12 days, risk of resistant strain emergence is minimal. Prior to enrollment, 
participants will be screened for the presence of common NRTI resistance mutations to set a 
baseline standard for MK-8527 sensitivity to the viral variants present in each participant 
[Johnson, V. A., et al 2013]. Participants identified with a common NRTI mutation (eg, 
M184V or M184I) will be excluded from the study. 
Blood samples will be collected predose on Day 1, and after dosing through Day 10 and 
potentially up to Day 28 or longer for HIV viral RNA quantification. Blood samples will also 
be collected prior to initiation of ART to assess the potential for resistant variants; initiation 
of ART will not depend on the results of this screening.
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4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
The safety and tolerability of MK-8527 will be monitored by standard clinical assessments, 
including AEs, laboratory tests, VS and ECGs, which is deemed sufficient based on the 
preclinical and clinical safety profile known to date. This will build upon the observations in 
Protocols P001, P002, and P003. Standard laboratory assessments include measurement of 
total lymphocyte counts; CD4+ T cell counts will also be assessed.
4.2.1.2
Pharmacokinetic Endpoints
One objective of this study is to further characterize the plasma MK-8527 and intracellular 
MK-8527-TP PK profile in HIV-1 infected males and females.
 
 
 
 
For the PK assessment, plasma concentrations of MK-8527 will be determined for the first 
24 hours following single dose administration. Active MK-8527-TP in PBMCs will be 
determined up to 28 days postdose. These data will enable estimation of a predicted target 
associated with significant viral load reduction in a weekly dosing regimen.
4.2.1.3
Pharmacodynamic Endpoints
A pharmacodynamic endpoint of a >1.0 log10 suppression of HIV-1 RNA from baseline on 
Day 7, relative to predose baseline, will be used. A 70% posterior probability of achieving 
the target VL 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 to ensure that the dose(s) that can 
achieve the pharmacodynamic target is (are) taken into subsequent studies in the patient 
population. This target is consistent with historical NRTI compounds that utilized VL 
reduction targets of 0.5 log10, and more recent NRTIs that have demonstrated VL lowering 
greater than 1.0 log10. In addition, these thresholds, and limiting NRTI monotherapy studies 
to 7-10 days in duration, are consistent with regulatory guidance [Committee for Medicinal 
Products for Human Use (CHMP) 2016]. A decrease of at least 1.0 log10 after 7 to 10 days 
supports assessment in a larger trial, as part of 2-drug regimen for treatment, or as 
monotherapy for prophylaxis.
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 
following a single dose of MK-8527. Periodic blood samples will be collected to assess MK 
8527 associated changes in absolute VL over time and will be compared relative to predose 
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baseline. In addition, samples will be collected to detect the emergence of HIV resistance 
mutations. 
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. Additionally, based on both 
PK and pharmacodynamic endpoints, the kinetics of VL reduction vs. dose and C168 will 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 ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy 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 FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR 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 participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6
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4.3
Justification for Dose
As this is a Phase 1 assessment of MK-8527 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound and active triphosphate anabolite are still being evaluated, 
modifications to the dose or dosing regimen may be required to achieve the scientific goals 
of the study objectives and/or to ensure appropriate safety monitoring of the study 
participants. Details of allowed modifications are provided in Section 8.11.6.
This study will not include a placebo arm. 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.
4.3.1
Starting Dose for This Study
4.3.2
Maximum Dose Exposure for This Study
In P001, the plasma MK-8527 AUC0-168 at the 10 mg dose
 
 
 
CCI
CCI
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4.3.3
Rationale for Dose Interval and Study Design
MK-8527is not considered a compound with a high degree of uncertainty related to the 
potential risk of harm to participants according to the publication "Guideline on Strategies to 
Identify and Mitigate Risks for First-in-Human and Early Clinical Trials with Investigational 
Medicinal Products" [European Medicines Agency 2017]. The degree of uncertainty was 
determined by careful evaluation of the following: mode of action of MK-8527, presence or 
absence of biomarkers, the nature of the target, the relevance of available animal models, 
findings in non-clinical safety studies, and clinical findings in healthy volunteers and 
treatment naïve HIV positive participants (P001, P002, and P003). Furthermore, it acts via a 
well-established mechanism (inhibition of HIV-1 viral replication), for which multiple 
marketed agents act similarly (tenofovir disoproxil fumarate, tenofovir alafenamide, 
lamivudine, emtricitabine, and abacavir). Safety assessment toxicity studies, ancillary 
pharmacology studies, and findings in clinical studies of MK-8527 provide no 
contraindications to further clinical investigation. 
This study (Protocol 004) proposes to study up to 4 Panels. In Panel A, 8 participants (all 8 
active treatment) were administered a single 1 mg dose of MK-8527 on Day 1 in spaced time 
intervals according to Phase 1 clinical research standards for compounds not considered to be 
of high risk. In Panel B, 6 participants were administered a single 0.5 mg dose of MK-8527. 
Based on review of the safety, tolerability, and anti-viral efficacy data from Panel B, it is 
currently planned to evaluate a lower dose of MK-8527 in Panel C and/or D; a lower strength 
formulation (0.25 mg capsule) will be provided to support such an evaluation. After careful 
review of the safety, tolerability, and anti-viral efficacy data from Panel C, a Panel D may be 
enrolled. There will be frequent, careful assessments of AEs throughout the postdose period. 
This recommendation is in keeping with the projected safety profile and the ability of the 
Phase 1 unit to monitor each participant closely.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
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decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
A primary objective of this Phase 1 study is to identify the lowest dose of MK-8527 that is 
well tolerated, has acceptable PK, pharmacodynamic, and achieves target viral load 
reduction. Therefore, it is possible that Panel D may not be enrolled if this objective is 
achieved after review of data from Panels A through C. This would not be defined as early 
termination of the study, but rather an earlier than anticipated achievement of the study 
objective(s). If a finding (eg, PK, pharmacodynamic, efficacy, biologic targets, etc.) from 
another preclinical or clinical study using the study intervention(s), comparator(s), drug(s) of 
the same class, or methodology(ies) used in this study results in the study(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.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Other than HIV-1 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 (eg, Western Blot).
3. Has a screening plasma HIV-1 RNA ≥ 5,000 copies/mL within 30 days prior to the 
treatment phase of this study.
4. Has a screening plasma CD4+ T-cell count of >200/mm3.
5. Is ART-naïve, which is defined as not having received any marketed antiretroviral agent 
for the treatment of HIV-1 infection. Previous use of an antiretroviral agent for PrEP or 
as an investigational treatment is permitted if the most recent administration of the 
previous agent was at least 30 days prior to study drug administration. 
6. Is willing to receive no other ART for the monitoring period of this study.
7. Has no evidence at screening for mutations conferring resistance to NRTIs (including but 
not limited to M184V, M184I) as previously defined.
8. 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
9. Is male or female, from 18 years to 60 years of age inclusive, at the time of providing 
informed consent
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Male Participants
10. If male, agrees to the following during the intervention period and for at least 8 weeks 
after the last dose of study intervention:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause, documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview) as detailed below:
-
Uses a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile-
vaginal penetration.
-
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), or be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 
during the intervention period and for at least 8 weeks after the last dose of study 
intervention. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
-
Has a negative highly sensitive pregnancy test (Urine or serum as required by local 
regulations) within 24 hours before the first dose of study intervention. If a urine test 
cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from participation if the 
serum pregnancy result is positive. Additional requirements for pregnancy testing 
during and after study intervention are in Section 8.3.5.
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-
Abstains from breastfeeding during the study intervention period and for at least 56 
days after study intervention MK-8527
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
12. Has provided documented informed consent for the study. The participant may also 
provide consent for FBR. However, the participant may participate in the study without 
participating in FBR.
Additional Categories
13. Is willing to comply with the trial restrictions (see Section 5.3 for a complete summary of 
trial restrictions).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has a history of clinically significant endocrine, GI, 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, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator.
3. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of 
the cervix or; (2) Other malignancies that have been successfully treated with appropriate 
follow up and therefore unlikely to recur for the duration of the study, in the opinion of the 
investigator and with agreement of the Sponsor (eg, malignancies that have been successfully 
treated ≥10 years prior to the prestudy [screening] visit).
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4. Has an estimated eGFR ≤80 mL/min/1.73 m2], based on the 2021 CKD-EPI Creatinine 
Equation [Delgado, C., et al 2021].
2021 CKD-EPI Creatinine (CKD-EPIcr_R) Equation:
eGFR = 142 X min (Scr/k,1) α X max (Scr/k,1)-1.200 X 0.994age X 1.012 [if female]
Where Scr is serum creatinine, k is 0.7 for females and 0.9 males, α is -0.241 for females 
and -0.302 for males, min indicates the minimum of Scr/k or 1, max indicates the 
maximum of Scr/k or 1.
eGFR values indexed to BSA 1.73 will be de-indexed by dividing the value obtained 
from either formula by 1.73 and then multiplying by participant BSA.
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 eGFR.
Participants who have an eGFR or measured CrCl of up to 10% below of either 80 
mL/min (for CrCl) or 80 mL/min/1.73m2 (for eGFR) may be enrolled in the study at the 
discretion of the investigator.
5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or nonprescription 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. Has had a major surgery and/or 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 intervention, throughout the 
study, until the poststudy visit. There may be certain medications that are permitted if the 
investigator and Sponsor agree (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 the following laboratory values at screening: direct bilirubin > 1.0 mg/dL, AST 
(SGOT) or ALT (SGPT) > 2 x upper limit of normal.
12. Has a QTc interval ≥470 msec (for males) or ≥480 msec (for females).
Other Exclusions
13. Is under the age of legal consent.
14. Is an excessive smoker (ie, more than 10 cigarettes/day) and is unwilling to restrict 
smoking to ≤10 cigarettes per day. Does not agree to follow the smoking restrictions as 
defined by the CRU.
15. Consumes greater than 3 servings of alcoholic beverages (1 serving 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 servings of alcoholic beverages per 
day may be enrolled at the discretion of the investigator.
16. 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.
17. Has a positive urine drug screen (except for cannabis or benzodiazepines, for which there 
is a current prescription from a licensed medical provider) at screening and/or predose; 
rechecks are allowed.
18. There is any concern by the investigator regarding safe participation in the study, or for 
any other reason the participant is considered inappropriate for participation in the study 
by the investigator.
19. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations, are specified in Appendix 2.
In each treatment period, participants will fast from all food and drinks, except water, for at 
least 8 hours before study intervention administration. Participants will fast from all food and 
drinks, except water, between study intervention administration and the first scheduled meal. 
Meals and snack(s) will be provided by the investigator at time points indicated in the study 
flowchart. Participants will fast from all food and drinks, except water, between meals and 
snacks. The caloric content and composition of meals will be the same in each for all 
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participants. After the 24-hour postdose procedures have been completed, subsequent meals 
and snacks will be unrestricted in caloric content, composition, and timing.
Water will be provided during study intervention administration. Water will be restricted 1 
hour before and 1 hour after study intervention 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 before administration of the initial dose of study 
intervention, throughout the study and until the poststudy visit.
Participants also will refrain from the consumption of all fruit juices 24 hours before and 
after study intervention administration. On all other days during the study, consumption of 
fruits and fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is 
allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours before the prestudy and poststudy visits and from 12 hours before 
and after study intervention 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 before the prestudy and 
poststudy visits and from 24 hours before and after study intervention administration. At all 
other times, alcohol consumption is limited to no more than approximately 3 alcoholic 
beverages or equivalent servings (1 serving 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.
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5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, throughout the study and until the poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
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.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies study intervention provided by the Sponsor will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted before dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Panel A
Experimental MK-8527
Drug
Capsule
1 mg
1.0 mg
Oral
Single Dose
Test 
Product
IMP
Sponsor
Panel B
Experimental MK-8527
Drug
Capsule
0.5 mg
0.5 
Oral
Single Dose
Test 
Product
IMP
Sponsor
Panel C
Experimental MK-8527
Drug
Capsule
0.25 mg
0.25 mg
Oral
Single Dose
Test 
Product
IMP
Sponsor
Panel D
Experimental MK-8527
Drug
Capsule
0.25 mg
0.25 mg
Oral
Single Dose
Test 
Product
IMP
Sponosor
IMP=investigational medicinal product; NIMP/AxIMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the European Economic Area (EEA). 
Country differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in [Table 2] will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific calculations or evaluations required to be performed to administer the proper dose to 
each participant are outlined in a separate document provided by the Sponsor. The rationale 
for selection of doses to be used in this study is in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment. A sample allocation 
schedule is shown in [Table 3].
Table 3
Sample Allocation Schedule
Panel
n
Dose of MK-8527a
A
8
1.0 mg
B
6
0.5 mg
C
6
0.25 mg
D
6
0.25 mg
a.
The decision to proceed to the next panel will be made following review of safety and viral load data out 
to at least Day 11 (ie., 240 hours postdose) from the proceeding panel.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
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.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention. 
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study-site staff.
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6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of the 
first dose of study intervention, they 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.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
during the ongoing study (ie, after randomization or intervention allocation) must first be 
discussed between the investigator and Sponsor before administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult. The participant will be allowed to continue in the study if both the 
Sponsor and the investigator agree.
Paracetamol/acetaminophen (up to 2 grams/day) or non-prescription doses of nonsteroidal 
anti-inflammatory drugs may be used for minor ailments without prior consultation with the 
Sponsor.
All participants will be encouraged to initiate ART within one month after their dose of MK 
8527 but not before 10 days (240 hours) postdose. This timing is required to gather full 
efficacy data for this novel long-acting anti-retroviral compound and is consistent with prior 
anti-retroviral monotherapy PoC trials, in which low-dose anti-retroviral monotherapy has 
been administered for as long as 28 days and with EMA guidance [European Medicines 
Agency 2016]. The exact timing of ART initiation and regimen will be decided by the 
participant in consultation with PI/his/her physician, If the physician and/or Investigator 
believe there is a strong indication to start ART before Day 11, this should be discussed with 
the Sponsor prior to starting, as with other concomitant medications (see above).
COVID-19 vaccine may be administered until 72 hours prior to the initial dose of study drug 
and/or starting from 48 hours after the last dose of study drug.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
Prior to each intervention, the clinical and laboratory safety data, and VL data from the 
previous dose level will be reviewed by the investigator and discussed with the Sponsor to 
permit a decision on whether to advance to the next dosing level. No dose modification will 
occur without the joint agreement of the investigator and the Sponsor.
Dose selection for Panel B were made jointly by the investigator and the Sponsor. Dose 
escalation decision occurred after VL data from at least 5 evaluable participants were
available from Panel A. The dose for Panels C and D were based on the review of all safety 
and VL data from participants in Panels A and B. 
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The decision to conduct Panel D will be made jointly by the investigator and the Sponsor, 
and will occur after VL data from Panel C is available. 
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 240 hours. 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 evaluate that particular dose level;
•
receive a lower dose of the study intervention;
•
receive the same or lower dose as a divided dose; 
•
receive the same or lower dose with or without food.
•
dosing may be stopped. 
Participant discontinuation criteria are outlined in Section 7.
6.6.1
Stopping Rules
Enrollment of the trial will be halted in the following circumstances:
1. One participant reports a SAE 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.
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 
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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.
6.7
Intervention After the End of the Study
There is no study-specified intervention after 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.
6.9
Standard Policies
Not Applicable
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention. Therefore, participants who receive a single-dose intervention 
cannot discontinue study intervention.
7.2
Participant Withdrawal 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.
A participant must be withdrawn from the study if:
•
The participant or participant’s legally acceptable representative withdraws consent from 
the study.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet 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 the volume mentioned in Appendix 8.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
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the participant provides documented informed consent. At the time of intervention, site 
personnel will add the treatment/randomization number to the participant identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 14 days before first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation.  Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Study Operations Manual and/or Dose Preparation Memo. 
Administration of study intervention will be witnessed by the investigator and/or study staff.
Refer to Section 5.3.1 regarding administration instructions regarding food and water intake.
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 single doses of MK-8527.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.11.4  to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a follow-
up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any AEs 
have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
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8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Domiciling
Participants will report to the CRU the evening before the scheduled day of study 
intervention administration for each treatment period and remain in the unit until 24 hours 
postdose. 
Participants who will be spending the night near the CRU can decrease domiciling at the 
CRU to 12 hours if there are no participant safety issues. Study staff will be with the 
participant overnight and the primary investigator/sub investigator will be on call.
At the discretion of the investigator, participants may be requested to remain in the CRU 
longer.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are 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; surrogate markers of efficacy are 
outlined in Section 8.7.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
•
BP and HR Measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
•
VS measurement should be taken before blood collection for laboratory tests.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semirecumbent 
position for at least 10 minutes before having VS measurements obtained. Semirecumbent 
VS will include HR, systolic and diastolic BP, RR, and body temperature at timepoints 
indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participants' arm is essential to increase the accuracy of BP measurements.
The predose (baseline) HR and BP will be a duplicate measurements, obtained at least 1 to 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). Postdose VS measurements will be single measurements.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained. Participants should 
be semirecumbent for at least 10 minutes and then stand upright for approximately 2 minutes 
before measurement of orthostatic VS.
8.3.3
Electrocardiograms
12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG machine 
that automatically calculates the HR and measures PR, QRS, QT, and [QTc] intervals. Refer 
to Appendix 9 for evaluation and potentially significant findings.
At each time point when triplicate ECG are required, 3 individual ECG tracings should be 
obtained at least 1 minutes apart. The full set of triplicates should be completed in no more 
than 6 minutes.
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Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before 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 before each ECG 
measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
Predose ECGs will be obtained in triplicate at least 1 to 2 minutes apart within 3 hours before 
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).
During each treatment period, if a participant demonstrates an increase in QTc interval ≥60 
msec compared with mean predose baseline measurement, the ECG will be repeated twice 
within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent the 
value at that time point. If the mean QTc interval increase from baseline for any postdose 
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.
During each treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, 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 
is ≥500 msec, the Sponsor should be notified and the ECGs should be reviewed by a 
cardiologist. The participant should be telemetry monitored (until the QTc is <500 msec) or 
should be considered for transfer to a location where closer monitoring and definitive care 
(eg, a CCU or ICU) is available.
If the QRS duration from any postdose ECG is 20% greater than the mean baseline QRS 
duration and is >120 msec (and change is not considered rate related or pacing induced) or 
there appears to be new onset intermittent bundle branch block, then the ECG will be 
immediately repeated twice within 5 minutes. The mean value of the QRS interval from the 3 
ECGs will represent the value at that time point. If the mean QRS interval increase from 
baseline for any postdose time point is >20%, the participant will continue to be monitored 
by repeat 12-lead ECGs every 15 minutes for at least 1 hour or until the QRS is within 20% 
of baseline. If a >20% prolongation of the QRS interval persists, a consultation with a 
cardiologist may be appropriate and the Sponsor should be notified.
If at any time the QRS duration is prolonged ≥200 msec (and change is not considered rate 
related or pacing induced), then the Sponsor should be notified. The ECGs should be 
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reviewed by a cardiologist and the participant should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) 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 cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 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.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing urine or serum (as required by local regulations) prior to dosing.
-
Pregnancy testing urine or serum (as required by local regulations) should be 
conducted at the end of relevant systemic exposure.
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-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
8.3.6
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption, or rash occurrence in determining etiology and study intervention relationship.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator under any of the following circumstances:
•
if the participant is receiving placebo run-in or other run-in treatment,
•
if the event causes the participant to be excluded from the study,
•
if it is the result of a protocol-specified intervention, including, but not limited to washout 
or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention randomization through 28 days after cessation of intervention, 
all AEs, SAEs and other reportable safety events must be reported by the investigator.
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Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 4
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs are 
not applicable to this study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
Sponsor does not recommend specific treatment for an overdose.
8.6
Pharmacokinetics
The decision as to which plasma and/or urine samples collected will be measured for 
evaluation of PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, 
samples at lower doses may not be measured if samples at higher doses reveal undetectable 
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drug concentrations). If indicated, these samples may also be measured and/or pooled for 
assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-8527 and PBMC MK-8527-TP
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 
in the operations/laboratory manual.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
8.10
Health Economics Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 4 weeks before intervention allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation/randomization if 
there are Day -1 procedures planned per protocol.
8.11.2
Treatment Period Visit
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all study procedures specified in the SoA may be completed at the discretion of the 
investigator and with Sponsor agreement. The subset of study procedures completed will be 
communicated in a PCL.
8.11.4
Poststudy
Participants will be required to return to clinic approximately 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.
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
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.
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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 pharmacodynamic 
collection (viral load) as outlined in [Table 5].
Table 5
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window
0 to <1 h
5 min
1 to <2 h
10 min
2 to <24 h
15 min
24 to <48 h
1 h
48 to <96 h
2 h
96 to 168 h
4 h
˃168 to <672 h
24 h
672 h
48 h
•
Predose standard safety evaluations: VS and ECG up to 3 hours; laboratory safety tests 
and physical exam up to 24 hours
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
exam
-
<24 hours postdose may be obtained within 15 min of the theoretical sampling time
-
24 hours to <48 hours postdose may be obtained within 1 hour of the theoretical 
sampling time
-
48 hours to <96 hours postdose may be obtained within 2 hours of the theoretical 
sampling time
-
96 hours to 168 hours postdose may be obtained within 4 hours of the theoretical 
sampling time
-
>168 hours to <672 hours postdose may be obtained within 24 hours of the 
theoretical sampling time
-
672-hours postdose may be obtained within 48 hours of the theoretical sampling time
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-8527 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participant
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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 those 
currently outlined in the protocol.
•
Entire panel(s) may be omitted
•
Adjustment of the dosing interval (eg, 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 processing and shipping details based 
on newly available data
The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (eg, to 
obtain data closer to the time of peak plasma concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may use 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 (Sections 9.2-9.9).
Statistical Methods
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 (predose, 
168 hours postdose) 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. 
Using the posterior distributions for each dose level the posterior distribution of the true 
mean will be generated, and the posterior probability that the true mean in the log10 plasma 
HIV-1 RNA reduction from baseline of MK-8527 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. 
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.
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 
Medicine Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
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9.3
Hypothesis/Estimation
Primary
At a dose that is safe and generally well tolerated, MK-8527 has antiretroviral activity, as 
measured by change from predose 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 
predose between MK-8527 is at least 1.0 log10 copies/mL.
Secondary
The GM C168h MK-8527-TP will be estimated.
9.4
Analysis Endpoints
Primary Pharmacodynamic Endpoint 
The primary pharmacodynamic variables in this study include plasma HIV -1 RNA reduction 
from predose at 4, 24, 96, 120, 144, 168, 240, 336, 504 and 672 hours postdose. The change 
in VL from predose to 168 hours is of primary interest.
Primary Safety Endpoint
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, AUC0-last, 
AUC0-inf, apparent terminal t1/2 for MK-8527-TP in PBMC and AUC0-last, AUC0-inf, 
Tmax, Cmax, Clast, and apparent terminal t1/2 for plasma MK-8527 following single oral 
administration of MK-8527 on Day 1.
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 (APaT) – 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 by 
individuals responsible for data collection/compliance, and its analysis and interpretation. 
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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 pharmacodynamic, secondary PK and exploratory PK and pharmacodynamic 
analyses.
9.6
Statistical Methods
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 (predose, 168 hours postdose) 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. 
Using the posterior distributions for each dose level the posterior distribution of the true 
mean will be generated, and the posterior probability that the true mean in the log10 plasma 
HIV-1 RNA reduction from baseline of MK-8527 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. 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.
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 back-transformed for 
reporting (percent change from baseline). Summary statistics for the raw laboratory safety 
tests, ECGs, and/or VS may also be computed, as deemed clinically appropriate.
Secondary (Pharmacokinetic)
Values of MK-8527 plasma and intracellular MK-8527-TP in PBMC pharmacokinetic 
parameters AUC0-168, AUC0-last, AUC0-inf, Cmax, and C168hr from participants in all 
panels will be analyzed. Each PK parameter will be analyzed separately for plasma and 
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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. Data will be examined for 
departures from the assumptions of the statistical model(s) as appropriate; eg, 
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 (AUC0-168, AUC0-last, AUC0-inf, Tmax, Cmax, C168hr, 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).
Secondary and Exploratory (Pharmacokinetic/Pharmacodynamic)
The PK-pharmacodynamic and dose-pharmacodynamic 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 (eg, C168hr, 
C336hr, C672hr, AUC0-168hr, AUC0-last, AUC0-inf, and Cmax) and dose may 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 (eg, 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 the primary hypothesis will be assessed using posterior probabilities, 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, or 0.43, for this study, there is ~80% power to yield 
at least 70% posterior probability if the true mean log10 reduction is at least 1.25 or 1.3log10 
with N=6 participants in a panel. The assumed SDs are from the CSR of MK-8527-002.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, 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 (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
This section is not applicable as there are no study governance committees.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
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 ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.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 trials 
Regulation 536/2014 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 Regulation 536/2014, 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.
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10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 6 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.
•
Because the glucose assessment is part of the standard chemistry laboratory tests and 
requires fasting (approximately 8 hours), participants should fast prior to all instances of 
chemistry laboratory collection.
Table 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or Urea
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
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Laboratory 
Assessments
Parameters
Other Screening 
Tests
•
FSH (as needed in WONCBP only)
•
Serum or urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) will be used at screening. The 
predose drug screen can be performed with a urine dipstick that may not include all 
of the above tests.
•
Virology (HIV including HIV-1 RNA and at least resistance mutations to NNRTIs, 
HBsAg, and hepatitis C virus antibody) 
•
CD4+ T-cell count (absolute and %)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; 
HIV=human immunodeficiency virus; INR=International Normalized Ratio; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; NNRTI=non-nucleoside reverse transcriptase inhibitors; 
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; ULN=upper limit of normal; WBC=white blood cell; WOCBP=women of childbearing 
potential; WONCBP=women of nonchildbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting 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.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
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-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
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-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
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-
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 email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not Applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantc,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
[If hormonal contraception efficacy for a female participant is potentially decreased due to interaction(s) with 
study intervention(s), add the following footnote. If hormonal contraception is prohibited, or if hormonal 
contraception efficacy is NOT decreased due to interaction with study intervention(s), delete the following 
footnote:]
c  Male condoms must be used in addition to female participant hormonal contraception.
d   If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to 
those which inhibit ovulation.
e   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
This appendix is not applicable to this study.
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10.8
Appendix 8: Blood Volume Table
Blood collection volumes for sites in South Africa
All Panels
Prestudy
Treatment Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Testsb
1
3
1
5
13
65
Serum β-hCG (if applicable) 
1
1
1
3
5
15
FSH (if applicable)
1
0
0
1
5
5
HIV and Hepatitis Screen
1
0
0
1
5
5
Blood for Planned Genetic 
Analysis
0
1
0
1
8.5
8.5
Blood for PBMC-TP Assay
0
12
1
13
16
208
Blood for MK-8527 Assay
0
11
0
11
3
33
Blood for HIV RNA, viral 
resistancec
1
12
1
14
13
182
Total Blood Volume per Participanta
Males
Females
Females Postmenopausal
501.5 mL
516.5 mL
506.5 mL
FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus;
PBMC=peripheral blood mononuclear cells; RNA=ribonucleic acid; 
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood 
(no more than 50 mL in total) may be obtained.
b
Blood for CD4 cell count is included in the laboratory safety blood draw volume.
c
Blood for HIV-1Viral RNA and Viral Resistance may be collected up to the post trial visit if 
participant do not start ART therapy. An additional 4 mL of blood may be drawn at 168 hours post 
dose if ultra deep sequencing is needed.
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Blood collection volumes for sites in Romania
All Panels
Prestudy
Treatment Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Testsb
1
3
1
5
10.5
52.5
Blood for Planned Genetic 
Analysis
0
1
0
1
8.5
8.5
Blood for PBMC-TP Assay
0
12
1
13
16
208
Blood for MK-8527 Assay
0
11
0
11
3
33
Blood for HIV RNA, viral 
resistancec
1
12
1
14
13
182
Blood for Hep C testing
1
0
0
1
5
5
Blood for CD4 cell Count
1
1
1
3
3
9
Total Blood Volume per Participanta
Males
Females
Females Postmenopausal
498 mL
498 mL
498 mL
FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus;
PBMC=peripheral blood mononuclear cells; RNA=ribonucleic acid; 
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood 
(no more than 50 mL in total) may be obtained.
b
Blood for Serum β-hCG (if applicable), FSH (if applicable), and HIV Screen are included in the laboratory 
safety blood draw volume.
c
Blood for HIV-1Viral RNA and Viral Resistance may be collected up to the post trial visit if 
participant do not start ART therapy. An additional 4 mL of blood may be drawn at 168 hours post 
dose if ultra deep sequencing is needed.
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
Potentially Significant 
Postrandomization 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 LAHB
New Onset LAHB
Right Axis Deviation
RBBB With 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)
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
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Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to 
take)
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
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
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; 
LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; mm=millimeter; 
ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT correction using Fredericia 
formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1
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10.10 Appendix 10: Algorithm for Assessing Out of Range laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A.
If all protocol-specified laboratory values are normal, the participant may enter the 
study.
B.
If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be excluded 
from the study.
C.
If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion 
criteria is outside the normal range, the following choices are available:
a.
The participant may be excluded from the study;
b. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety 
test source document).
c.
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
d. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may 
enter the study.
b. If the repeat test value is still abnormal, the study investigator will 
evaluate the potential participant with a complete history and physical 
examination, looking especially for diseases that could result in the 
abnormal laboratory value in question. If such diseases can be ruled out, 
and if the abnormal laboratory value is not clinically relevant, then the 
participant may enter the study.
D.
If there is any clinical uncertainty regarding the significance of an abnormal value, 
the participant will be excluded from the study.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-168hr
area under the curve for 0 to 168 hours
BDS
blood drug screen
BP
blood pressure
BT
body temperature
C168hr
concentration at 168 hours
CCU
Cardiac care unit
Cmax
maximum plasma concentration
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
Ctrough
trough concentration
CYP
cytochrome P450
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EU CTR
European Union Clinical Trial Regulations
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
first site ready
GCP
Good Clinical Practice 
GI
gastrointestinal
GM
Geometric mean
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
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Abbreviation
Expanded Term
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVD
in vitro diagnostic
LAM
lactational amenorrhea method
MAD
multiple ascending dose study
NA
not applicable
NCS
not clinically significant
NHP
non-human primate
NOAEL
no observed adverse effect level 
NRTI
Nucleoside reverse transcriptase inhibitor
PBMC
peripheral blood mononuclear cells
PCL
Protocol Clarification Letter
PK
pharmacokinetic
PN
protocol number
PP
per-protocol
PR
pulse rate
PrEP
pre-exposure prophylaxis
PRO
patient-reported outcome
qd
once daily
QTc
QT interval corrected for heart rate
RNA
ribonucleic acid
RR
respiratory rate
RT
reverse transcriptase
SAD
single ascending dose
SAE
serious adverse event 
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SHIV
Simian-Human Immunodeficiency Virus
SGPT
Serum glutamic pyruvic transaminase
SLAB
Supplemental laboratory test(s)
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PRODUCT: MK-8527
104
PROTOCOL/AMENDMENT NO.: 004-02
MK-8527-004-02 FINAL PROTOCOL
19-JUL-2023
Abbreviation
Expanded Term
SoA
schedule of activities
SOP
Standard Operating Procedures
t1/2
half life
tid
three times daily
Tmax
time to maximum plasma concentration
TP
trisphosphate
UDS
urine drug screen
ULN
upper limit of normal
VL
Viral load
VS
vital signs
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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PRODUCT: MK-8527
105
PROTOCOL/AMENDMENT NO.: 004-02
MK-8527-004-02 FINAL PROTOCOL
19-JUL-2023
11
REFERENCES
[Committee for Medicinal 
Products for Human Use 
(CHMP) 2016]
Committee for Medicinal Products for Human 
Use (CHMP). Guideline on clinical development 
of medicinal products for the treatment of HIV 
infection (EMEA/CPMP/EWP/633/02 Rev. 3) 
[Internet]. London: EMA; 2016. Available from: 
http://www.ema.europa.eu/docs/en_GB/docume
nt_library/Scientific_guideline/2016/07/WC5002
09918.pdf.
[04RP5F]
[Delgado, C., et al 2021]
Delgado C, Baweja M, Crews DC, Eneanya 
ND, Gadegbeku CA, Inker LA, et al. A 
unifying approach for GFR estimation: 
recommendations of the NKF-ASN Task Force 
on reassessing the inclusion of race in 
diagnosing kidney disease. J Am Soc Nephrol. 
2021;32:2994–3015.
[07ZP4L]
[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]
[European Medicines 
Agency 2017]
European Medicines Agency. Guideline on 
strategies to identify and mitigate risks for 
first-in-human and early clinical trials with 
investigational medicinal products. London: 
European Medicines Agency; 2017. 22 p. 
EMEA/CHMP/SWP/28367/07 Rev. 1.
[04YWZ8]
[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]
[Michailidis, E., et al 2014]
Michailidis E, Huber AD, Ryan EM, Ong YT, 
Leslie MD, Matzek KB, et al. 4'-Ethynyl-2-
fluoro-2'-deoxyadenosine (EFdA) inhibits 
HIV-1 reverse transcriptase with multiple 
mechanisms. J Biol Chem. 2014 Aug 
29;289(35):24533-48.
[04R5Q4]
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[Panel on Antiretroviral 
Guidelines for Adults and 
Adolescents 2021]
Panel on Antiretroviral Guidelines for Adults 
and Adolescents. Guidelines for the use of 
antiretroviral agents in adults and adolescents 
with HIV: Aug 2021. Washington (DC): 
Department of Health and Human Services 
(HHS). [Last updated: 2021 Jun 3]. 454 p.
[07WT2T]
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