Clinical trial NCT03859739
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-04-26; Completion date: 2020-05-29
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and anti-retroviral activity of MK-8558 monotherapy in anti-retroviral-naïve human immunodeficiency virus type 1 (HIV-1) infected participants. The primary hypothesis is that at a dose that exhibits an acceptable safety and tolerability profile, MK-8558 has superior anti-retroviral activity compared to historical placebo data.

Detailed description:

Arms: arm 1: Single oral dose of MK-8558 administered at 400 mg following a 10-hour fast. arm 2: Single oral dose of MK-8558 administered at dose level 2 following a 10-hour fast. Dose level 2 shall not exceed 900 mg. Per protocol, dose will be selected following review of data from panel A. arm 3: Single oral dose of MK-8558 administered at dose level 3 following a 10-hour fast. Dose level 3 shall not exceed 1600 mg. Per protocol, dose will be selected following review of data from panel B. arm 4: Single oral dose of MK-8558 administered at dose level 4 following a low-fat breakfast. Dose level 4 shall not exceed 1600 mg. Per protocol, Panel D is optional pending results of Panels A-C, and dose will be selected following review of data from panel C.
Interventions: intervention 1: MK-8558
Intervention descriptions: intervention 1: Single dose of MK-8558 administered as a tablet at a dose up to 1600 mg.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03859739 
Document Date: 
22-AUG-2019
A Single-Dose Clinical Trial to Study the Safety, Tolerability,
Pharmacokinetics, and Anti-Retroviral Activity of MK-8558 
Monotherapy in Anti-Retroviral-Naïve HIV-1 Infected Participants


PRODUCT: MK-8558  
1
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Single-Dose Clinical Trial to Study the Safety, Tolerability, 
Pharmacokinetics, and Anti-Retroviral Activity of MK-8558 Monotherapy in Anti-
Retroviral-Naïve HIV-1 Infected Participants 
Protocol Number: 002-03
Compound Number: MK-8558
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
EudraCT
2018-003904-37
Approval Date: 22 August 2019
 
 
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PRODUCT: MK-8558  
2
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
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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PRODUCT: MK-8558  
7
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................22
2.2.1
Pharmaceutical and Therapeutic Background .............................................22
2.2.2
Ongoing Clinical Studies.............................................................................24
2.3
Benefit/Risk Assessment......................................................................................31
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................35
4.2.1
Rationale for Endpoints ...............................................................................37
4.2.1.1
Safety Endpoints................................................................................37
4.2.1.2
Pharmacokinetic Endpoints ...............................................................37
4.2.1.3
Pharmacodynamic Endpoints.............................................................38
4.2.1.4
Planned Exploratory Biomarker Research.........................................38
4.2.1.4.1
Planned Genetic Analysis ........................................................38
4.2.1.5
Future Biomedical Research..............................................................39
4.2.2
Rationale for the Use of Historical Placebo.................................................39
4.3
Justification for Dose...........................................................................................39
4.3.1
Starting Dose for This Study........................................................................43
4.3.2
Maximum Dose/Exposure for This Study ...................................................43
4.3.3
Rationale for Dose Interval and Study Design ............................................44
4.4
Beginning and End of Study Definition .............................................................45
4.4.1
Clinical Criteria for Early Study Termination .............................................45
5
STUDY POPULATION ................................................................................................46
5.1
Inclusion Criteria.................................................................................................46
5.2
Exclusion Criteria................................................................................................49
5.3
Lifestyle Considerations......................................................................................51
5.3.1
Meals and Dietary Restrictions....................................................................51
 
 
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PRODUCT: MK-8558  
8
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
5.3.1.1
Diet Restrictions.................................................................................51
5.3.1.2
Fruit Juice Restrictions ......................................................................53
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................53
5.3.2.1
Caffeine Restrictions..........................................................................53
5.3.2.2
Alcohol Restrictions...........................................................................53
5.3.2.3
Tobacco Restrictions..........................................................................53
5.3.3
Activity Restrictions ....................................................................................53
5.4
Screen Failures.....................................................................................................54
5.5
Participant Replacement Strategy......................................................................54
6
STUDY INTERVENTION............................................................................................54
6.1
Study Intervention(s) Administered...................................................................54
6.2
Preparation/Handling/Storage/Accountability .................................................56
6.2.1
Dose Preparation..........................................................................................56
6.2.2
Handling, Storage, and Accountability........................................................56
6.3
Measures to Minimize Bias: Randomization and Blinding..............................57
6.3.1
Intervention Assignment..............................................................................57
6.3.2
Stratification.................................................................................................57
6.3.3
Blinding........................................................................................................57
6.4
Study Intervention Compliance..........................................................................57
6.5
Concomitant Therapy..........................................................................................57
6.5.1
Rescue Medications and Supportive Care ...................................................58
6.6
Dose Modification (Escalation/Titration/Other)...............................................58
6.6.1
Stopping Rules.............................................................................................59
6.7
Intervention After the End of the Study............................................................60
6.8
Clinical Supplies Disclosure................................................................................60
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................60
7.1
Discontinuation of Study Intervention...............................................................60
7.2
Participant Withdrawal From the Study...........................................................61
7.3
Lost to Follow-up .................................................................................................61
8
STUDY ASSESSMENTS AND PROCEDURES........................................................61
8.1
Administrative and General Procedures ...........................................................62
8.1.1
Informed Consent.........................................................................................62
8.1.1.1
General Informed Consent.................................................................62
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................63
8.1.2
Inclusion/Exclusion Criteria ........................................................................63
8.1.3
Participant Identification Card.....................................................................63
 
 
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PRODUCT: MK-8558  
9
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
8.1.4
Medical History ...........................................................................................63
8.1.5
Prior and Concomitant Medications Review...............................................64
8.1.5.1
Prior Medications...............................................................................64
8.1.5.2
Concomitant Medications..................................................................64
8.1.6
Assignment of Screening Number...............................................................64
8.1.7
Assignment of Treatment/Randomization Number.....................................64
8.1.8
Study Intervention Administration ..............................................................64
8.1.8.1
Timing of Dose Administration.........................................................64
8.1.9
Discontinuation and Withdrawal .................................................................65
8.1.9.1
Withdrawal From Future Biomedical Research ................................65
8.1.10
Participant Blinding/Unblinding..................................................................65
8.1.11
Domiciling ...................................................................................................65
8.1.12
Calibration of Equipment.............................................................................66
8.2
Efficacy/Immunogenicity Assessments ..............................................................66
8.3
Safety Assessments...............................................................................................66
8.3.1
Physical Examinations.................................................................................66
8.3.2
Vital Signs....................................................................................................67
8.3.2.1
Orthostatic Vital Signs.......................................................................67
8.3.3
Electrocardiograms ......................................................................................67
8.3.4
Clinical Safety Laboratory Assessments .....................................................68
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................69
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................69
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......72
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...72
8.4.4
Regulatory Reporting Requirements for SAE .............................................72
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................72
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................73
8.4.7
Events of Clinical Interest (ECIs) ................................................................73
8.5
Treatment of Overdose........................................................................................73
8.6
Pharmacokinetics.................................................................................................74
8.6.1
Blood Collection for Plasma MK-8558 .......................................................74
8.7
Pharmacodynamics..............................................................................................74
8.8
Biomarkers ...........................................................................................................74
8.8.1
Planned Genetic Analysis Sample Collection..............................................74
8.9
Future Biomedical Research Sample Collection...............................................75
 
 
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PRODUCT: MK-8558  
10
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
8.10
Visit Requirements...............................................................................................75
8.10.1
Screening......................................................................................................75
8.10.2
Treatment Period Visit.................................................................................75
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........75
8.10.4
Post-study.....................................................................................................75
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure .......76
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................77
9
STATISTICAL ANALYSIS PLAN .............................................................................78
9.1
Statistical Analysis Plan Summary.....................................................................78
9.2
Responsibility for Analyses.................................................................................79
9.3
Hypotheses/Estimation ........................................................................................79
9.4
Analysis Endpoints...............................................................................................80
9.5
Analysis Populations............................................................................................80
9.6
Statistical Methods...............................................................................................80
9.7
Interim Analyses ..................................................................................................82
9.8
Multiplicity ...........................................................................................................82
9.9
Sample Size and Power Calculations .................................................................83
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................84
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........84
10.1.1
Code of Conduct for Clinical Trials.............................................................84
10.1.2
Financial Disclosure.....................................................................................86
10.1.3
Data Protection.............................................................................................86
10.1.3.1
Confidentiality of Data ......................................................................87
10.1.3.2
Confidentiality of Participant Records...............................................87
10.1.3.3
Confidentiality of IRB/IEC Information............................................87
10.1.4
Publication Policy........................................................................................87
10.1.5
Compliance with Study Registration and Results Posting Requirements ...88
10.1.6
Compliance with Law, Audit, and Debarment ............................................88
10.1.7
Data Quality Assurance ...............................................................................89
10.1.8
Source Documents .......................................................................................89
10.1.9
Study and Site Closure.................................................................................90
10.2
Appendix 2: Clinical Laboratory Tests..............................................................91
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................93
10.3.1
Definition of AE ..........................................................................................93
10.3.2
Definition of SAE ........................................................................................94
 
 
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PRODUCT: MK-8558  
11
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
10.3.3
Additional Events Reported in the Same Manner as SAE...........................95
10.3.4
Recording AE and SAE ...............................................................................95
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................99
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................100
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................101
10.5.1
Definitions..................................................................................................101
10.5.2
Contraception Requirements......................................................................102
10.5.3
Pregnancy Testing......................................................................................103
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................104
10.7
Appendix 7: Country-specific Requirements..................................................109
10.8
Appendix 8: Approximate Blood Volumes Drawn by Trial Visit and by 
Sample Type .......................................................................................................110
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ..................111
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...112
10.11 Appendix 11: Abbreviations .............................................................................113
11
REFERENCES.............................................................................................................115
 
 
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PRODUCT: MK-8558  
13
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
LIST OF FIGURES
Figure 1
Trial Design Diagram for Panels A, B, C, and D ......................................34
 
 
059N6P


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PRODUCT: MK-8558  
16
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of HIV-1 Infection
Population
HIV-1 Infected Participants, Naïve to Anti-Retroviral 
Therapy
Study Type
Interventional
Intervention Model
Sequential
This is a multi-site study.
Type of Control
Historical placebo control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 8 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 24 participants will be allocated.
 
 
059N6P


PRODUCT: MK-8558  
17
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment 
Period
Use
Panel A
MK-
8558
400 mg
Once
Oral
Single Dose
Experimental
Panel B
MK-
8558
≤900 mg
Once
Oral
Single Dose
Experimental
Panel C
MK-
8558
≤1600 mg
Once
Oral
Single Dose
Experimental
Panel D
MK-
8558
≤1600 mg
Once
Oral 
Single Dose 
Experimental 
Total 
Number
24 participants (4 panels of 6 participants each)
Duration of 
Participatio
n
Each participant will participate in the study for approximately 9 weeks from 
the time the participant signs the Informed Consent Form (ICF) through the 
final contact. After a screening phase of 4 weeks, each participant will receive 
the assigned intervention (single dose MK-8558). After study drug (MK-8558) 
administration, each participant will be followed for approximately five 
weeks.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
 
 
059N6P


PRODUCT: MK-8558  
18
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
1.2
Schema
The study design is depicted in Table 1.
Table 1
Dosing Scheme for MK-8558
Panela
Dose of MK-8558
A
400 mg
Bb
≤900 mg
Cb
≤1600 mg
Db,c
≤1600 mg with food
a.
In each panel, 6 participants will receive a single dose of MK-8558. 
b.
The decision to proceed to the next panel, and the selection of dose will be made 
following review of data from the preceding panel. 
c.
Optional panel. If the study objectives are met by Panels A-C, Panel D may not be 
required.
 
 
059N6P


PRODUCT: MK-8558  
19
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
1.3
Schedule of Activities (SoA)
All Panels (Panels A-D)a
Study Period
Screeningb
Intervention
Post-
studyc
Scheduled Hour
Pre-
dose
0
0.5
1
1.5
2
3
4
5
6
8
12
24
48
72
120
168
240
336
504
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Inclusion/Exclusion Criteria
X
X
Participant Identification Card
X
Medical History (includes substance 
usage)d
X
Prior/Concomitant Medication 
Review
X
------------------------------------------------------------------------------------------------------------------------
X
Participant Domiciling in Clinical 
Research Unit (CRU)e
X
-----------------------------------------------------
X
Intervention Allocation 
X
Clinical and Safety Procedures
MK-8558 Administration
X
Standard Mealf
X-----------------------X
Standard Breakfastg
X
Full physical examination
X
Xh
X
X
X
Height
X
Weight
X
X
X
Vital Signs (heart rate, blood 
pressure)i
X
Xj
X
X
X
X
Vital Signs (respiratory rate, body 
temperature)
X
X
X
X
X
X
Orthostatic Vital Signs (heart rate, 
blood pressure)j
X
X
X
X
X
12-lead ECGk
X
Xl
X
X
X
X
Serum Follicle Stimulating Hormone 
(FSH)m
X
 
 
059N6P


PRODUCT: MK-8558  
20
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
All Panels (Panels A-D)a
Study Period
Screeningb
Intervention
Post-
studyc
Scheduled Hour
Pre-
dose
0
0.5
1
1.5
2
3
4
5
6
8
12
24
48
72
120
168
240
336
504
HIV/Hepatitis screen (per site SOP)
X
Urine Drug Screen (per site SOP)n
X
Xh
Clinical and Safety Procedures- Continued
Hematology, Urinalysis, Chemistryo
X
Xh
X
X
X
CD-4 cell count 
X
Serum C-reactive protein (CRP)
X
Urine/serum β-hCGp
X
X
X
AE/SAE review
X
------------------------------------------------------------------------------------------------------------------------
X
Pharmacokinetics
Blood for Plasma MK-8558 Assayq
X
X
X
X
X
X X X
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamics
Blood for HIV RNA, viral resistancer
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarkers
Blood for Genetic Analysiss
X
 
 
059N6P


PRODUCT: MK-8558  
21
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
All Panels (Panels A-D)a
Study Period
Screeningb
Intervention
Post-
studyc
Scheduled Hour
Pre-
dose
0
0.5
1
1.5
2
3
4
5
6
8
12
24
48
72
120
168
240
336
504
a.
Panels A-D will be conducted sequentially.  Panels B-D will proceed after review of data from prior panel. 
b.
Participants will be screened within approx. 4 weeks prior to administration of study drug.
c.
The post-study visit will occur approximately 35 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-study visit occurs prior to 35 days following the dose of study drug. 
d.
Substances include: Drugs, alcohol, tobacco, and caffeine.
e.
Participants will be admitted to the CRU the evening before scheduled dosing.
f.
Standard meals will be given approx. 4 (lunch) and 10 (dinner) hrs post-dose. Snacks will be offered at approximately 8 and 13 hrs post-dose. See Section 
5.3.1.
g.
A standard breakfast is to be administered approx. 30 minutes prior to dosing in Panel D only. The fat content of this breakfast (i.e., high, moderate, or low) 
will be determined following the review of emerging safety and PK data from the ongoing studies, Protocols 001 and 002.
h.
Pre-dose physical exam, urine drug screen and laboratory assessments may be conducted within 24 hrs prior to dosing.
i.
Participants should be resting in the semi-recumbent position for at least 10 minutes prior to obtaining HR and BP. 
j.
Following measurement of the semi-recumbent HR and BP, participants assume a standing position for approximately 2 minutes and then orthostatic HR and 
BP will be obtained.  
k.
ECGs are performed after the participant has remained in a semi-recumbent position for at least 10 minutes.
l.
Pre-dose ECGs and VS (HR and BP) will be obtained in triplicate at least 1-2 minutes apart within 3 hrs prior to dosing. 
m. For post-menopausal females only.
n.
Drug screen at screening and pre-dose are mandatory; any additional drug screens are conducted per site SOP and/or at the investigator’s discretion.
o.
Safety laboratory samples (hematology, urinalysis, and chemistry) will be collected after at least an 8-hr fast. Screening hematology labs will include 
PT/INR measurements. 
p.
Serum/urine (as required by local regulations) β-human chorionic gonadotrophin (β-hCG) to be performed in women of childbearing potential (WOCBP) 
only.
q.
Leftover plasma samples will be stored for future biomedical research if the participant signs the Future Biomedical Research consent. 
r.
For participants who initiate follow-on anti-retroviral therapy (ART), blood for HIV-1 viral RNA and viral resistance will be collected at timepoints up to the 
initiation of ART. At the timepoint immediately prior to initiation of ART an additional blood sample collected for viral resistance testing may be taken for 
extraction of proviral DNA. This proviral DNA will be frozen and analyzed for the presence of viral resistance mutations only if standard Sanger sequencing 
cannot be performed because plasma viral load is too low at this time point. In addition, ultra-deep sequencing may be performed on this proviral DNA 
sample in the event that further information on viral resistance is required.
s.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected 
at that site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these 
purposes. If the sample is collected, leftover extracted DNA will be stored for future biomedical research if the participant signs the future biomedical 
research consent. If the planned genetic analyses are not approved, but future biomedical research is approved and consent is given, this sample will be 
collected for the purpose of future biomedical research.
 
 
059N6P


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PRODUCT:  MK-8558  
33
PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Objectives
Endpoints
•
To explore the relationship between 
genetic variation and response to the 
treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study.
•
Germline genetic variation
4
STUDY DESIGN
4.1
Overall Design
This is an open-label, single-dose, historical placebo-controlled, multiple panel trial of MK-
8558 in participants with HIV-1 infection.
Up to four panels (Panels A-D), consisting of 6 participants per panel, will be enrolled. In 
each panel, participants will receive a single oral dose of MK-8558 (as outlined in Table 1) 
and undergo safety assessments and blood sampling for PK and viral load analysis. 
Panels will be enrolled in a sequential manner, i.e., Panel B will initiate, and its dose level 
selected, following the review of safety, tolerability, viral dynamics, and PK data from Panel 
A (to at least 7 days post-dose). Similarly, selection of Panel C and D dose levels will occur 
following review of safety, tolerability, and viral dynamics data from Panels B and C, 
respectively, within this trial, and of emerging data from Protocol 001.
Data from the ongoing trial, MK-8558 Protocol 001 were used in the selection of the first 
dose (Panel A) with the inclusion of updated data within a previous substantial amendment 
(Protocol 002-01) to support the enrollment of Panels B, C and D. 
 
 
059N6P


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PRODUCT:  MK-8558  
45
PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Sufficient time is allowed between dosing in subsequent panels to allow for the analysis and 
review of these data. There will be frequent, careful assessments of AEs throughout the post-
dose 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 signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics 
Committee(s) [IRB(s)/IEC(s)] will be apprised of the maximum duration of the study beyond 
the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
A primary objective of this early Phase 1 study is to identify the maximum safe and well-
tolerated dose and/or dosing regimen that achieve PK, pharmacodynamic, and/or biologic 
targets in humans based on preclinical or early clinical data. Therefore, it is possible that 
study participants may not receive all doses specified in the protocol if this objective is 
achieved at lesser dose levels in this study. This would not be defined as early termination of 
the study, but rather an earlier than anticipated achievement of the study objective(s). If a 
finding (eg, PK, pharmacodynamic, efficacy, biologic targets, etc.) from another preclinical 
or clinical study using the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study results in the study(ies) or program being stopped for 
nonsafety reasons, this also does not meet the definition of early study termination.
Early study termination is defined as a permanent discontinuation of the study due to 
unanticipated concerns of safety to the study participants arising from clinical or preclinical
studies with the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study.
 
 
059N6P


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PRODUCT:  MK-8558  
49
PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has acute (primary) HIV-1 infection.
2. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic (with the exception of Gilbert’s disease), 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 (e.g., 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.
3. Is mentally or legally incapacitated at the time of pre-study (screening) visit or expected 
during the conduct of the study or has a history of a 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.
4. Has a history of cancer (malignancy).
Exceptions: Participants with adequately treated disease deemed “cured,” who, in the 
opinion of the trial investigator, are highly unlikely to sustain a recurrence for the 
duration of the trial may be enrolled at the discretion of the investigator. 
5. Participant has an estimated creatinine clearance (CrCl) ≤ 90 mL/min based on the 
Cockcroft-Gault (CG) Equation.
Cockcroft-Gault Equation: 
ClCr = (140-age[yr])(body wt [kg])
(72)(serum creat [mg/dL])
[When creatinine is measured in micromole/litre, use this formula]
ClCr = (140-age[yr])(body wt[kg])
(72)(serum creatinine [micromol/L] x 0.0113)
For females, multiple the result by 0.85.
At the discretion of the investigator, a measured creatinine clearance, as determined by a 24-
hour urine collection, may be used in place of, or in conjunction with, the estimate of the 
creatinine clearance.
 
 
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PRODUCT:  MK-8558  
50
PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Participants who have a measured creatinine clearance of up to 10% below 90 mL/min may
be enrolled in the study at the discretion of the investigator.
6. Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic 
allergic reaction) to prescription or non-prescription drugs or food; or has hereditary
galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
7. Is positive for hepatitis B surface antigen.
8.
Has a history of chronic hepatitis C unless there has been documented cure and/or 
participant with a positive serologic test for Hepatitis C Virus (HCV) has a negative HCV 
VL.
9. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the pre-study (screening) visit.
Prior/Concomitant Therapy
10. Is unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 
half-lives) prior to administration of the initial dose of study drug, throughout the study, 
until the post-study visit. There may be certain medications that are permitted (see 
Section 6.5). 
Prior/Concurrent Clinical Study Experience
11. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the pre-study (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
12. Has a clinically significant abnormality on the ECG performed at the pre-study 
(screening) visit and/or prior to administration of the initial dose of study drug.
Other Exclusions
13. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
14. Is under the age of legal consent or not capable of giving consent.
15. Has been committed to an institution by way of official or judicial order.
16. Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict 
smoking to ≤10 cigarettes per day.
 
 
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PRODUCT:  MK-8558  
51
PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
17. Consumes more than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
18. Consumes excessive amounts, defined as more 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.
19. Has a positive urine drug screen (except for cannabis) at screening and/or pre-dose; 
rechecks are allowed.
20. Presents any concern to the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
21. 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 Section 8.
In each treatment panel (except for Panel D, described separately below), participants will 
fast from all food and drinks, except water, for at least 10 hours prior to study drug 
administration. Participants will fast from all food and drinks except water between study 
drug administration and the first scheduled meal. Meals and snack(s) will be provided by the 
investigator at time points indicated in the SoA. Participants will fast from all food and 
drinks except water between meals and snacks. The caloric content and composition of meals 
will be the same in each treatment panel. After the 24-hour post-dose procedures have been 
completed, subsequent meals and snacks will be unrestricted in caloric content, composition 
and timing.
In Panel D, following an overnight fast of at least 10 hours, breakfast will be provided to 
participants approximately 30 minutes prior to study drug administration. Breakfast should 
be consumed in its entirety within approximately 20 minutes. The start and stop time of the 
breakfast will be recorded. Within approximately 10 minutes after consuming the breakfast, 
subjects will be administered trial drug as indicated in Section 8.1.8, and participants will fast 
from all food and drink, except water, for at least 4 hours following dosing. In Panel D,
participants will consume a high-fat, moderate-fat, or low-fat breakfast (to be determined 
following the review of emerging safety and PK data from the ongoing studies, Protocols 001
and 002). The contents of the breakfasts are listed in Table 8, Table 9, and Table 9.
 
 
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PRODUCT:  MK-8558  
52
PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Table 7
Contents of the Standard, High-Fat Breakfast
2 fried or scrambled eggs
2 strips bacon
2 slices toast with 2 pats of butter
4 oz (113 g) hash browns (fried potato)
240 mL whole milk
The nutritional content of the high-fat breakfast is as follows:
Total fat = 55.6 g
Total carbohydrates = 55 g
Total protein = 31.1 g
Total calories = 500.4 in fat, 220 in carbohydrates, and 124.4 in protein.
Table 8
Contents of the Standard, Moderate-Fat Breakfast
Brown bread (70 g)
Butter (15 g)
Cheese (40 g)
Jam (15 g)
240 mL Whole milk
The nutritional content of the moderate-fat breakfast is as follows:
Total fat = 34 g (31% of calories)
Total carbohydrates = 53 g (48% of calories)
Total protein = 22 g (20% of calories)
Total calories = 619 Kcalories
Table 9
Contents of the Standard, Low-Fat Breakfast
2 small bread rolls (60 g)
Light cream cheese (65 g)
Fat free milk (160 mL)
The nutritional content of the low-fat breakfast is as follows:
Total fat = 9 g (8% of calories)
Total carbohydrates =  43 g (37% of calories)
Total protein = 15 g (13% of calories)
Total calories = 312 Kcalories
 
 
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PRODUCT:  MK-8558  
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PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
The exact meal contents may be substituted with agreement between Sponsor and 
Investigator and must be documented in an administrative letter. The specific nutritional 
content of the breakfast may be modified during the study based on newly available data.
Instructions on whether to take MK-8558 with or without food and/or drink may be modified 
during the study based on newly available data.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study, and until the post-study visit.
Participants also will refrain from the consumption of all fruit juices 24 hours prior to and 
after study drug administration. On all other days during the study, consumption of fruits and 
fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the pre-study and post-study visits and from 12 hours prior to 
and after study drug administration. At all other times, caffeinated beverages or xanthine-
containing products will be limited to no more than 6 units per day amounts (1 unit = 120 mg 
of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the pre-study and 
post-study visits and from 24 hours prior to and after study drug administration. At all other 
times, alcohol consumption is limited to no more than approximately 3 alcoholic beverages 
or equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine 
[118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Smoking (and/or the use of nicotine/nicotine-containing products) should be restricted to ≤10 
cigarettes per day and participants will be required to follow the smoking restrictions defined 
by the CRU while on site.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (e.g., weight lifting, 
running, bicycling, heavy gardening, moving heavy objects, etc.) from the pre-study 
(screening) visit until administration of the initial dose of study drug, throughout the study, 
and until the post-study visit. Participants will be asked to rest semi-recumbent for 4 hours 
 
 
059N6P


PRODUCT:  MK-8558  
54
PROTOCOL/AMENDMENT NO.:  002-03  
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
post-dose, except to stand for the measurement of orthostatic vital signs (if needed) or any 
other trial related procedure.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information may be 
included, as outlined in the electronic case report forms (eCRF) entry guidelines. Minimal 
information may include demography, screen failure details, eligibility criteria, and any AEs 
or SAEs meeting reporting requirements.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention or withdraws from the study, a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number. The study site should 
contact the Sponsor for the replacement participant’s treatment/randomization number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies [study interventions (MK-8558) provided by the Sponsor] will be packaged 
to support enrollment and replacement participants as required. When a replacement 
participant is required, the Sponsor or designee needs to be contacted prior to dosing the 
replacement supplies. Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 10.
 
 
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PRODUCT: MK-8558  
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PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
Table 10
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/Treatment 
Period
Use
IMP/
NIMP
Sourcing
Panel A
Experim
ental 
MK-8558
Drug
Tablet
10 mg 
100 mg
400 mg
Oral 
Single Dose
Experimental 
IMP
Provided 
centrally 
by the 
Sponsor 
Panel B
Experim
ental 
MK-8558
Drug
Tablet 
10 mg 
100 mg 
≤900 mg
Oral 
Single Dose
Experimental 
IMP
Provided 
centrally 
by the 
Sponsor 
Panel C
Experim
ental 
MK-8558
Drug
Tablet 
10 mg 
100 mg 
≤1600 
mg
Oral 
Single Dose
Experimental 
IMP
Provided 
centrally 
by the 
Sponsor 
Panel D
Experim
ental
MK-8558
Drug
Tablet
10 mg 
100 mg
≤1600 
mg 
Oral
Single Dose 
Experimental
IMP
Provided 
centrally 
by the 
Sponsor 
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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PRODUCT: MK-8558  
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PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
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All supplies indicated in Table10 will be provided per the "Sourcing" column depending 
upon local country operational requirements. If local sourcing, every attempt should be made 
to source these supplies from a single lot/batch number where possible (e.g., not applicable in 
the case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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PRODUCT: MK-8558  
57
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be assigned to panel and treatment according to an allocation 
schedule. A sample allocation schedule is shown in Table 11.
Table 11
Sample Allocation Schedule
Panel 
N
Dose of MK-8558a
A
6
400 mg
Bb
6
≤900 mg
Cb
6
≤1600 mg
Db
6
≤1600 mg
with food
a.
Doses may be adjusted downward following review of safety and viral load data from preceding panels. 
b.
The doses to be administered in Panels B, C and D will be based on the results of safety and viral load data 
out to at least Day 8 in Panels A, B and C, respectively. 
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.
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, he/she may be included in the study if the investigator 
can rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination,
during the ongoing study (i.e., after randomization or intervention allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
 
 
059N6P


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Based on the review of data (specified above), modifications to planned dosing may be 
implemented, including: 

administration to a subsequent panel the same dose level to further evaluate that
particular level;

administration of a lower dose of the study treatment;

administration of the same or lower dose as a divided dose; or

administration of the same or a lower dose with or without food.
Or, dosing may be stopped. Participant discontinuation criteria are outlined in Section 7.
6.6.1
Stopping Rules
Enrollment of the trial will be halted in the following circumstances:
1. One participant (cumulatively) reports a serious AE with a potential causal relationship to 
the study drug or two (2) participants per panel report severe AEs with a potential causal 
relationship to study drug.
2. Three (3) or more of the enrolled participants (cumulatively) 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 (cumulatively) 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 (cumulatively) 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
If one of the above circumstances occurs, enrollment and dosing will be halted, and an 
internal safety review will be conducted prior to making a decision about terminating the
study. The safety of participants will be assessed on an ongoing basis, and while conditions
that could warrant early trial termination are not limited to those noted above, these criteria
are meant to pre-specify circumstances under which the trial may be terminated early. In the
event that the trial is interrupted or safety data suggest that the benefit-to-risk assessment has
been meaningfully altered and must be reassessed, the Regulatory Authority will be notified.
 
 
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6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
regimen will still continue to participate in the study as specified in Section 1.3 and Section
or if available, a protocol clarification letter.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9 and 8.10.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
1.
The participant requests to discontinue study intervention.

The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, placed the participant at unnecessary risk 
from continued participation in the study.

The participant has a positive urine drug screen (excluding cannabis) confirmed upon 
recheck at any time during the course of the study.
For participants who are discontinued from study intervention all applicable discontinuation 
activities will be performed according to Section 8.1.9, or if available, a protocol clarification 
letter.
 
 
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Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
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 withdraws consent from the study.

The participant is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
 
 
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•
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 (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 380.5 mL (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant prior to participating in a clinical 
study or future biomedical research.If there are changes to the participant’s status during the 
study (eg, health or age of majority requirements), the investigator or medically qualified 
designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
 
 
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The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant should be 
informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent form or addendum to 
the original consent form that captures the participant’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history, including details of substance usage, will be obtained by the investigator 
or qualified designee.
 
 
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be 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 re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
Approximately 240 mL of water will be provided during trial drug administration. Additional 
water (in increments of 50 mL) may be provided for participants receiving a dose of MK-
8558 requiring more than 2 tablets.
Water will be restricted 1 hour prior to and 1 hour after study drug administration. Details on 
water and dietary restrictions are outlined in Section 5.3.1.
8.1.8.1
Timing of Dose Administration
All doses of MK-8558 will be given in the morning at approximately the same time in each 
treatment panel. 
 
 
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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 post-study visit as per the number of 
days described in Section 8.10.4) to have the applicable procedures conducted. However, the 
investigator may decide to perform the post-study procedures at the time of discontinuation 
or as soon as possible after discontinuation. If the post-study visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a follow-
up telephone call at the end of the follow-up period ( Section 8.4.1) to if any AEs have 
occurred since the post-study clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Domiciling
Participants will report to the CRU the evening prior to the scheduled day of study 
intervention administration and remain in the unit until 24 hours post-dose. At the discretion
of the investigator, participants may be requested to remain in the CRU longer
 
 
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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 pre-study to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8:
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Type.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Investigators 
should pay special attention to clinical signs related to previous serious illnesses. The pre-
dose physical examination may be performed within 24 hours prior to dosing. 
Body Mass Index (BMI)
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1-0.4, round down and 0.5-0.9, round up.
Height and weight will be measured and recorded with the participant’s shoes off and jacket 
or coat removed. 
 
 
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8.3.2
Vital Signs
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a semi-recumbent for at least 10 minutes prior to having 
vital sign (VS) measurements obtained. Semi-recumbent VS will include heart rate (HR) and 
blood pressure (BP). The correct size of the BP cuff and the correct positioning on the 
participants' arm is essential to increase the accuracy of BP measurements. Measurements 
will be assessed with a completely automated device. Manual techniques will be used only if 
an automated device is not available.
The pre-dose Day 1 HR and BP will be in triplicate measurements, obtained at least 1-2 
minutes apart within 3 hours prior to dosing MK-8558. The mean of these measurements will 
be used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed). Post-dose VS measurements will be single measurements.
Participants may stand for the measurement of orthostatic VS (if needed) during the 4 hour 
interval after dosing.
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.
Respiratory Rate
Respiratory rate will be counted per site’s SOP.
8.3.2.1
Orthostatic Vital Signs
Orthostatic VS (HR and BP) will also be obtained. Participants should be semi-recumbent for 
at least 10 minutes and then stand upright for 2 minutes prior to measurement of orthostatic 
VS.
8.3.3
Electrocardiograms
•
Special care must be taken for proper lead placement by qualified personnel. Skin should 
be clean and dry prior to lead placement. Participants may need to be shaved to ensure 
proper lead placement.  Female participants may need to remove interfering 
undergarments.
•
Participants should be resting in the semi-recumbent position for at least 10 minutes prior 
to each electrocardiogram (ECG) measurement.
•
The correction formula to be used for QTc is Fridericia.
 
 
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•
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.
•
Pre-dose ECGs will be obtained in triplicate at least 1-2 minutes apart within 3 hours 
prior to dosing MK-8558. The mean of these measurements will be used as the baseline 
to calculate change from baseline for safety evaluations (and for rechecks, if needed).  
Post-dose ECG measurements will be single measurements.
•
During each treatment period, if a participant demonstrates an increase in QTcF interval 
≥60 msec compared with mean pre-dose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The mean value of the QTcF interval from the 3 ECGs will 
represent the value at that time point. If the mean QTcF interval increase from baseline 
for any post-dose 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 QTcF is within 60 
msec of baseline. If prolongation of the QTcF interval ≥60 msec persists, a consultation 
with a study cardiologist may be appropriate and the Sponsor should be notified.
•
If the QTcF interval is 500 msec (confirmed upon recheck and manual measurement), the 
Sponsor should be notified and the ECGs should be reviewed by a cardiologist. The 
participant should be telemetry-monitored (until the QTcF is <500 msec) or should be 
considered for transfer to a location where closer monitoring and definitive care (e.g., a 
cardiac or intensive care unit) is available.
•
If the participant has unstable hemodynamics, or has any clinically significant 
dysrhythmias noted on telemetry, the participant should be immediately transferred to an 
acute care setting for definitive therapy.
•
If prolongation of the QTcF is noted, concomitant medications that prolong QTcF should 
be held until the QTcF is within 60 msec of baseline and the QTcF is <500 msec.
•
A study cardiologist will be consulted by the investigator as needed to review ECG 
tracings with 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 case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
 
 
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•
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 35 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, or surrogate).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before intervention allocation/randomization, must be reported by the investigator for 
randomized participants only if the event is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment, or a procedure.
From the time of intervention allocation/randomization through 35 days following cessation 
of intervention, all AEs, SAEs and other reportable safety events must be reported by the 
investigator.
 
 
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Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 12.
 
 
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Table 12
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
allocated participants for outcome. Further information on follow-up procedures is given in 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to this study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include: 

An overdose of Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
In the event that a participant has taken (accidentally or intentionally) any drug administered 
as part of the protocol that exceeds the dose as prescribed by the protocol, it is up to the 
investigator or the reporting physician to decide whether a dose is to be considered an 
overdose, in consultation with the Sponsor.
There is no specific guidance available regarding overdose with MK-8558, due to the lack of 
clinical experience with overdosing. In case of acute over-dosage, standard supportive care 
should be provided as clinically appropriate. The Sponsor clinical director should be 
contacted immediately.
 
 
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8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of 
PK/pharmacodynamics will be collaboratively determined by the Sponsor (e.g., samples at 
lower doses may not be assayed if samples at higher doses reveal undetectable drug 
concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-8558
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples (for 
HIV RNA measurement and viral resistance testing) will be provided in the Study Operations 
Manual.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:

Blood for Genetic Analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the Study Operations Manual.
 
 
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8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Leftover DNA for future research

Leftover main study plasma from MK-8558 assay stored for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 4 weeks prior to intervention allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in Section 
5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation/randomization if 
there are Day -1 procedures planned per protocol.
8.10.2
Treatment Period Visit
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all of the 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.
8.10.4
Post-study
Participants will be required to return to clinic approximately 35 days after the last dose of 
study intervention for the post-study visit. If the post-study visit occurs less than 35 days 
after the last dose of study intervention, a subsequent follow-up telephone call should be 
made at 35 days post the last dose of study intervention to determine if any AEs have 
occurred since the post-study clinic visit.
 
 
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8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood samples for plasma MK-8558 and HIV-1 viral RNA are the critical 
procedures.
At any post-dose time point, the blood sample for MK-8558 and the blood sample for viral 
RNA need to be collected as close to the exact time point as possible. All other procedures 
should be completed as close to the prescribed/scheduled time as possible. Study procedures 
can be performed prior or after the prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
PK Collection as outlined in Table 13.
Table 13
Blood Collection Windows for Plasma PK and HIV RNA
PK/PD
Collection
PK/PD Collection 
Window
0 – <1.0 hr
5 min
1 - <24 hrs
15 min
24 - <48 hrs
2 hrs
48 - <96 hrs
4 hrs
96 – <168 hrs
     8 hrs
≥168 hrs
24 hrs

Pre-dose standard safety evaluations: vital signs and ECG at 3 hours; laboratory 
safety tests and physical exam at 24 hours

Post-dose standard safety evaluations: vital signs, ECG, laboratory safety tests, and 
physical exam
o
<24 hours post-dose may be obtained within 30 minutes of the theoretical 
sampling time
o
24 - <48 hours post-dose may be obtained within 2 hours of the theoretical 
sampling time
 
 
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o
48 – <96 hours post-dose may be obtained within 4 hours of the theoretical 
sampling time
o
96 – <168 hours post-dose may be obtained within 8 hours of the theoretical 
sampling time
o
≥168 hours post-dose may be obtained within 24 hours of the theoretical 
sampling time
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-8558 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound is still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Repeat of or decrease in the dose of the study intervention administered in any given 
period/panel
•
Entire period(s) or panel(s) may be omitted
•
Adjustment of the dosing interval (e.g., divided doses [QD to BID, TID])
•
Remove a planned PK pause if agreed by Sponsor and investigator if no further 
increases in total daily dose
•
Addition of PK pause
•
Instructions to take study intervention with or without food or drink may also be 
modified based on newly available data
•
Modification of the fed cohort to another panel. In the event that this modification is 
implemented, the planned dosing and feeding regimen with supporting data will be 
communicated in an official memo.
•
Modification of the PK/pharmacodynamic sample processing and shipping details 
based on newly available data or for operational reasons
The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (e.g., to 
 
 
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9.4
Analysis Endpoints
Primary Endpoints:
Safety: Primary safety endpoints will include AEs, in addition to laboratory safety tests, 
ECGs, and VS. 
Pharmacodynamics (PD): 
The primary PD variables in this study include plasma HIV-1 RNA pre-dose and at the time 
points listed in the Study Flow Chart up until the time at which ART is initiated. 
Secondary Endpoints (PK):
The secondary endpoints in this study include: MK-8558 plasma AUC0-last, AUC0-inf, 
AUC0-168hr, Tmax, Cmax, C168hr, CL/F, Vz/F, and terminal t1/2.
9.5
Analysis Populations
All Participants as Treated (APaT): The All Participants as Treated Population consists of 
all participants who received at least one dose of treatment.  This population will be used for 
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the 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.  
Any participants or data values excluded from analysis will be identified, along with their 
reason for exclusion, in the CSR. At the end of the study, all participants who are compliant 
with the study procedure as aforementioned and have available data from at least one 
treatment will be included in the Per-Protocol dataset. This population will be used for the 
PK and PD analyses.
9.6
Statistical Methods
Primary (Safety): 
Incidence of AEs will be descriptively summarized. Summary statistics and plots will be 
generated for the change from baseline values in the VS, ECG parameters, and selected 
laboratory safety parameters for participants, as deemed clinically appropriate. Depending on 
the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back-transformed for reporting 
(percent change from baseline). Summary statistics for the raw laboratory safety tests, ECGs, 
and/or vital signs may also be computed, as deemed clinically appropriate.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
 
 
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
 
 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
 
 
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contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 14 will be performed by the local laboratory.
•
If the local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing (for WOCBP only):
•
Pregnancy testing requirements for study inclusion are described in Section 5.1, and 
the defined time points for pregnancy testing are included in the SoA.
•
Pregnancy testing (urine or serum, as required by local regulations) should be 
performed at a minimum at the following time points:
•
At screening, to confirm absence of pregnancy
•
Within 24 hours prior to the first dose of study medication
•
At the Post-Study Visit, corresponding with the end of relevant systemic exposure 
and the time frame for female participant contraception in Section 5.1 (i.e., 35 
days following the last dose of study medication).
•
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.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a) Results in death
b) Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c) Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d) Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e) Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f)
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor. 
•
Is a cancer 
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
 
 
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
 
 
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-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
 
 
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•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
 
 
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•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
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. 
 
 
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10.5.2
Contraception Requirements
For male participants: refer to Section 5.1.
Requirements for WOCBP:
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
IUD (non-hormonal intra-uterine device)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 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.
1.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
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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10.5.3
Pregnancy Testing
For WOCBP only: pregnancy testing requirements are outlined in Appendix 2.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
 
 
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b.
Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.
Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
 
 
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specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements 
Not applicable.
 
 
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10.8
Appendix 8: Approximate Blood Volumes Drawn by Trial Visit and by Sample 
Type
Panels A, B, C and D
Pre-study
Treatment Period
Post-study
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Testsa
1
3
1
5
13
65
Serum β-hCGb
1
1
1
3
5
15
PT/INR
1
0
0
1
3
3
Blood for Planned Genetic 
Analysis
0
1
0
1
8.5
8.5
Blood for MK-8558
0
19
0
19
4
76
Blood for HIV RNA, viral 
resistancecd
1
11
1
13
16
208
Proviral DNAe
0
1
0
1
5
5
Approx. Total Blood Volume per Participant for Panels A, B, C and D f
380.5 mL
a)
Blood volume includes CD4 cell count, HIV/Hepatitis Screen, and FSH. 
b)
β-human chorionic gonadotrophin (β-hCG) to be performed in women of childbearing potential (WOCBP) only. 
Volumes provided for serum testing; serum or urine may be performed in accordance with by local regulations.
c)
Blood volume includes ultra-deep sequencing which may be performed if needed.
d)
For all panels blood for HIV-1 viral RNA and viral resistance may be collected up to the post-study visit if 
participants do not start ART. The number of collections denoted in this row reflects the maximum quantity required 
if a participant dose not initiate ART during the trial and the post-study period. 
e)
At the timepoint immediately prior to initiation of ART an additional blood sample collected for viral resistance 
testing may be taken for extraction of proviral DNA. This proviral DNA will be frozen and analyzed for the presence 
of viral resistance mutations only if standard Sanger sequencing cannot be performed because plasma viral load is too 
low at this timepoint. In addition, ultra-deep sequencing may be performed on this proviral DNA sample in the event 
that further information on viral resistance is required.
f)
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. Note: never to exceed 50 mL.
 
 
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
Not applicable. 
 
 
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at pre-study (screening) visit and/or pre-dose 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 not 
clinically significant (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).
If the repeat test value is within the normal range, the participant may enter the study.
If the repeat test value is still abnormal, the study investigator will evaluate the potential 
participant with a complete history and physical examination, looking especially for 
diseases that could result in the abnormal laboratory value in question. If such 
diseases can be ruled out, and if the abnormal laboratory value is not clinically 
relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
 
 
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PRODUCT: MK-8558  
114
PROTOCOL/AMENDMENT NO.: 002-03 
MK-8558-002-03 FINAL PROTOCOL
22-AUG-2019
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Abbreviation
Expanded Term
MSD
MERCK SHARP & DOHME
NCS
Not clinically significant
NOAEL
no observed adverse effect level 
NOEL
no observed effect level
NRTI
nucleoside reverse transcriptase inhibitor
P-gp
P-glycoprotein
PK
pharmacokinetic
PD
Pharmacodynamic
POC
proof-of-concept
PT
Prothrombin Time
QD
Once daily 
QTc
Interval of heart beat 
QTcF
QTc with Fridericia correction
RNA
ribonucleic acid
SAE
serious adverse event 
SD
Standard deviation 
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
Tmax
Time to get to maximum concentration in blood
VL
Viral load
VS
Vital sign 
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential
 
 
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