Clinical trial NCT03272347
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-11-27; Completion date: 2022-03-09
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability, antiretroviral activity, and pharmacokinetics of 3 doses of islatravir (MK-8591) in combination with doravirine (DOR) and lamivudine (3TC) administered to antiretroviral treatment-naïve adult participants with human immunodeficiency virus type 1 (HIV-1) infection.

Detailed description:

Arms: arm 1: Participants will be treated once daily (QD) with 0.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) for a minimum of 24 weeks. Between week 24 through week 52, 3TC and placebo to DOR/3TC/TDF may be discontinued. Around Week 60, participants may be switched to a selected open label dose of islatravir and DOR 100 mg QD and continue treatment until Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192. arm 2: Participants will be treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. Between week 24 through week 52, 3TC and placebo to DOR/3TC/TDF may be discontinued. Around Week 60, participants may be switched to a selected open label dose of islatravir and DOR 100 mg QD and will continue treatment until Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192. arm 3: Participants will be treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. Between week 24 through week 52, 3TC and placebo to DOR/3TC/TDF may be discontinued. Around Week 60, participants may be switched to a selected open label dose of islatravir and DOR 100 mg QD and will continue treatment until Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192. arm 4: Participants will be treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. Between week 24 through week 52 placebo treatments may be discontinued and participants will receive only DOR/3TC/TDF QD open label up to Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192.
Interventions: intervention 1: Islatravir intervention 2: Placebo to Islatravir intervention 3: Doravirine intervention 4: Placebo to Doravirine intervention 5: Lamivudine intervention 6: Placebo to Lamivudine intervention 7: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate intervention 8: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate intervention 9: Doravirine/Islatravir
Intervention descriptions: intervention 1: Islatravir at 0.25 mg, 0.75 mg or 2.25 mg is orally administered QD in capsule form for up to 52 weeks. After Week 60 a selected open label dose may be administered. intervention 2: Placebo to islatravir is orally administered QD in capsule form for up to 52 weeks intervention 3: Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks intervention 4: Placebo to Doravirine is orally administered QD in tablet form for up to 52 weeks intervention 5: Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks intervention 6: Placebo to Lamivudine is orally administered QD in tablet form for up to 52 weeks intervention 7: Fixed dose combination of 100 mg doravirine + 300 mg lamivudine + 300 mg tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 144 weeks. intervention 8: Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks intervention 9: Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03272347 
Document Date: 
06-Jul-2020
A Phase 2B, Randomized, Double-Blind, Active-Comparator-
Controlled, Dose-Ranging Clinical Trial to Evaluate the Safety, 
Tolerability, Antiretroviral Activity, and Pharmacokinetics of 
MK-8591 Given in Combination with Doravirine (DOR) and
Lamivudine (3TC) in HIV-1-Infected Treatment-Naïve Adults


Product:  MK-8591
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Protocol/Amendment No.: 011-05
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06-Jul-2020
Confidential
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.,
WHITEHOUSE STATION, NJ, U.S.A.
Protocol Title: A Phase 2B, Randomized, Double-Blind, Active-Comparator-Controlled,
Dose-Ranging Clinical Trial to Evaluate the Safety, Tolerability, Antiretroviral Activity, and
Pharmacokinetics of MK-8591 Given in Combination with Doravirine (DOR) and
Lamivudine (3TC) in HIV-1-Infected Treatment-Naïve Adults
Protocol Number: 011-05
Compound Number: MK-8591
Sponsor Name and Legal Registered Address:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   134,036
EudraCT NUMBER: 2017-000437-32
Approval Date:  06 July 2020
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical trial in accordance with the design outlined in this protocol
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document 
Date of Issue 
Overall Rationale
Amendment 05 
06-JUL-2020 
At the eDMC meeting review of the Week 96 data, it was determined that no further meetings
of the eDMC would be needed and that the study could proceed as planned. The Sponsor
therefore has decided to remove the Week 120 interim analysis and to perform data analysis
on an annual basis so that the next analysis would occur at Week 144.
Amendment 04 
06-MAR-2020 The study has been extended for an additional 48 weeks (Part 4:  2-drug Dosing with MK-
8591A) to allow participants in Part 3 receiving the selected dose of MK-8591 in combination
with DOR QD or MK-1439A in the control group to switch to a 2-drug fixed-dose
combination (FDC) of MK-8591/DOR (referred to as MK-8591A) QD in Part 4, and to
collect additional safety and efficacy data.  MK-8591A will be provided as open-label
supplies.  Additional site visits have been added at Weeks 148, 156, 168, 180, and 192.
Amendment 03 
10-OCT-2019 
The terminology in the protocol has been updated from “virologic failure”to “clinically
significant confirmed viremia,”which is consistent with clinical management of participants
with HIV-1 and updated US DHHS guidelines. In addition, the study has been extended to
allow participants to receive an additional 24 weeks of open-label study treatment, and to
collect additional safety and efficacy data.  Thus, following Week 120, additional site visits
have been added at Week 132 and Week 144.
Amendment 02 
18-JAN-2018 
Revised the safety follow-up period from ~14 days (2 weeks) to ~42 days (6 weeks) after the
final dose of study treatment due to updated data which indicated the half-life of MK-8591 in
plasma was expected to be between 87 and 128 hours after cessation of dosing for the dose
range studied in this study. Therefore, a safety follow-up period of ~42 days allowed for
AE/SAE recording and reporting during this time.
Amendment 01 
20-SEP-2017 
Incorporated several regulatory requests and corrected/added several minor items.
Original Protocol 
04-AUG-2017 
Not applicable
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 05
Overall Rationale for the Amendment:
At the eDMC meeting review of the Week 96 data, it was determined that no further meetings of the eDMC would be needed and that
the study could proceed as planned. The Sponsor therefore has decided to remove the Week 120 interim analysis and to perform data
analysis on an annual basis so that the next analysis would occur at Week 144.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
2.1 Schedule of Activities –
Screening and Treatment
Visits (Parts 1-3)
The note for dispensing study 
medication using IVRS/IWRS has
been updated to clarify medication
dispensation for participants who
continue to Part 4 of the study.
Updated for clarity.
The note for the study medication
diary has been updated to include
instructions for participants who agree
to continue to Part 4.
Updated to clarify that at Week 144 study medication
diaries for Part 4 will be provided to all participants entering
Part 4.
Hepatitis screening for participants in
Group 4 who plan to switch from
MK-1439A to MK-8591A at
Week 144 to enter Part 4 has been
moved from Week 144 to Week 132.
Hepatitis screening was moved from Week 144 to Week
132 so results will be available for these participants prior to
switching to MK-8591A.
 
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Section # and Name
Description of Change
Brief Rationale
2.2 Schedule of Activities –
Treatment Visits (Part 4)
Removed dispensation of study
medication at Week 192.
Updated to clarify that no study medication will be
dispensed at Week 192.
A note was added to clarify that only
the study medication diary will be
reviewed at Week 192.
Added for clarity; no study medication diary will be
distributed at this visit.
5.1 Overall Design
Text was added to the last paragraph
of this section stating no additional
eDMC reviews of safety data will
occur following the review of the
Week 96 interim analysis.
Statement consistent with removal of the Week 120 interim
analysis.
9.5.5 DEXA Assessments 
Text referencing the Site Imaging 
Manual has been added at the end of
this section.
Added for clarity.
10.1 Statistical Analysis
Plan Summary, 10.7 Interim
Analyses
The interim analysis at Week 120 was
removed.
The Week 96 interim analysis included approximately 18
months of data showing continued virologic suppression for
study participants on the 2-drug regimen with MK-8591 +
DOR. After the Week 96 eDMC review, the eDMC deemed
that further reviews were unnecessary as the study is no
longer blinded and the eDMC does not think the safety
profile of MK-8591 + DOR will substantially change.
Approximately 30 months of data confirming MK-8591 +
DOR virologic suppression will be available for the next
interim analysis at Week 144.
Throughout
Minor typographical and grammatical
edits.
To improve clarity, consistency, and/or to align with Merck
policy.
 
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Table of Contents
DOCUMENT HISTORY ....................................................................................................... 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................. 4
1. 
Synopsis...................................................................................................................... 14
2. 
Schedule of Activities (SoA)..................................................................................... 19
Schedule of Activities - Screening and Treatment Visits (Parts 1-3) ............... 19
Schedule of Activities - Treatment Visits (Part 4) ............................................. 28
Schedule of Activities – Viremia Confirmation, Early Discontinuation
(D/C), and End of Trial (EOT) Site Follow-Up Visits ....................................... 30
3. 
Introduction............................................................................................................... 32
Study Rationale..................................................................................................... 32
Background ........................................................................................................... 33
Pharmaceutical and Therapeutic Background .................................................... 33
Completed Preclinical and Clinical Trials.......................................................... 35
Ongoing Clinical Trials....................................................................................... 36
Information on Other Trial-Related Therapy...................................................... 37
Benefit/Risk Assessment....................................................................................... 37
4. 
Objectives/Hypotheses and Endpoints.................................................................... 38
5. 
Study Design.............................................................................................................. 41
Overall Design....................................................................................................... 41
Study Diagram.................................................................................................... 43
Number of Participants........................................................................................ 45
Beginning and End of Study Definition.............................................................. 45
Clinical Criteria for Early Trial Termination...................................................... 45
Clinical Criteria for Termination of a Treatment Group(s) ................................ 45
Scientific Rationale for Study Design.................................................................. 45
Rationale for Endpoints ...................................................................................... 46
Efficacy Endpoints....................................................................................... 46
5.4.1.1.1 Virologic Failure Criteria...................................................................... 47
 
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5.4.1.1.2 Definition of Clinically Significant Confirmed Viremia...................... 47
Safety Endpoints.......................................................................................... 48
Pharmacokinetic Endpoints ......................................................................... 48
Pharmacodynamic Endpoints....................................................................... 48
Planned Exploratory Biomarker Research................................................... 48
5.4.1.5.1 Planned Genetic Analysis..................................................................... 48
Future Biomedical Research........................................................................ 49
Rationale for The Use of Comparator/Placebo................................................... 49
Justification for Dose............................................................................................ 49
6. 
Study Population....................................................................................................... 50
Inclusion Criteria.................................................................................................. 50
Exclusion Criteria................................................................................................. 52
Lifestyle Restrictions ............................................................................................ 54
Meals and Dietary Restrictions........................................................................... 54
Caffeine, Alcohol, and Tobacco ......................................................................... 54
Activity ............................................................................................................... 54
Screen Failures...................................................................................................... 54
Participant Replacement Strategy ...................................................................... 55
7. 
Treatments................................................................................................................. 55
Treatments Administered .................................................................................... 55
Dose Modification (Escalation/Titration/Other)................................................ 56
Method of Treatment Assignment....................................................................... 56
Stratification........................................................................................................ 57
Blinding.................................................................................................................. 57
Preparation/Handling/Storage/Accountability.................................................. 58
Dose Preparation................................................................................................. 58
Handling, Storage and Accountability................................................................ 58
Treatment Compliance......................................................................................... 58
Concomitant Therapy........................................................................................... 59
Rescue Medications & Supportive Care............................................................. 60
Treatment After the End of the Study................................................................ 60
Clinical Supplies Disclosure................................................................................. 61
 
 
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8.
Discontinuation/Withdrawal Criteria..................................................................... 61
Discontinuation of Study Treatment................................................................... 61
Withdrawal from the Study................................................................................. 62
Lost to Follow Up.................................................................................................. 63
9. 
Study Assessments and Procedures......................................................................... 63
Administrative and General Procedures............................................................ 63
Informed Consent................................................................................................ 63
General Informed Consent........................................................................... 64
Consent and Collection of Specimens for Future Biomedical Research..... 64
Consent for Infant Safety Follow-up ........................................................... 64
Inclusion/Exclusion Criteria ............................................................................... 64
Participant Identification Card............................................................................ 64
Medical History .................................................................................................. 65
Prior and Concomitant Medications Review...................................................... 65
Prior Medications......................................................................................... 65
Concomitant Medications............................................................................ 65
Assignment of Screening Number...................................................................... 65
Assignment of Treatment/Randomization Number............................................ 65
Treatment Administration................................................................................... 65
Timing of Dose Administration................................................................... 66
Withdrawal/Discontinuation............................................................................... 67
Withdrawal From Future Biomedical Research .......................................... 67
Participant Blinding/Unblinding......................................................................... 68
Calibration of Equipment.................................................................................... 68
Efficacy Assessments ............................................................................................ 69
HIV-1 RNA......................................................................................................... 69
Management of Study Participants with Viremia............................................... 69
Viremia Confirmation.................................................................................. 69
Participants With Clinically Significant Confirmed Viremia (≥200
copies/mL) ................................................................................................... 69
Participants With Low-Level Viremia (≥50 and 200 copies/mL)............. 70
CD4+ T-cell Counts............................................................................................ 70
 
 
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Viral Resistance Testing ..................................................................................... 70
Adverse Events, Serious Adverse Events and Other Reportable Safety
Events..................................................................................................................... 70
Time Period and Frequency for Collecting AE, SAE and Other Reportable
Safety Event Information.................................................................................... 71
Method of Detecting AE, SAE and Other Reportable Safety Events................. 73
Follow-up of AE, SAE and Other Reportable Safety Event Information........... 73
Regulatory Reporting Requirements for SAE .................................................... 73
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying
as AEs or SAEs................................................................................................... 73
Pregnancy and Exposure During Breastfeeding ................................................. 73
Events of Clinical Interest (ECI)......................................................................... 74
Treatment of Overdose......................................................................................... 74
Safety...................................................................................................................... 74
Physical Examinations........................................................................................ 75
Vital Signs........................................................................................................... 75
Electrocardiograms ............................................................................................. 75
Clinical Safety Laboratory Assessments............................................................. 75
DEXA Assessments............................................................................................ 76
Infant Safety Follow-up Assessments................................................................. 76
Pharmacokinetics.................................................................................................. 77
Pharmacodynamics............................................................................................... 78
Future Biomedical Research Sample Collection................................................ 78
Biomarkers ............................................................................................................ 79
Laboratory Markers Associated with Clinical Outcome .................................... 79
Planned Genetic Analysis Sample Collection..................................................... 79
Visit Requirements ............................................................................................... 79
Switch from Part 1 (3-drug Dose Ranging) to Part 2.......................................... 79
Transition from Part 2 to Part 3 .......................................................................... 81
Transition from Part 3 to Part 4 .......................................................................... 81
Viremia Confirmation Visit................................................................................ 82
End of Treatment Follow-up Visit...................................................................... 82
10. 
Statistical Analysis Plan ........................................................................................... 82
 
 
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Statistical Analysis Plan Summary ..................................................................... 82
Responsibility for Analyses/In-House Blinding ................................................. 84
Hypotheses/Estimation......................................................................................... 85
Analysis Endpoints ............................................................................................... 85
Efficacy/Pharmacokinetic Endpoints.................................................................. 86
Efficacy Endpoints....................................................................................... 86
Pharmacokinetic Endpoints ......................................................................... 87
Safety Endpoints................................................................................................. 87
Analysis Populations............................................................................................. 87
Efficacy Analysis Populations............................................................................ 87
Safety Analysis Population................................................................................. 88
Statistical Methods................................................................................................ 88
Statistical Methods for Efficacy Analyses.......................................................... 88
Statistical Methods for Safety Analyses ............................................................. 93
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 94
Demographic and Baseline Characteristics ................................................. 94
Population PK and PK/PD Analyses ........................................................... 94
Interim Analyses ................................................................................................... 95
Interim Analysis at Week 24............................................................................... 95
Interim Analysis at Week 48............................................................................... 95
Interim Analysis at Week 96............................................................................... 95
Periodic Safety Assessments............................................................................... 95
Virologic Failure Assessments ........................................................................... 95
Multiplicity............................................................................................................ 95
Sample Size and Power Calculations .................................................................. 96
Sample Size and Power for Efficacy Analyses................................................... 96
Sample Size and Power for Safety Analyses ...................................................... 96
Subgroup Analyses ............................................................................................... 98
Compliance (Medication Adherence).................................................................. 98
Extent of Exposure................................................................................................ 99
11. 
References.................................................................................................................. 99
12. 
Appendices............................................................................................................... 103
 
 
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Appendix 1: Abbreviations and Trademarks .................................................. 103
Appendix 2: Clinical Laboratory Tests ............................................................ 106
12.2 Appendix 2A: Division of AIDS (DAIDS) Tables for Grading the Severity
of Adult and Pediatric Adverse Events............................................................. 109
Appendix 3: Study Governance Considerations.............................................. 116
Merck Code of Conduct for Clinical Trials .................................................................. 116
Financial Disclosure...................................................................................................... 118
Data Protection.............................................................................................................. 118
Confidentiality of Data ................................................................................................. 118
Confidentiality of Participant Records.......................................................................... 118
Confidentiality of IRB/IEC Information....................................................................... 119
Committees Structure.................................................................................................... 119
Executive Oversight Committee................................................................................... 119
Data Monitoring Committee......................................................................................... 119
Publication Policy......................................................................................................... 119
Compliance with Trial Registration and Results Posting Requirements...................... 120
Compliance with Law, Audit and Debarment .............................................................. 120
Data Quality Assurance ................................................................................................ 121
Source Documents ........................................................................................................ 122
Study and Site Closure.................................................................................................. 122
Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting.............................................................. 123
Definition of AE ........................................................................................................... 123
Definition of SAE ......................................................................................................... 124
Additional Events reported........................................................................................... 125
Recording AE and SAE ................................................................................................ 125
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............... 128
Appendix 5: Contraceptive Guidance and Pregnancy Testing ...................... 130
Definitions..................................................................................................................... 130
Contraception Requirements......................................................................................... 130
Pregnancy Testing......................................................................................................... 132
Appendix 6: Collection and Management of Specimens for Future
Biomedical Research........................................................................................... 133
 
 
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LIST OF TABLES
Table 1 
Study Treatments................................................................................................. 55
Table 2 
Study Medication Labeling ................................................................................. 66
Table 3 
Reporting Time Periods and Timeframes for Adverse Events and Other
Reportable Safety Events .................................................................................... 72
Table 4 
Infant Safety Follow-up: Data Collection Through 1-Year of Age .................... 77
Table 5 
Timing for Collection of Population Pharmacokinetics Samples ....................... 78
Table 6 
Guidelines for Switching to Part 2 Beginning at the Week 24 Visit................... 80
Table 7 
Definitions of Study Time Points........................................................................ 89
Table 8 
Summary of the Two Approaches to Handle Missing Values ............................ 91
Table 9 
Analysis Strategy for Key Efficacy Variables..................................................... 92
Table 10 
Analysis Strategy for Safety Parameters............................................................. 94
Table 11 
Difference in Efficacy Proportions (MK-8591 Treatment Group minus
MK-1439A Group) That Can Be Ruled Out With 80% Power and 95%
Confidence with 30 Participants Per Group........................................................ 96
Table 12 
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on
Hypothetical Number of Participants with AEs Among 30 Participants in
Each Treatment Group ........................................................................................ 97
Table 13 
Difference in Incidence of AEs (MK-8591 treatment group minus MK-
1439A) That Can Be Ruled Out With 30 Participants in Each Treatment
Group................................................................................................................... 98
Table 14 
Protocol-Required Laboratory Assessments and Approximate Blood Draw
Volumes............................................................................................................. 106
Table 15 
Contraceptive Methods...................................................................................... 131
 
 
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LIST OF FIGURES
Figure 1 
Study Diagram..................................................................................................... 44
 
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1. Synopsis
Protocol Title: 
A Phase 2B, Randomized, Double-Blind, Active-Comparator-Controlled, Dose-
Ranging Clinical Trial to Evaluate the Safety, Tolerability, Antiretroviral Activity, and
Pharmacokinetics of MK-8591 Given in Combination with Doravirine (DOR) and
Lamivudine (3TC) in HIV-1-Infected Treatment-Naïve Adults
Short Title:
Dose Ranging Trial of MK-8591 Given in Combination with Doravirine (DOR) and
Lamivudine (3TC)
Objectives/Hypotheses and Endpoints:
There are no hypotheses to be tested in this trial.  Objectives refer to the original regimen
to which participants were randomized (Groups 1 to 3:  1 of 3 different doses of MK-8591
administered with doravirine [DOR] 100 mg + lamivudine [3TC] 300 mg, or Group 4:
MK-1439A [DOR 100 mg + 3TC 300 mg + tenofovir disoproxil fumarate [TDF] 300
mg]), but participants in the MK-8591 treatment groups will be switched in Part 2 to a
2-drug regimen with MK-8591 + DOR after at least 24 weeks on the 3-drug regimen if
their human immunodeficiency virus type 1 (HIV-1) RNA is <50 copies/mL.  In Part 3,
participants in the MK-8591 treatment groups will receive the selected dose of MK-8591 +
DOR, and Group 4 will continue to receive MK-1439A.  In Part 4, all participants in each
group will receive MK-8591A (FDC of MK-8591/DOR).
In HIV-1-infected antiretroviral treatment-naïve adults:
Objective/Hypothesis
Endpoint
Primary
 Objective:  To evaluate the
antiretroviral activity of different
doses of MK-8591 administered with
DOR + 3TC compared to
MK-1439A, as assessed by the
proportion of participants with HIV-
1 RNA <50 copies/mL at Week 24
and at Week 48
 Proportion of participants with HIV-1
RNA <50 copies/mL at Week 24 and
Week 48
 Objective:  To evaluate the safety
and tolerability of different doses of
MK-8591 administered with DOR +
3TC compared to MK-1439A
 Number of participants experiencing
adverse events (AEs)
 Number of participants discontinuing
study drug due to AEs
 
 
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Secondary
 Objective:  To evaluate the sustained
antiretroviral suppression in
participants on the selected dose of
MK-8591 + DOR compared to
MK-1439A as assessed by the
proportion of participants with HIV-
1 RNA <50 copies/mL 24 and 48
weeks after switching to Part 2
 Proportion of participants with HIV-1
RNA <50 copies/mL 24 and 48 weeks
after entering Part 2
 Objective:  To evaluate the
immunologic effect of different
doses of MK-8591 administered with
DOR + 3TC compared to MK-
1439A at Week 24, Week 48, Week
96, and Week 144
 Change from baseline in CD4+ T-cell
count at Week 24, Week 48, Week 96,
and Week 144
 Objective:  To evaluate the
antiretroviral suppression and
immunologic effect of MK-8591A
administered during open-label
dosing in Part 4 of the trial
 Proportion of participants with HIV-1
RNA <50 copies/mL at Week 192 (48
weeks after entering Part 4)
 Change from baseline in CD4+ T-cell
count at Week 192
 Objective:  To evaluate the safety
and tolerability of different doses of
MK-8591 administered with DOR
compared to MK-1439A 24 weeks
after switching to Part 2
 Number of participants experiencing AEs
 Number of participants discontinuing
study drug due to AEs
 Objective:  To evaluate the safety
and tolerability of the selected dose
of MK-8591 administered with DOR
compared to MK-1439A at Week 96
and through study duration.
 Number of participants experiencing
AEs
 Number of participants discontinuing
study drug due to AEs
 Objective:  To evaluate the safety
and tolerability of MK-8591A during
open-label dosing in Part 4 of the
trial.
 Number of participants experiencing
AEs
 Number of participants discontinuing
study drug due to AEs
Overall Design:
Trial Phase 
Phase 2b
Clinical Indication  
Treatment of HIV-1 infection
 
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Product:  MK-8591
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Population
Treatment-naïve adults with HIV-1 infection
Trial Type
Interventional
Type of Design  
Parallel, active comparator, dose-ranging
Type of Control 
Active control
Trial Blinding
Double-blind
Estimated Duration
of Trial
The Sponsor estimates that the trial will require
approximately 4.3 years from the time the first participant
signs the informed consent until the last participant’s last
study-related phone call or visit.
Number of Participants:
Approximately 120 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups 
3-Drug Dose Ranging (Part 1)
Participants will be randomized in a 1:1:1:1 ratio to 1 of
4 treatment groups:
Group 1 (n=30):
MK-8591 (0.25 mg) once daily (QD) +
DOR (100 mg) QD +
3TC (300 mg) QD +
placebo for MK-1439A QD
Group 2 (n=30):
MK-8591 (0.75 mg) QD +
DOR (100 mg) QD +
3TC (300 mg) QD +
placebo for MK-1439A QD
Group 3 (n=30):
MK-8591 (2.25 mg) QD +
DOR (100 mg) QD +
3TC (300 mg) QD +
placebo for MK-1439A QD
Group 4 (n=30):
MK-1439A (DOR 100 mg + 3TC 300 mg + TDF 300 mg)
QD +
placebo for DOR QD +
 
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placebo for 3TC QD +
placebo for MK-8591 QD
Groups 1 to 3 will receive 1 of 3 doses of MK-8591 QD
administered with DOR QD and 3TC QD (3-drug dose
ranging).  Group 4 will receive MK-1439A.  Matching
placebos will be administered in Part 1.  Randomization
will be stratified by screening HIV-1 RNA level (≤100,000
copies/mL or >100,000 copies/mL).  Participants will
receive a minimum of 24 weeks of treatment in Part 1. 
Participants will be eligible to switch to Part 2 at Week 24
if they have not met viral failure criteria (Section 5.4.1.1.1)
and the Week 20 HIV-1 RNA result is <50 copies/mL. 
Participants whose HIV-1 RNA result is ≥50 copies/mL at
Week 20 will continue to receive blinded study drug until
the HIV-1 RNA result is <50 copies/mL.  Participants who
do not achieve HIV RNA <50 copies/mL by the Week 48
assessment or have met any of the other viral failure criteria
prior to Week 48 will be discontinued from treatment and
complete the early discontinuation and end of trial phone
and site follow-up visits.
2-Drug Dose Ranging/Maintenance (Part 2):
Participants in Groups 1 to 3 who were eligible to switch to
Part 2 will continue treatment with the dose of MK-8591
QD they were randomized to in Part 1 in combination with
DOR QD.  In Part 2, 3TC is dropped from the regimen for
those in the MK-8591 groups, the dose of MK-8591
remains blinded and DOR is provided in an open-label
fashion.  Participants in Group 4 will receive open-label
MK-1439A QD.  Matching placebos are no longer
administered to any treatment group in Part 2.
Group 1:  MK-8591 (0.25 mg) QD + DOR (100 mg) QD
(n~ 30)
Group 2:  MK-8591 (0.75 mg) QD + DOR (100 mg) QD
(n~ 30)
Group 3:  MK-8591 (2.25 mg) QD + DOR (100 mg) QD
(n~ 30)
Group 4:  MK-1439A QD (n~ 30)
2-Drug Selected Dose Maintenance (Part 3):
Once the dose of MK-8591 has been selected and
communicated to site personnel, participants in Groups 1
to 3 will switch to the selected dose of MK-8591 QD at the
 
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next scheduled visit and continue treatment in combination
with open-label DOR QD.  Participants in Group 4 will
continue to receive open-label MK-1439A.
Groups 1-3:  MK-8591 (selected dose) QD + DOR
(100 mg) QD (n~ 90)
Group 4:      MK-1439A QD (n~ 30)
2-Drug Dosing with MK-8591A (Part 4):
Participants receiving the selected dose of MK-8591 in
combination with DOR QD or MK-1439A in the control
group in Part 3 will all be switched to the 2-drug FDC of
MK-8591A QD in Part 4.  MK-8591A will be provided as
open-label supplies.
Groups 1-3:  MK-8591A (MK8591 0.75 mg/DOR 100
mg) QD (n ~ 90)
Group 4:       MK-8591A (MK8591 0.75 mg/DOR 100
mg) QD (n ~ 30)
Duration of
Participation
Each participant enrolled will participate in the trial for
approximately 206.5 weeks from the time the participant
signs the informed consent form through the final contact. 
After a screening phase of up to 8.5 (60 days) weeks,
participants will receive assigned treatment for
approximately 192 weeks.  After the end of treatment, each
participant will be followed for 6 weeks.
A list of abbreviations used in this document can be found in Appendix 1.
 
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2. Schedule of Activities (SoA)
Schedule of Activities - Screening and Treatment Visits (Parts 1-3)
Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91 
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1 
V161
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Administrative and General Procedures
Informed consent 
X
X 
X
Obtain consent on or
prior to scheduled visit.
Informed consent for
Future Biomedical 
Research
X
Participant
identification card
X
Inclusion/exclusion  
X 
X
Inclusion/exclusion
should be reviewed
prior to dose on Day 1
to ensure no changes to
participant’s eligibility
since screening.
Medical history  
X
Includes history of
tobacco, alcohol, and
illicit drug use.
Prior/concomitant
medication review
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
Prior to dose on Day 1.
 
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Product:  MK-8591
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Protocol/Amendment No.: 011-05
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Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91 
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1
V161 
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Register trial visit in
IVRS/IWRS
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Treatment
randomization
X
Prior to dose on Day 1.
Dispense study
medication using
IVRS/IWRS
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
At Week 144,
participants in Groups
1-3 who agree to
continue to Part 4 will
receive MK-8591A
(3 bottles of study
medication will be
dispensed until the next
visit at Week 156). 
Participants in Group 4
who agree to continue
to Part 4 and switch
from MK-1439A to
MK-8591A will be
dispensed 1 bottle of
study medication until
the next visit at Week
148.
 
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Product:  MK-8591
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Protocol/Amendment No.: 011-05
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Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91 
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1
V161 
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Provide & review
study medication diary
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Prior to dose on Day 1. 
At Week 144, all
participants who agree
to continue to Part 4
will be provided study
medication diaries for
Part 4.
Safety Procedures
Full physical
examination
X 
X 
X 
X 
X 
X 
X 
X 
X
Directed physical
examination
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X X 
X
Prior to dose on Day 1.
Vital signs
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Prior to dose on Day 1. 
Include pulse, blood
pressure, respiratory
rate, and body
temperature.
Weight
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Height
X
 
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Product:  MK-8591
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Protocol/Amendment No.: 011-05
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Confidential
Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91 
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1
V161 
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
12-lead ECG  
X 
X 
X 
X
Within 7 days prior to
dose on Day 1.  Only
performed once the
participant is confirmed
to meet all eligibility
criteria.
Review adverse events X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Birth control
confirmation
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Serum pregnancy test 
X
For women of
childbearing potential
only.  Performed by the
central laboratory.
Urine pregnancy test 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
For women of
childbearing potential
only. Performed by the
local laboratory (kits
provided) prior to dose
on Day 1.Serum
pregnancy test must be
performed to confirm a
positive urine test
result.
 
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Product:  MK-8591
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Protocol/Amendment No.: 011-05
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Confidential
Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1 
V161
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Hematology
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Prior to dose on Day 1. 
See Appendix 2 for list
of specific laboratory
tests.
Chemistry  
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Prior to dose on Day 1. 
See Appendix 2 for list
of specific laboratory
tests.
Urinalysis
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Prior to dose on Day 1. 
See Appendix 2 for list
of specific laboratory
tests.
Hemostatic function
test
X
See Appendix 2 for list
of specific laboratory
tests.
HIV-1 screen
X
See Appendix 2 for list
of specific laboratory
tests.
 
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Product:  MK-8591
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Protocol/Amendment No.: 011-05
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06-Jul-2020
Confidential
Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91 
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1 
V161
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Hepatitis screen  
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X
Post-randomization
HBV/HCV sample
collected until the
participant switches to
Part 2. Refer to
Sections 8.1 and 9.10.1.
See Appendix 2 for list
of specific laboratory
tests.  Week 132 applies
only to participants in
Group 4 who plan to
switch from MK-1439A
to MK-8591A in Part 4,
at Week 144.
DEXA scan  
X 
X 
X 
X
Prior to dose on Day 1. 
May occur prior to Day
1 once the participant is
confirmed to meet all
eligibility criteria.  May
require additional
planning/scheduling. 
DEXA scans for fat
distribution and bone
mineral density.
 
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Protocol/Amendment No.: 011-05
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Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1 
V161
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Efficacy Procedures
HIV-1 RNA (real time
PCR)
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
Prior to dose on Day 1. 
See Section 2.3 if
criteria are met for
clinically significant
confirmed viremia.
CD4+ T-cell count 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior to dose on Day 1.
Blood (plasma) for
viral resistance
X
Exploratory Laboratory Procedures
HIV-1 RNA single-
copy assay
X 
X 
X 
X
Only performed if HIV-
1 RNA is below the
limit of detection of the
real time PCR assay.
Biomarkers/FBR/PK/PD
IL-6
X
X
X
X
X 
Prior to dose on Day 1.
D-dimer
X
X
X
X
X 
Prior to dose on Day 1.
Soluble CD163
X
X
X
X
X 
Prior to dose on Day 1.
Urinary analytes
X
X
X
X
X
Prior to dose on Day 1. 
See Appendix 2 for list
of specific laboratory
tests.
 
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Product:  MK-8591
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Protocol/Amendment No.: 011-05
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Confidential
Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91 
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1
V161 
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Blood for Genetic
Analysis
X
Collected from
randomized participants
only; FBR consent is
not required to
participate in the study.
Population PK blood
draws
X 
X X X X 
X
Prior to dose on Day 1.
Two samples (pre-dose
and between 0.5 and 2
hours post-dose,
respectively) will be
collected at W4 and W8
for participants who
take their dose during
the day; for participants
who take their dose in
the evening, only a
post-dose sample will
be collected the
following day
irrespective of time of
dose. One sample will
be collected at W12,
W16, and W48 at any
time irrespective of
dose.
 
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Product:  MK-8591
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Protocol/Amendment No.: 011-05
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Confidential
Trial Epoch:
Part 1
3-Drug
Dose Ranging
Part 2
2-Drug
Dosing Ranging/Maintenance1
Part 3
2-Drug
Selected Dose Maintenance2
Visit Number: V1 V2 V3 V4 V5 V6 V7 V8 V91 
V10 
1 
V11 
1 
V12
1
V13
1
V14
1
V15
1
V161 
V17
2
V182 V19V20 V21 V22 V23 V24
NOTES
Treatment Week
(W):
Screen
Randomization
(Day 1)
(Fasting)3
W2
W4
W8
W12
W16
W20
W24 (Fasting)3
W28
W32
W36 (Fasting)3
W40
W44
W48 (Fasting)3
W52
W60
W72 (Fasting)3
W84
W96 (Fasting)3
W108
W120
(Fasting)3
W132
W144 (Fasting)3
The expected date of each
visit should be calculated
using the date of Day 1.
Scheduling Window
≤60
days NA
± 3
days
± 5 days 
± 7 days
To ensure timely study
medication resupply.
Blood (plasma) for
repeat HIV-1 drug
resistance testing or
PK as needed
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X
At the screening visit,
the sample will be used
if needed to repeat the
HIV-1 drug resistance. 
At all other visits, the
sample will be used to
test PK as needed in the
event of clinically
significant confirmed
viremia.
DEXA=dual-energy x-ray absorptiometry; ECG=electrocardiogram; FBR=Future Biomedical Research; HIV-1=human immunodeficiency virus type 1; IL-6=interleukin-6;
IVRS/IWRS=Interactive Voice/Web Response System; PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; RNA=ribonucleic acid; V=visit;
W=week.
1 After a minimum of 24 weeks of dosing in Part 1, participants who were virologically suppressed at the previous visit (HIV-1 RNA <50 copies/mL) and had not met any viral
failure criteria (Section 5.4.1.1.1) were switched to Part 2 (Section 9.10.1).  Participants who had not met viral failure criteria, but whose HIV-1 RNA levels were ≥50
copies/mL continued to receive the 3-drug regimen (Part 1) until the HIV-1 RNA is <50 copies/mL.  Prior to Amendment 03, participants who met viral failure criteria or
participants who did not achieve HIV RNA <50 copies/mL following the Week 48 assessments were to be discontinued from treatment (Section 5.4.1.1.1, Section 8.1, and
Section 9.10.1) and complete the early discontinuation and end-of-trial follow-up visits. As of Amendment 03, if a participant has a viral load of ≥50 copies/mL at any time
during the study, a Viremia Confirmation visit must be conducted within 2 to 4 weeks of the initial HIV-1 viremia (Sections 2.2 and 5.4.1.1.2); a participant with confirmed
HIV-1 virologic rebound will be discontinued from treatment (Section 5.4.1.1.2 and Section 8.1).
2 The transition from Part 2 to Part 3 will most likely occur at Week 60 or beyond.  Participants in treatment Groups 1 to 3 will continue on the blinded dose of MK-8591 until
dose selection is announced.
3 Fasting for at least 8 hours.
 
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Schedule of Activities - Treatment Visits (Part 4)
Trial Epoch:
Part 4
2-Drug Dosing with MK-8591A
Visit Number: V25 1
V26 
V27 
V28 
V29 
NOTES
Treatment Week (W):
W148
W156
W168
W180
W192
(Fasting)2
The expected date of each visit should be calculated using the date of
Day 1.
Scheduling Window
± 7 days
To ensure timely study medication resupply.
Administrative and General Procedures
Concomitant medication review
X 
X 
X 
X 
X
Register trial visit in IVRS/IWRS
X 
X 
X 
X 
X
Dispense study medication using IVRS/IWRS
X 
X 
X 
X
Provide & review study medication diary
X 
X 
X 
X 
X 
At Week 192, review only.
Evaluation to receive continued study intervention
X 
See Section 7.8.
Safety Procedures
Full physical examination
X
Directed physical examination
X 
X 
X 
X
Vital signs
X 
X 
X 
X 
X 
Include pulse, blood pressure, respiratory rate, and body temperature.
Weight
X 
X 
X 
X 
X
Review adverse events
X 
X 
X 
X 
X
Birth control confirmation
X 
X 
X 
X 
X
Urine pregnancy test
X 
X 
X 
X 
X
For women of childbearing potential only. Serum pregnancy test
must be performed to confirm a positive urine test result.
Hematology
X 
X 
X 
X 
X 
See Appendix 2 for list of specific laboratory tests.
Chemistry
X 
X 
X 
X 
X 
See Appendix 2 for list of specific laboratory tests.
Urinalysis
X 
X 
X 
X 
X 
See Appendix 2 for list of specific laboratory tests.
DEXA scan
X
May require additional planning/scheduling.  DEXA scans for fat
distribution and bone mineral density.
 
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Trial Epoch:
Part 4
2-Drug Dosing with MK-8591A
Visit Number: V25 1
V26 
V27 
V28 
V29 
NOTES
Treatment Week (W):
W148
W156
W168
W180
W192
(Fasting)2
The expected date of each visit should be calculated using the date of
Day 1.
Scheduling Window
± 7 days
To ensure timely study medication resupply.
Efficacy Procedures
HIV-1 RNA (real time PCR)
X 
X 
X 
X 
X
See Section 2.3 if criteria are met for clinically significant confirmed
viremia.
CD4+ T-cell count
X 
X
Biomarkers/FBR/PK/PD
IL-6
X
D-dimer
X
Soluble CD163
X
Urinary analytes
X 
See Appendix 2 for list of specific laboratory tests.
Blood (plasma) for repeat HIV-1 drug resistance testing or
PK as needed
X 
X 
X 
X 
X
The sample will be used to test PK as needed in the event of clinically
significant confirmed viremia.
DEXA=dual-energy x-ray absorptiometry; ECG=electrocardiogram; FBR=Future Biomedical Research; HIV-1=human immunodeficiency virus type 1; IL-6=interleukin-6;
IVRS/IWRS=Interactive Voice/Web Response System; PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; RNA=ribonucleic acid; V=visit;
W=week.
1. V25 (W148) is only applicable to participants in Group 4 who agree to switch from open-label MK-1439A to MK-8591A in Part 4 of the study. 
2. Fasting for at least 8 hours.
 
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Schedule of Activities –Viremia Confirmation, Early Discontinuation (D/C), and End of Trial (EOT) Site Follow-Up
Visits
Trial Period
Viremia
Confirmation
Early Discontinuation of Treatment
End of Trial
Notes
Visit Name: 
Viremia
Confirmation
Early D/C
EOT Site
Follow-Up
EOT Site
Follow-Upa
Visit Window:
Within 2 to 4
weeks of HIV-1
Viremia (≥50
copies/mL)
NA
≥42 to ≤49 days after
EOT
≥42 to ≤49 days
after EOT
Prior/concomitant
medication review
X
X
X
X
Register trial visit in
IVRS/IWRS
X
X
Provide & review study
medication diary
X
X
Full physical
examination
X
X
X
Vital signs
X
X
X
Includes pulse, blood
pressure, respiratory rate,
and body temperature.
12-lead ECG
X
Review adverse events
X
X
X
X
Birth control
confirmation
X
X
X
X
Serum pregnancy test
X
X
X
For women of
childbearing potential
only.  Performed by the
central laboratory.
Hematology
X
X
X
See Appendix 2 for list of
specific laboratory tests.
Chemistry
X
X
X
See Appendix 2 for list of
specific laboratory tests.
 
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Trial Period
Viremia
Confirmation
Early Discontinuation of Treatment 
End of Trial
Notes
Visit Name: 
Viremia
Confirmation
Early D/C
EOT Site
Follow-Up
EOT Site
Follow-Upa
Visit Window:
Within 2 to 4
weeks of HIV-1
Viremia (≥50
copies/mL)
NA
≥42 to ≤49 days after
EOT
≥42 to ≤49 days
after EOT
Urinalysis
X
X
X
See Appendix 2 for list of
specific laboratory tests.
HIV-1 RNA
X
X
X
CD4+ T-cell count
X
Blood (plasma) for
HIV-1 drug resistance
X 
X
If a HIV-1 drug resistance
sample was collected at
the viremia confirmation
visit, it is not necessary to
collect another sample at
Early D/C.
HIV-1 RNA single-
copy assay
X
Only performed if HIV-1
RNA is below the limit of
detection of the real time
PCR assay
IL-6
X
D-dimer
X
Soluble CD163
X
Urinary analytes
X
See Appendix 2 for list of
specific laboratory tests.
Blood (plasma) for 
repeat HIV-1 drug
resistance testing or PK
as needed
X 
X 
X
D/C=discontinuation; ECG=electrocardiogram; EOT=end of treatment; HIV-1=human immunodeficiency virus type 1; IL-6=interleukin-6; IVRS/IWRS=Interactive Voice/Web
Response System; PCR=polymerase chain reaction; PK=pharmacokinetic; RNA=ribonucleic acid.
a. 
The EOT site follow-up visit is only for those participants who will not continue with MK-8591A after the end of the study (Section 7.8).
 
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3. Introduction
MK-8591 (also referred to as islatravir) is a novel, potent human immunodeficiency virus
type 1 (HIV-1) nucleoside reverse transcriptase translocation inhibitor (NRTTI) being
developed for the treatment of HIV-1 infection.  MK-8591 is an inactive nucleoside that is
converted to the pharmacologically active triphosphate form via endogenous intracellular
kinases. MK-8591 is the first member of a new class of antiretroviral agents, known as
NRTTIs, which block HIV reverse transcriptase by a novel dual mechanism ofaction. In
contrast to all NRTIs used for the treatment of HIV infection, which lack a 3'-OH to block
incorporation of incoming nucleotide, MK-8591 retains a 3' OH.  It acts through multiple
mechanisms, including both immediate chain termination by inhibition of translocation and
delayed chain termination prevents nucleotide excision (a significant mechanism of NRTI
drug resistance) from occurring [Michailidis E 2014]. MK-8591 is highly differentiated from
other HIV-1 treatments based on its high potency, long half-life, favorable drug resistance
profile, and broad pharmacologic distribution.
Doravirine (DOR, MK-1439) is a novel non-nucleoside reverse transcriptase inhibitor
(NNRTI) in Phase 3 development for the treatment of HIV-1.  DOR is differentiated from
other NNRTIs by its activity against prevalent mutations that confer resistance to other
NNRTIs, low potential for drug-drug interactions (DDIs), promising efficacy, low likelihood
of selection for viral resistance in vivo, and good tolerability.
Lamivudine (3TC) is a well-tolerated NRTI and is approved for treatment of HIV in
combination with other antiretroviral agents.
Study Rationale
The currently preferred recommendation for first-line treatment of HIV-1 infection in
treatment-naïve patients includes 3 drugs from 2 different classes.  Although a 3-drug
regimen has been the standard of care in HIV-1 infection, there are increasing lines of
evidence that a 2-drug regimen (depending on the 2 drugs combined) may work as well, and
therefore, have the potential to simplify the treatment regimen.  A 2-drug regimen could
mean a smaller pill burden, fewer DDIs, and a lesser likelihood of safety or tolerability issues
compared to the addition of a third drug into the regimen.  Current antiretroviral agents have
known safety and tolerability issues, which can be improved upon.  Specific NRTIs have
been associated with lactic acidosis, loss of bone mineral density (BMD), renal toxicity, and
hypersensitivity reactions.  Specific NNRTIs have been associated with adverse central
nervous system events, rash, lipid abnormalities, decreased efficacy in patients with high
viral load, and significant DDIs.  A need exists for new antiretroviral NRTI and NNRTI
agents like MK-8591 and DOR that possess a high barrier to viral resistance with an
improved safety and tolerability profile and are convenient to take.
This trial will be broken into 4 parts: 1) 3-drug dose ranging treatment initiation, 2) 2-drug
dose ranging maintenance of Part 1 participants, 3) 2-drug maintenance with the selected
dose of MK-8591, and 4) 2-drug dosing with MK-8591A.  This trial design allows for dose
ranging of MK-8591 in the traditional setting of 3 antiretroviral agents followed by
evaluation of MK-8591 in the setting of a 2-drug regimen.
 
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Background
Refer to the Investigator’s Brochures (IB) for detailed background information on MK-8591
and DOR as single entities, MK-8591A as an FDC, and MK-1439A.
Pharmaceutical and Therapeutic Background
Human immunodeficiency virus type 1 infection, which causes acquired immune deficiency
syndrome (AIDS) and for many years was associated with substantial morbidity and
mortality, has now become a chronic disease that can be controlled through lifelong
combination antiretroviral therapy (ART).  Currently, there are more than 30 individual drugs
and FDC regimens available for the treatment of HIV-1 infection.  These agents belong to 6
distinct mechanistic classes:  NRTIs, NNRTIs, protease inhibitors (PIs), fusion inhibitors,
co–receptor antagonists, and integrase strand transfer inhibitors (InSTIs).  Successful
combinations of antiretroviral medications generally utilize 3 agents from at least 2 different
mechanistic classes.  The goal of ART is to suppress HIV-1 to undetectable levels so that
immune function is preserved or restored.  Yet, while ART can delay disease progression and
death, as well as reduce the risk of HIV-1 transmission, it does not cure the infection.  As a
result, lifelong treatment must be maintained, which may lead to therapy fatigue and
noncompliance, specifically if treatment regimen adherence is difficult (e.g., pill burden,
frequency of treatment).  Lifelong treatment may also be associated with intolerable adverse
effects.  These factors can potentially lead to treatment failures with the possible
development of drug-resistant virus [AIDS info 2016].
The ART regimen for a treatment-naïve HIV-1-infected patient generally consists of a 3-drug
approach containing 2 NRTIs plus a drug from the PI, NNRTI, or InSTI class.  As shown in
clinical trials and by retrospective evaluation of cohorts of participants in clinical care, this
strategy for initial treatment has resulted in HIV-1 RNA suppression and CD4+ T-cell count
increases in most participants [Moore, R. D. 2011] [Gill, V. S., et al 2010] [Lee, F. J., et al
2014].  However, significant concerns remain regarding toxicities of some widely used
antiretroviral agents, including decline in BMD, hepatic and renal effects, neuropsychiatric
toxicities, gastrointestinal toxicities such as diarrhea associated with multiple PIs, and serum
lipid abnormalities associated with multiple mechanistic classes.  Therefore, new agents that
offer high potency, distinct resistance profiles, dosing convenience, and favorable safety and
tolerability profiles are needed.
MK-8591 is a specific HIV-1 NRTTI with demonstrated properties of high potency, long
half-life, a strong resistance profile, and broad pharmacologic distribution.  At the lowest
proposed dose to be used in this trial, 0.25 mg, the inhibitory quotient (IQ; lowest
concentration reached by a drug before the next dose is administered [Ctrough]/half-maximal
inhibitory concentration [IC50]) at the projected steady-state peripheral blood mononuclear
cell (PBMC) MK-8591-triphosphate (TP) levels are ~70×for wild-type HIV-1
(0.007 pmol/106 cells), and are ≥14 ×the in vitro intracellular IC50 for relevant mutant
viruses (such as those with RT M184V). These IQs were investigated in P009 in the 0.25 mg
panel (daily dosing of MK-8591 for 28 days; see details in Section 3.2.3).  On average, the
MK-8591-TP IQ for wild-type virus at steady state was 119x and for relevant mutants was
23x. These IQs greatly exceed those achieved by tenofovir alafenamide (TAF) and 3TC,
both of which exhibit IQs of ~3 ×for wild-type virus at steady state. The high IQ projected
 
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at the lowest proposed dose of MK-8591 for wild-type and NRTI-resistant HIV-1 variants
make it a strong candidate to substitute for a more traditional backbone comprised of 2
NRTIs, each with substantially lower IQs.  In preclinical studies, MK-8591 exhibited a
superior resistance profile compared to lamivudine and azidothymidine (zidovudine),
demonstrated no inhibitory activity against human DNA polymerases, and demonstrated an
acceptable safety and tolerability profile.  It is not expected that MK-8591 will be a victim or
perpetrator of drug interactions.
MK-8591 has been evaluated in 3 completed Phase 1 trials (Section 3.2.2) and 2 ongoing
Phase 1 trials (Section 3.2.3).  MK-8591-001, MK-8591-002, and MK-8591-005 are
complete. MK-8591-001 was a double-blind, randomized, placebo-controlled, single-rising
dose trial that evaluated the safety and PK of an oral suspension of MK-8591 (doses 5 to 400
mg) in healthy adults.  MK-8591-002 was a double-blind, randomized, placebo-controlled
trial that evaluated the safety and PK of once weekly, multiple doses of MK-8591 (10 mg, 30
mg, and 100 mg) administered as oral capsules to healthy adults. MK-8591-005 was an
open-label, fixed-sequence, 2-period study that assessed the 2-way interaction of MK-8591
and dolutegravir or tenofovir disoproxil fumarate (TDF).  On the basis of unblinded data
from MK-8591-001, MK-8591-002, and MK-8591-005, MK-8591 is considered generally
well tolerated.
While the current paradigm for HIV treatment is a 3-drug regimen, simplified, 2-drug
regimens have been sought after for many years, both for therapy initiation as well as part of
induction-maintenance strategies.  In this study, MK-8591 will be studied initially in a 3-drug
regimen in combination with DOR and 3TC (Part 1).  Dose ranging of MK-8591 will then
continue in the setting of a 2-drug regimen in participants who are virologically suppressed
(Part 2). A selected dose of MK-8591 will be chosen for Part 3 following 48 weeks of total
treatment (3-drug and 2-drug regimens combined).  It is anticipated that administration of
MK-8591 in combination with a second ART (2-drug regimen) in HIV-1-infected
participants will result in HIV-1 suppression and increases in CD4+ T-cell counts similar to
those seen with a traditional 3-drug regimen.
DOR is an NNRTI that, like MK-8591, can be administered once daily (QD), is highly
potent, and has a favorable viral resistance profile.  In the completed Phase 2b clinical trial of
DOR, response rates (defined as the percentage of participants with HIV-1 RNA
<40 copies/mL) were numerically higher in the DOR group (71.4%) than the comparator
(efavirenz) group (64.3%), and DOR was generally well tolerated in Phase 1 and Phase 2b.
The extensive DDI analysis of DOR to date has demonstrated only the interaction with
cytochrome P450 (CYP)3A4 inhibitors and inducers, which was predicted based on the in
vitro studies.  As MK-8591 in vitro was not observed to inhibit or induce CYP3A4, it is not
anticipated to affect the PK of DOR. MK-8591 has not demonstrated significant DDI in the
2 DDI studies to date. An examination of potential DDIs between MK-8591 and
dolutegravir or TDF demonstrated no meaningful interaction, and the DDI study between
MK-8591 and levonorgestrel/ethinyl estradiol also demonstrated no DDI.  The elimination of
MK-8591 is anticipated to be balanced between renal filtration and adenosine deaminase-
mediated metabolism. Thus, MK-8591 is unlikely to be a victim ofdrug interactions
mediated by CYP or transporter inhibitors. DOR has not been tested as an inhibitor of
adenosine deaminase. However, considering the important role of adenosine deaminase in
 
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endogenous nucleotide metabolism and hematopoietic development, the lack of hematologic
findings in the chronic toxicity studies and in the Phase 2 and Phase 3 studies to date
suggests DOR is not likely to inhibit this enzyme, and thus, the potential for an interaction
with MK-8591 through this pathway is low.
In Part 4, MK-8591A, the FDC ofMK-8591 (0.75 mg) and DOR (100 mg) will be
administered open-label as a single tablet QD.  MK-8591 and DOR represent 2 distinct
classes of antiretrovirals that inhibit reverse transcription by different mechanisms. Based on
the profiles of each of these drugs and data available to-date, the combination MK-
8591/DOR is expected to be safe, well-tolerated, and highly efficacious, with a high barrier
to resistance. The combination has demonstrated additive antiretroviral activity in vitro and
has suppressed emergence of resistance at clinically-relevant concentrations.
The comparator in this trial through Week 144 is MK-1439A, an FDC of DOR 100 mg +
3TC 300 mg + TDF 300 mg.  The 300 mg doses of 3TC and TDF, used either as single
entities or as part of an FDC, are the standard doses of these 2 commercially-available and
commonly-used NRTIs.  The 3-drug regimen of MK-1439A is currently approved for the
treatment of HIV-1 infection in adults. Refer to Section 5.4.2 and the approved labeling for
additional information.
Completed Preclinical and Clinical Trials
A 1-month daily oral combination toxicity study in rats was completed to support the clinical
co-administration of MK-8591/DOR.  In this study, MK-8591 and DOR were evaluated
either alone or in combination at clinically relevant dose levels.  There were no antemortem,
clinical pathology, ophthalmic, or postmortem (gross, organ weight, or histopathology) test
article-related findings with either MK-8591 or DOR when evaluated alone or in
combination at up to the highest dose levels evaluated. MK-8591 and DOR systemic (AUC)
exposures achieved in this study at these no-observed effect levels exceeded those expected
clinically at projected therapeutic dose levels (Exposure Multiples [EM] of ~ 15Xa and ~
4Xb, respectively).  This MK-8591/DOR combination toxicity study in rats together with the
nonclinical safety packages for MK-8591 and DOR alone support the continued clinical
development of combined dose of MK-8591 and DOR.
Refer to the MK-8591 and DOR IBs for additional information on completed preclinical and
clinical trials of MK-8591, DOR, and MK-1439A.
a.
EM for MK-8591 was calculated using the estimated steady state human exposure over 24 hours, AUC 0-24 hr
(0.21 μM∙hr), at the highest anticipated Phase 2 once-daily dose of 2.25 mg.
b.
EM for DOR (MK-1439) was calculated based on  a PK/PD analysis from Part 1 of the MK-1439 Phase 2b study
(PN007), where the expected  therapeutic 100-mg once-daily clinical dose results in an AUC 0-24hr of 37 μM•hr at steady
state.
Protocol MK-8591-003 was a trial to evaluate the antiretroviral activity of single-dose MK-
8591 in HIV-1-infected participants.  MK-8591 was administered to treatment-naïve HIV-1-
positive adults at single doses of 0.5 mg, 1 mg, 2 mg, 10 mg, and 30 mg.  Viral load
reduction data showed a greater than 1.0 log drop in HIV-1 RNA on average at all doses
tested.  No viral load rebound was observed through 7 to 10 days of follow-up after
administration of the single doses of MK-8591. Additionally, 2 Phase 1 trials are complete
(MK-8591-009 and MK-8591-010).  P009 was a multiple-dose study to assess the safety and
 
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PK of QD MK-8591 administration in healthy adult subjects, and P010 evaluated the
potential interaction of MK-8591 with DOR in healthy adult subjects.  Results are as follows:
 P009 investigated MK-8591 QD dosing for 28 days at 0.25 mg and 0.75 mg and for
42-days at 5 mg.  It was observed that the apparent terminal half-life of MK-8591 in
plasma was longer than observed in weekly dosing studies (87–230 hours with QD
dosing compared to 50-60 hours with weekly dosing).  The longer observed half-life
for MK-8591 in plasma is possibly due to the conversion of the active triphosphate
(MK-8591-TP) back to MK-8591 (parent) and subsequent diffusion of MK-8591 into
plasma.  A 42-day post last dose follow-up period was employed for the 5-mg panel
in P009 with no notable observations.
 P010 investigated QD MK-8591 dosing for 14 days at 2.25 mg alone and in
combination with DOR.  No interaction was noted between MK-8591 and DOR.  An
apparent terminal half-life of 128 hours was noted for MK-8591.
Examination of these data indicates that the half-life of MK-8591 in plasma is expected to be
between 87 and 128 hours after cessation of dosing for the dose range to be studied in P011. 
As such, a safety follow-up period of 42 days will be used and will allow for AE/SAE
recording and reporting during this time.
Ongoing Clinical Trials
There are 4 planned Phase 3 trials evaluating MK-8591A in participants who are
virologically suppressed, heavily treatment experienced, and treatment naïve (MK-8591A-
017/-018, MK-8591A-019, and MK-8591A-020, respectively). There are 3 ongoing Phase 3
trials of DOR or MK-1439A:  MK-1439-018, MK-1439A-021, and MK-1439A-024.  MK-
1439-018 is an ongoing Phase 3, multicenter, double-blind, randomized, active comparator-
controlled clinical trial in treatment-naïve HIV-1-infected adult participants to evaluate the
safety and efficacy of DOR 100 mg QD versus ritonavir-boosted darunavir (DRV + r; DRV
800 mg QD plus ritonavir [r] 100 mg QD), each in combination with 2 NRTIs (emtricitabine
[FTC]/TDF or abacavir/3TC). The primary efficacy endpoint (Week 48) of the 96-week base
study has been achieved; the 96-week open-label extension is ongoing. A total of 769
participants were randomized and have completed 48 weeks of dosing.  The primary analysis
at Week 48 demonstrated that DOR was non-inferior to DRV + r at Week 48, the primary
time point for analysis, with 83.8% (321/383) and 79.9% (306/383) of participants,
respectively, achieving HIV-1 RNA <50 copies/mL (difference 3.9%, 95% confidence
interval [CI] -1.6, 9.4).  This finding was supported by the Week 96 efficacy results. In the
subgroup of participants with baseline HIV-1 RNA >100,000 copies/mL, 81.0% (64/79) of
DOR recipients and 76.4% (55/72) of DRV + r recipients achieved HIV-1 RNA <50
copies/mL at Week 48.  Only 1 of 383 (<1%) participants in the DOR treatment group
developed phenotypic and genotypic resistance to DOR (RT V106I, H221Y, and F227C;
>90-fold increased IC50) by Week 48. The results of the primary efficacy analysis at Week
48 were supported by the Week 96 results. No participants in the DRV + r group developed
genotypic or phenotypic resistance. DOR was generally safe and well tolerated.  Refer to the
DOR IB for additional information.
 
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MK-1439A-021 is a multicenter, double-blind, randomized, active comparator-controlled
clinical trial to evaluate the safety and efficacy of MK-1439A QD versus efavirenz
600 mg/FTC 200 mg/TDF 300 mg (EFV/FTC/TDF) QD in treatment-naïve HIV-1-infected
participants. The 96-week base study has completed, and the open-label extension is
continuing. The primary analysis at Week 48 demonstrated that MK-1439A was non-inferior
to EFV/FTC/TDF with 84.3% (307/364) and 80.8% (294/364), respectively, achieving HIV-
1 RNA <50 copies/mL (difference 3.5%, 95 CI -2.0, 9.0). In the subgroup of participants
with baseline HIV-1 RNA >100,000 copies/mL, 81.2% (56/69) of MK-1439A and 80.8%
(59/73) of EFV/FTC/TDF recipients achieved HIV-1 RNA <50 copies/mL at Week 48.  The
results of the primary efficacy analysis at Week 48 were supported by the Week 96 results. A
primary safety endpoint was the proportion of subjects with neuropsychiatric adverse events
(AEs) through Week 48 in the pre-specified categories of 1) dizziness, 2) sleep
disorders/disturbances, and 3) altered sensorium. MK-1439A was superior to EFV/FTC/TDF
with having a significantly lower proportion of subjects with neuropsychiatric events in the 3
pre-specified categories by Week 48. In addition, it was demonstrated that MK-1439A had a
statistically significant lower increase from baseline than EFV/FTC/TDF on fasting LDL-C
cholesterol (mg/dL) and fasting non-HDL-C cholesterol (mg/dL).
MK-1439A-024 is an on-going open-label trial of MK-1439A in participants who are
virologically suppressed on a PI-, NNRTI-, or elvitegravir-based regimen and are switched to
MK-1439A.  The 48-week base study has completed, and the open-label extension is
ongoing.  Results showed that an immediate switch to MK-1439A on Study Day 1 was
noninferior to continuation of a ritonavir- or cobicistat-boosted PI-based or cobicistat-
boosted EVG-based or NNRTI-based regimen for 24 weeks.  As part of the study, the effect
of an immediate switch to MK-1439A on Study Day 1 on fasting LDL-C and fasting HDL-C
compared with the effect noted on these lipids among participants who continued on a
ritonavir-boosted, PI-based regimen for 24 weeks was evaluated. Results showed that an
immediate switch to MK-1439A on Study Day 1 demonstrated superior fasting LDL-C and
fasting non-HDL-C profiles relative to the profiles observed among participants in the DSG;
for both serum lipid parameters, the effect was statistically significant (p <0.0001).
Information on Other Trial-Related Therapy
The standard marketed QD dose of 3TC was selected for inclusion in this study as the second
NRTI in the MK-8591 treatment groups in Part 1 because of its demonstrated efficacy and
safety in numerous treatment-naïve and treatment-experienced HIV-1 trials conducted over
many years, and because of its extensive real world use.  Preclinical data with MK-8591 also
demonstrated that MK-8591 had additive antiviral activity with 3TC in vitro with no
evidence of antagonism (refer to the MK-8591 IB).
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical trials will directly benefit from treatment
during participation as clinical trials are designed to provide information about the safety and
effectiveness of an investigational medicine.  Participants in this study will be closely
monitored for viremia (Section 5.4.1.1.2).  In the event a participant fails, he/she will
continue to have multiple alternative treatment options.
 
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MK-8591 is a promising new NRTTI for the treatment of HIV-1 infection.  It is a potent
inhibitor of HIV-1 replication in vitro and is active against both wild-type virus and most
common NRTI-resistant variants at concentrations achieved with QD dosing.  MK-8591 is
not expected to have many of the safety concerns associated with other NRTIs.  In addition,
MK-8591 is not expected to have major DDIs that would limit its utility in clinical practice. 
Therefore, MK-8591 could represent a valuable addition to the HIV-1 treatment paradigm for
treatment-naïve patients in both 3-drug and 2-drug treatment regimens.  Additional details
regarding specific benefits and risks for participants in this clinical trial may be found in the
accompanying MK-8591 IB and informed consent documents.
DOR is a potent NNRTI for treatment of HIV-1 infection.  It is a potent inhibitor of HIV-1
replication in vitro and is active against both wild-type virus and most common NNRTI-
resistant variants at concentrations achieved with QD dosing.  DOR displays excellent
potency against wild-type virus with an IC50 of 12 nM in the presence of 100% normal
human serum.  Preclinical studies also indicate a favorable in vitro resistance profile that is
distinct from other NNRTIs, with an IC50 of 21 nM, 31 nM, and 55 nM against mutants
containing the most frequently transmitted NNRTI-resistant mutations in RT, K103N,
Y181C and G190A, respectively, under the same conditions.  The preclinical toxicity profile
of DOR is also favorable.  Clinical pharmacology studies indicate that DOR can be dosed
QD, without regard to food, and DOR is not a metabolic inducer or inhibitor, reducing the
likelihood of significant DDI.  Additional details regarding specific benefits and risks for
participants participating in this clinical trial may be found in the accompanying DOR IB and
informed consent documents.
4. Objectives/Hypotheses and Endpoints
There are no hypotheses to be tested in this trial.  Objectives refer to the original regimen to
which participants were randomized (Groups 1 to 3: 1 of 3 different doses of MK-8591
administered with DOR + 3TC, or Group 4: MK-1439A), but participants in the MK-8591
treatment groups will be switched in Part 2 to a 2-drug regimen with MK-8591 + DOR after
at least 24 weeks on the 3-drug regimen if their HIV-1 RNA is <50 copies/mL.  In Part 3,
participants in the MK-8591 treatment groups will receive the selected dose of MK-8591 +
DOR, and Group 4 will continue to receive MK-1439A.  In Part 4, all participants in each
group will receive MK-8591A (FDC of MK-8591/DOR).
In HIV-1-infected antiretroviral treatment-naïve adults:
Objective
Endpoint
Primary
 Objective:  To evaluate the antiretroviral
activity of different doses of MK-8591
administered with DOR + 3TC compared
to MK-1439A, as assessed by the
proportion of participants with HIV-1
RNA <50 copies/mL at Week 24 and at
Week 48
 Proportion of participants with HIV-1
RNA <50 copies/mL at Week 24 and
Week 48
 
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Objective
Endpoint
 Objective:  To evaluate the safety and
tolerability of different doses of
MK-8591 administered with DOR + 3TC
compared to MK-1439A
 Number of participants experiencing
AEs
 Number of participants discontinuing
study drug due to AEs
Secondary
 Objective:  To evaluate the sustained
antiretroviral suppression in participants
on the selected dose of MK-8591 + DOR
compared to MK-1439A as assessed by
the proportion of participants with HIV-1
RNA <50 copies/mL 24 and 48 weeks
after switching to Part 2
 Proportion of participants with HIV-1
RNA <50 copies/mL 24 and 48 weeks
after entering Part 2
 Objective:  To evaluate the immunologic
effect of different doses of MK-8591
administered with DOR + 3TC compared
to MK-1439A at Week 24, Week 48,
Week 96, and Week 144
 Change from baseline in CD4+ T-cell
count at Week 24, Week 48, Week 96,
and Week 144
 Objective:  To evaluate the antiretroviral
suppression and immunologic effect of
MK-8591A administered during open-
label dosing in Part 4 of the trial
 Proportion of participants with HIV-1
RNA <50 copies/mL at Week 192 (48
weeks after entering Part 4)
 Change from baseline in CD4+ T-cell
count at Week 192
 Objective:  To evaluate the safety and
tolerability of different doses of MK-
8591 administered with DOR compared
to MK-1439A 24 weeks after switching
to Part 2
 Number of participants experiencing
AEs
 Number of participants discontinuing
study drug due to AEs
 Objective:  To evaluate the safety and
tolerability of the selected dose of MK-
8591 administered with DOR compared
to MK-1439A at Week 96 and through
study duration.
 Number of participants experiencing
AEs
 Number of participants discontinuing
study drug due to AEs
 Objective:  To evaluate the safety and
tolerability of MK-8591A during open-
label dosing in Part 4 of the trial.
 Number of participants experiencing
AEs
 Number of participants discontinuing
study drug due to AEs
 
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Objective
Endpoint
Tertiary/Exploratory
 Objective:  To evaluate the antiretroviral
activity of different doses of MK-8591
administered with DOR + 3TC compared
to MK-1439A as assessed by different
HIV-1 RNA thresholds and different time
points
 Proportion of participants with HIV-1
RNA <50 copies/mL at Week 96 and
Week 144 and <40 copies/mL at Week
24, Week 48, Week 96, and Week 144
 Objective:  To explore the antiretroviral
activity of different doses of MK-8591
administered with DOR + 3TC compared
to MK-1439A
 Time to Loss of Virologic Response
 Proportion of participants achieving an
HIV-1 RNA level below the limit of
detection of a single-copy assay at
Week 24, Week 48, Week 96, and
Week 144
 Objective:  To assess the development of
HIV-1 drug resistance to MK-8591
administered with DOR + 3TC in
participants who have protocol-defined
virologic failure (prior to Amendment
03) or clinically significant confirmed
viremia (as of Amendment 03)
 Frequency and type of viral genotypic
and phenotypic resistance to study
treatment
 Objective:  To evaluate the effects of
MK-8591 administered with DOR + 3TC
on body fat distribution and bone loss
 Percentage and absolute change from
baseline in peripheral fat and trunk fat
at Week 48, Week 96, Week 144, and
Week 192
 Change from baseline in body mass
index at Week 48, Week 96, Week
144, and Week 192
 
Percentage change from baseline in
spine BMD and hip BMD at Week 48,
Week 96, Week 144, and Week 192
 Objective:  To evaluate the PK of
MK-8591
 
PK values such as AUC, Cmax and C24
 Objective:  To explore the impact of MK-
8591 administered with DOR + 3TC on
laboratory markers
 
Blood levels of IL-6, sCD163, d-
dimer, and urine levels of albumin,
protein, beta-
2microglobulin/creatinine ratio and
retinol binding protein/creatinine ratio
 
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Objective
Endpoint
 Objective: 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
3TC=lamivudine; AE=adverse event; AUC=area under the curve; BMD=bone mass density;
C24=concentration at 24 hours; Cmax=maximum serum concentration; DOR=doravirine; HIV-1=human
immunodeficiency virus type 1; IL-6=interleukin-6; PK=pharmacokinetics; RNA=ribonucleic acid
5. Study Design
Overall Design
This randomized, active-controlled, multicenter, blinded trial will evaluate the safety,
tolerability, antiretroviral activity, and PK of 3 doses of MK-8591 (also referred to as
islatravir) QD given in combination with DOR QD and 3TC QD (Part 1 only) to
antiretroviral treatment-naïve adult participants with HIV-1 infection. This is a 4-part trial:
1) dose ranging as part of a 3-drug regimen in Part 1 (double-blind with in-house blinding),
2) 2-drug dose ranging maintenance in Part 2 (site blinded to dose of MK-8591),
3) maintenance with the selected dose of MK-8591 or MK-1439A in Part 3 (open-label), and
4) dosing with MK-8591A in Part 4 (open-label).
In Part 1, participants will be randomized in a 1:1:1:1 ratio to receive one of 4 study
treatments QD, as follows:
 Group 1: MK-8591 0.25 mg + DOR 100 mg + 3TC 300 mg + placebo for MK-1439A
(n=30)
 Group 2: MK-8591 0.75 mg + DOR 100 mg + 3TC 300 mg + placebo for MK-1439A
(n=30)
 Group 3: MK-8591 2.25 mg + DOR 100 mg + 3TC 300 mg + placebo for MK-1439A
(n=30)
 Group 4: MK-1439A + placebo for DOR + placebo for 3TC + placebo for MK-8591
(n=30)
Randomization will be stratified by screening HIV-1 RNA level (≤100,000 copies/mL or
>100,000 copies/mL).  Participants will receive at least 24 weeks of treatment in Part 1.  An
interim analysis will be performed by the Sponsor on the accrued data through Week 24 to
assess the safety and efficacy objectives for the 3-drug regimen.  Sponsor personnel will be
unblinded to treatment group assignments.  The results of this analysis will be shared with
an external Data Monitoring Committee (eDMC); however, they will not be shared with the
investigators. Participants may be switched to Part 2 starting at Week 24 depending on the
HIV-1 RNA results from the previous visit. Participants in Part 1 must be virologically
 
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suppressed (i.e., have not met viral failure criteria [Section 5.4.1.1.1] and have HIV RNA
<50 copies/mL), to move to Part 2 (Section 9.10). Participants who have not achieved HIV-
1 RNA <50 copies/mL by Week 20 and have not met viral failure criteria (Section
5.4.1.1.1) will continue to receive study medication in Part 1 (3-drug double blind) until
their HIV-1 RNA is <50 copies/mL. Prior to Amendment 03, participants who met viral
failure criteria (Section 5.4.1.1.1) or who were not virologically suppressed following the
Week 48 assessments were to be discontinued from treatment and complete the early
discontinuation and end oftrial follow-up visits (Section 9.10 and Section 8.1). As of
Amendment 03, if a participant has a viral load of ≥50 copies/mL at any time during the
study, a Viremia Confirmation visit must be conducted within 2 to 4 weeks of the initial
HIV-1 viremia (Section 2.3 and Section 5.4.1.1.2); a participant with confirmed HIV-1
virologic rebound will be discontinued from treatment (Section 5.4.1.1.2 and Section 8.1).
Participants who met the protocol-defined virologic failure criteria in Part 1 were
communicated to the unblinded statistician. If 3 or more participants (10% or more out of
30 expected participants) in any treatment group are observed to have virologic failure
by the unblinded statistician, this will be reported to the eDMC. The eDMC may
recommend dropping a treatment group on the basis of this criterion.
In Part 2, participants in Groups 1 to 3 will receive the 2-drug regimen of MK-8591 QD
given in combination with open-label DOR QD.  Participants will continue to receive the
dose of MK-8591 to which they were randomized, and 3TC will be dropped from the
regimen.  The dose of MK-8591 will remain blinded.  Participants in Group 4 will continue
to receive MK-1439A QD.  DOR (Groups 1 to 3) and MK-1439A (control group) will be
provided as open-label supply and matching placebos will no longer be administered.  The
total duration of treatment for individual participants in Part 2 will be dependent upon the
time point at which the participant is switched to Part 2 and is anticipated to be ~20 to 48
weeks. A second interim analysis will be conducted when all participants have reached
Week 48.  This analysis will include participants who have completed at least 24 weeks in
Part 1 (3-drug regimen) and participants who have been in Part 2 for various durations of
time (0–24 weeks). Dose selection of MK-8591 will occur following the second interim
analysis.  The primary efficacy endpoint is the proportion of participants achieving HIV-1
RNA <50 copies/mL.  The primary safety endpoint is the proportion of participants with
certain clinical and laboratory AEs.  The detailed results of the Week 48 interim analysis
will be shared with an eDMC.  The selected MK-8591 dose will be communicated to both
the eDMC and the investigators.  It is expected that dose selection will be communicated at
Week 60 or beyond.
Once the dose of MK-8591 has been selected and communicated to the sites, participants
receiving MK-8591 will be switched to the selected dose given in combination with DOR
QD (Part 3).  Both MK-8591 and DOR will be provided in an open-label fashion. 
Participants in the control group will continue to receive open-label MK-1439A. An interim
analysis will be conducted when all participants have reached Week 96; detailed results of
the Week 96 interim analysis will be shared with the eDMC.
Participants in Part 3 receiving the selected dose of MK-8591 in combination with DOR
QD or MK-1439A in the control group will all be switched to the 2-drug FDC tablet of
MK-8591A QD in Part 4.  MK-8591A will be provided as open-label supplies.
 
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Blood samples will be collected to assess antiretroviral, safety, and immunologic endpoints. 
Additional blood samples will be collected from all participants to support the evaluation of
MK-8591 population PK as described in Section 9.6.  Participants will have dual-energy x-
ray absorptiometry (DEXA) scans to evaluate body fat distribution and BMD as described in
Section 9.5.5.
As of Amendment 03, participants with clinically significant confirmed viremia (as described
in Section 5.4.1.1.2) during the trial will return to the site for repeat HIV-1 RNA testing
within 2 to 4 weeks of HIV-1 viremia (≥50 copies/mL) at a viremia confirmation visit.  If
viremia is confirmed and the HIV-1 RNA results meet the criteria for testing specified in
Section 10.4.1, a plasma sample will be sent to the central laboratory for resistance testing
(Section 9.2.4).  Participants with confirmed HIV-1 virologic rebound (Section 5.4.1.1.2) will
be discontinued from treatment and will complete the early discontinuation and end oftrial
follow-up visits (Section 8.1).
The safety of the participants in this trial will also be monitored during the trial by an eDMC
that will provide an ongoing review of the efficacy and safety data with periodic reviews to
occur approximately every 4 to 6 months, on an ad hoc basis as needed, or as specified in the
DMC charter.  The eDMC will recommend steps to ensure the safety of study participants
and the integrity of the trial.  To guarantee the unrestricted performance of its task, the
eDMC will receive study data from an external independent statistician for the ongoing
periodic reviews.  Details regarding the ongoing periodic reviews by the eDMC will be
described in a charter document.  Following eDMC review of the Week 96 interim analysis,
no additional eDMC reviews will occur.
Specific procedures to be performed during the trial, as well as their prescribed times and
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure
are provided in Section 9 –Study Assessments and Procedures.
Study Diagram
The trial design is depicted in Figure 1.
 
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Figure 1 
Study Diagram
 
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Number of Participants
Approximately 120 participants will be randomized, as described in Section 10.6.
Beginning and End of Study Definition
The overall trial begins when the first participant signs the informed consent form (ICF). 
The overall trial ends when the last participant completes the last study-related phone call or
visit, withdraws from the trial or is lost to follow-up (i.e. the participant is unable to be
contacted by the investigator).
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The eDMC recommends termination of the trial and the Executive Oversight Committee
(EOC) agrees per Appendix 3, or as stated in the DMC charter
2. Incidence or severity of adverse drug reactions in this or other trials suggest a potential
health hazard to participants
3. Plans to modify or discontinue the development of the trial drugs
Clinical Criteria for Termination of a Treatment Group(s)
Participants who meet the protocol-defined virologic failure criteria (Section 5.4.1.1.1) in
Part 1 will be communicated to the unblinded statistician. If 3 or more participants (10% or
more out of 30 expected participants) in any treatment group are observed to have virologic
failure by the unblinded statistician, this will be reported to the eDMC. The eDMC may
recommend dropping a treatment group on the basis of this criterion.  In the event a decision
is made to terminate a treatment group, the disposition of the participants in that arm will be
determined after consultation with the eDMC.
A treatment group may also be discontinued at the request of a regulatory agency.
Scientific Rationale for Study Design
This trial will be conducted in HIV-1–infected treatment-naïve participants and different
doses of a new NRTTI, MK-8591, and a new NNRTI, DOR will be evaluated.  Only
participants with no evidence of baseline HIV resistance mutations to any approved HIV-1
RT inhibitor, protease inhibitor, or integrase inhibitor will be allowed to enroll.  This is to
ensure that an effective antiviral regimen can be constructed for a participant who may
experience virologic failure and resistance to both classes of NRTIs and NNRTIs. 
A 3-drug combination, in which the ART regimen generally consists of 2 NRTIs plus 1 drug
from the NNRTI, protease inhibitor, or integrase inhibitor class, is the current standard of
care for HIV-1–infected treatment-naïve adults.  In Part 1 of this trial, the 3 different dose
levels of the NRTTI, MK-8591, will be given in combination with 2 other HIV-1 ART: DOR
(an NNRTI) and lamivudine (an NRTI). Thus, Part 1 of this trial is designed to assess
MK-8591 in the setting of a standard 3-drug regimen.
 
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Part 2 and Part 3 of this trial is designed to assess the ability of the different doses of
MK-8591 and the selected dose of MK-8591, respectively, given in combination with DOR
to maintain HIV-1 RNA suppression following at least 24 weeks of treatment with the 3-drug
regimen.  Similar clinical trials have assessed the utility of a 2-drug maintenance regimen
after an initial 3-drug treatment regimen.
Part 4 of this trial is designed to assess the ability of the selected dose of MK-8591 in
combination with DOR in the FDC of MK-8591A to maintain HIV-1 RNA suppression.
Participants who received MK-1439A (Group 4) and consent to continue in Part 4 will be
switched to MK-8591A in order to: (1) generate safety and efficacy data in virologically-
suppressed participants who switch to MK-8591A, and (2) provide access to treatment with
investigational MK-8591A through study duration and after completing the study, until MK-
8591A becomes commercially available (Section 7.8).
Follow-up through 1-year of age for infants born to participants who become pregnant while
receiving study intervention provides the ability to monitor growth and development as well
as potential adverse effects that may be associated with prenatal drug exposure. Growth
parameters (ie, length, weight, and head circumference) within normal range at
approximately 1-year of age are key noninvasive indicators that a serious congenital
malformation caused by in utero drug exposure is unlikely.
Rationale for Endpoints
Efficacy Endpoints
The primary efficacy parameter in the study is viral load as measured by HIV-1 RNA, which
is consistent with other clinical trials in HIV-infected participants and the current regulatory
guidance.  Suppressing HIV-1 RNA to low levels preserves the immune system and prevents
the development of opportunistic infections and progression of the disease.  Clinical trials of
antiretroviral agents in multiple classes have demonstrated that suppression of HIV-1 RNA to
levels below 50 copies/mL is a clinically meaningful endpoint.  Therefore, the primary
efficacy endpoint of this study is the proportion of participants achieving HIV-1 RNA <50
copies/mL.  The primary time point for dose selection is Week 48.
At the Week 48 time point, it is expected that the majority of participants will have had 24
weeks of treatment on the 3-drug regimen and 24 weeks of treatment on the 2-drug regimen. 
However, it is possible that some participants may take longer to meet the criterion to switch
to the 2-drug regimen and may have received treatment for more than 24 weeks on the 3-drug
regimen and less than 24 weeks on the 2-drug regimen at Week 48.  It is also possible that
some participants may have received treatment on the 3-drug regimen for all 48 weeks.
Secondary measurements for efficacy include HIV-1 RNA <50 copies/mL and change from
baseline in CD4+ T-cell counts.  Exploratory efficacy measurements include HIV-1 RNA
<40 copies/mL at different time points, time to loss of virologic response (TLOVR), HIV-1
RNA level below the limit of detection of a single-copy assay, and HIV-1 drug resistance for
participants who meet protocol-defined virologic failure criteria (prior to Amendment 03,
Section 5.4.1.1.1) or clinically significant confirmed viremia (as of Amendment 03, Section
5.4.1.1.2) and whose virus can be amplified.
 
 
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5.4.1.1.1 Virologic Failure Criteria
Prior to Amendment 03, protocol-defined virologic failure for this study was defined as 1 of
the following:
1. 
Confirmed (i.e., 2 consecutive measurements at least 1 week apart) HIV-1 RNA
≥50 copies/mL after initial response of HIV-1 RNA <50 copies/mL at any time
during the study; OR
2. 
Confirmed (i.e., 2 consecutive measurements at least 1 week apart) HIV-1 RNA >1
log increase from the HIV-1 RNA nadir after a >1 log decrease in HIV-1 RNA from
baseline at any time during the study; OR
3. 
Confirmed (i.e., 2 consecutive measurements at least 1 week apart) HIV-1 RNA
≥200 copies/mL at any time from Week 24 through Week 48; OR
4. 
Confirmed (i.e., 2 consecutive measurements at least 1 week apart) HIV-1 RNA
≥50 copies/mL at Week 48
Prior to Amendment 03, participants were to be discontinued from treatment and complete
the early discontinuation and end of trial phone and site follow-up visits, regardless of
compliance to study therapy if they met the protocol-defined virologic failure criteria (See
Section 8.1).
In addition to the 4- to 6-month review of safety and efficacy data, participants who met the
protocol-defined virologic failure criteria in Part 1 were communicated to the unblinded
statistician. If 3 or more participants in any treatment group were observed by the unblinded
statistician to have virologic failure, this was to be reported to the eDMC.  The eDMC was to
convene to review unblinded data and could recommend dropping a treatment group on the
basis of this criterion. 
5.4.1.1.2 Definition of Clinically Significant Confirmed Viremia
Beginning with Amendment 03, for the purpose of managing participants in this study,
clinically significant confirmed viremia is defined as:
 Virologic Rebound: Two consecutive (2 to 4 weeks apart) occurrences of HIV-1
RNA ≥200 copies/mL after achieving HIV-1 RNA <50 copies/mL at any time during
the study.
There is currently no global standard for definition of patients with low-level viremia (viral
load ≥50 and <200 copies/mL), and the predictive implication of such low-level viremia is
uncertain [Vandenhende, M. A., et al 2015] [Charpentier, C., et al 2014]. The US DHHS
guidelines currently define virologic failure as confirmed HIV RNA ≥200 copies/mL and do
not recommend that low-level viremia (detectable HIV RNA <200 copies/mL) automatically
result in treatment modification or more frequent virologic monitoring [Panel on
Antiretroviral Guidelines for Adults and Adolescents 2018]. Participants with HIV-1 RNA
between 50 and 200 copies/mL have a lower risk of developing resistance compared to those
with HIV-1 RNA >200 copies/mL and should continue on their current regimen, with HIV-1
RNA levels monitored as outlined in Section 9.2.2.
 
 
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An HIV-1 RNA level of ≥50 copies/mL must be confirmed and requires further management
as described in Section 9.2.2.
Safety Endpoints
The primary safety endpoints are the number of participants experiencing AEs and the
number of participants discontinuing study drug due to AEs.  Safety evaluations will include
physical examinations (including vital signs) and laboratory tests (hematology, chemistry and
urinalysis) performed per the Schedule of Activities (SoA) in Section 2.  Adverse events will
be evaluated at each visit and assessed according to the guidelines in Section 9.3 and
Appendix 2A.  Participants may be asked to return for unscheduled visits in order to perform
additional safety monitoring.
This trial will also explore the impact of MK-8591 + DOR + 3TC in Part 1, MK-8591 +
DOR in Part 2 and Part 3, and MK-8591A in Part 4 on fat distribution and BMD (i.e.,
DEXA), inflammatory and urinary markers, including blood levels of the pro-inflammatory
cytokine interleukin-6 (IL-6), D-dimer, soluble CD163, and urine levels of the analytes urine
albumin, urine protein, retinol binding protein/creatinine ratio, and beta-2-
microglobulin/creatinine ratio (Section 9.5.5, Section 9.9.1).  DEXA scans will be performed
and blood/urine samples will be collected from all participants as indicated in the SoA
(Section 2).
Pharmacokinetic Endpoints
The sparse PK data will be used for a population PK model.  Plasma samples will be
collected as indicated in the SoA (Section 2) and Section 9.6.
Pharmacodynamic Endpoints
There are no pharmacodynamics endpoints in this trial.
Planned Exploratory Biomarker Research
5.4.1.5.1 Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, and
severity and progression of disease. Variable response to therapy may be due to genetic
determinants that impact drug absorption, distribution, metabolism, and excretion;
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease
being treated. Therefore, where local regulations and IRB/IEC allow, a sample will be
collected for DNA analysis from consenting participants.
DNA samples will be used for research related to the study treatment(s), the disease under
study and related diseases. They may also be used to develop tests/assays including
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic
research may consist of the analysis of one or more candidate genes or the analysis of genetic
markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be
conducted if it is hypothesized that this may help further understand the clinical data.
 
 
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The samples may be analyzed as part of a multi-study assessment of genetic factors involved
in the response to understand study disease or related conditions.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA specimens consented for
future biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere
in the protocol (as part of the main trial) and will only be conducted on specimens from
appropriately consented participants. The objective of collecting/retaining specimens for
Future Biomedical Research is to explore and identify biomarkers that inform the scientific
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use
such information to develop safer, more effective drugs/vaccines, and/or to ensure that
participants receive the correct dose of the correct drug/vaccine at the correct time.  The
details of Future Biomedical Research are presented in Appendix 6  –Collection and
Management of Specimens for Future Biomedical Research.
Rationale for The Use of Comparator/Placebo
The comparator for this trial is MK-1439A, the FDC of DOR 100 mg/3TC 300 mg/TDF
300 mg.  DOR is a novel NNRTI being studied for the treatment of HIV-1 infection.  It is a
potent inhibitor of HIV-1 replication in vitro and is active against both wild-type virus and
the most common NNRTI-resistant variants at concentrations achieved with QD dosing.  The
available long-term (beyond Week 48) data from a Phase 2 trial (MK-1439A-007) in
treatment-naïve HIV-infected participants and Week 48 Phase 3 data from MK-1439 PN018
and MK-1439A PN021 trials demonstrate that DOR in combination with FTC/TDF and
3TC/TDF has a favorable safety and tolerability profile and potent efficacy.  The use of MK-
1439A will allow direct comparison of MK-8591 to 3TC/TDF in the 2 drug maintenance
parts of the study. Refer to the DOR IB for additional information.
Justification for Dose
Three doses of MK-8591 will be evaluated in this trial: 0.25 mg, 0.75 mg, and 2.25 mg.  A
dose of MK-8591 will be selected after analysis of 48 weeks of dosing in Parts 1 and 2.
Participants will be switched to the selected dose in Part 3 (administered with DOR as single
entities) and Part 4 (administered with DOR as an FDC) and will complete the remaining
treatment duration with that dose (Section 5.1).
The 0.25 mg dose is expected, based on population PK modeling, to achieve target PK
values, specifically concentration after 24 hours (C24) of 0.05 pmol/106 cells of the active
MK-8591-TP in peripheral blood mononuclear cells (PBMCs) after 1 dose.  A C24 of 0.05
pmol/106 cells is 5-fold over the in vitro intracellular IC50, providing an ample margin over
wild-type virus. The C24 of MK-8591-TP was investigated in P009 (daily dosing of 0.25 mg
MK-8591 for 28 days) and found, on average, to be 0.115 pmol/106 cells (16-fold over the in
vitro intracellular IC50). While the HIV-1 RT M184V resistance substitution can decrease
MK-8591 susceptibility up to 5-fold in cell culture, at a 0.25 mg QD dose of MK-8591, this
substitution will be covered after 1 dose.  Other substitutions with higher fold shifts will be
covered within three 0.25 mg doses (72 hours) of MK-8591.  In comparison, TAF, TDF, and
3TC at steady state (240 hours) achieve intracellular tenofovir diphosphate or 3TC-TP
 
 
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concentrations that are only ~4-fold, ~3-fold, and less than 1-fold, respectively, over the in
vitro wild-type IC50.  The additional MK-8591 doses of 0.75 mg and 2.25 mg will permit
exploration of the safety and efficacy of MK 8591 with increased exposure and have been
chosen to minimize overlap of the exposures between doses.  Based on Phase 1 safety, PK,
Phase 1b efficacy, and viral dynamic simulations, all doses selected for this trial should be
well tolerated, safe, and confer adequate antiviral effect.
The maximum MK-8591 daily dose studied in this trial is 2.25 mg.
6. Study Population
Male and female participants with HIV-1 infection who are naïve to antiretroviral therapy
and 18 years of age or older will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Has HIV-1 infection as determined by a positive enzyme-linked immunosorbent assay
and a screening plasma HIV-1 RNA (completed by the central laboratory) ≥1000
copies/mL within 60 days of the treatment phase of the study.
2. Has a screening CD4+ T-cell count ≥200 cells/mm3 (completed by the central
laboratory) within 60 days prior to the treatment phase of this study.
3. Is naïve to ART.
Note:  Naïve is defined as having received no (0 days) ART therapy for the treatment
of active HIV-1 infection including prevention of mother-to-child transmission.
4. Has the following laboratory values (completed by the central laboratory) within 60
days prior to the treatment phase of this study:
a) International normalized ratio ≤1.2
b) Urine protein is within normal limits (no more than trace protein by urine
dipstick)
c) Hemoglobin ≥9.0 g/dL if female or ≥10.0 g/dL if male
d) Absolute neutrophil count ≥1000/mm3
e) Platelet count ≥100,000/mm3
f) Total serum bilirubin ≤the upper limit of normal (ULN)
g) Alkaline phosphatase <1.5 × ULN
h) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <1.5 ×
ULN
 
 
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Note: A single repeat of a laboratory screening test will be allowed for test results that
are unexpected based on documented prior laboratory results, but the repeat test
results must be available within the 60-day screening window.
5. Has a calculated creatinine clearance (Clcr) ≥50 mL/min within 60 days prior to the
treatment phase of this study , based on the following Cockcroft-Gault equations:
 If male
Clcr (mL/min) = (140-age [y]) × weight [kg]) 
                          72 × serum creatinine (mg/dL)
 If female
Clcr (mL/min) =   (140-age [y]) ×weight [kg])    ×0.85
                          72 × serum creatinine (mg/dL)
6. In the opinion of the investigator, the participant should be considered clinically
stable, with no signs or symptoms of acute infection, at the time of entry into the study
(i.e., clinical status and all chronic medications should be unchanged for at least 2
weeks prior to the start of treatment in this study).
Demographics
7. Is a male or female at least 18 years of age on the day informed consent is signed.
8. A female participant is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during
the treatment period and for at least 6 weeks (corresponding to time needed to
eliminate any study treatments (MK-8591, DOR, or 3TC) or MK-1439A after the last
dose of study treatment.
9. All participants, male and female, agree to use barrier methods of contraception when
engaged in any sexual activity during treatment and for 6 weeks following treatment.
Informed Consent
10. The participant (or legally acceptable representative, if applicable) provides written
informed consent for the trial.  The participant (or legally acceptable representative, if
applicable) may also provide consent for Future Biomedical Research.  However, the
participant may enroll in the main trial without consenting to Future Biomedical
Research.
 
 
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Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a history or current evidence of any condition, therapy, laboratory abnormality
or other circumstance that might, in the opinion of the investigator, confound the
results of the study or interfere with the participant’s participation for the full
duration of the study, such that it is not in the best interest of the participant to
participate.
2. Is, at the time of signing informed consent, a user of recreational or illicit drugs or
has had a history of drug or alcohol abuse or dependence that may interfere with
trial participation.  The nature and potential clinical context of the participant's
illicit drug use, in relation to their exclusion from this trial, will be at the discretion
of the investigator.
3. Has significant hypersensitivity or other contraindication to any of the components
of the study drugs as determined by the investigator.
4. Has a history of malignancy ≤5 years prior to signing informed consent except for
adequately treated basal cell or squamous cell skin cancer or in situ cervical
cancer.
5. Is female and is expecting to donate eggs at any time during the study (donation of
sperm should follow local guidelines for HIV-positive individuals).
Note: Investigators should provide appropriate guidance to female participants
regarding egg donation after completion of the study treatment.  Consistent with
the recommendations for contraceptive use, it is recommended that all female
participants refrain from egg donation for 6 weeks following their last dose of
study treatment.
6. Is breastfeeding or expecting to conceive.
7. A WOCBP who has a positive urine pregnancy test on Day 1 before the first dose
of study treatment.  If the urine test is positive or cannot be confirmed as negative,
a serum pregnancy test will be required.
Prior/Concomitant Therapy
8. Has been treated for a viral infection other than HIV-1, such as hepatitis B, with an
agent that is active against HIV-1, including, but not limited to, the following: 
adefovir, TDF, TAF, entecavir, FTC, or 3TC.
9. Has used systemic immunosuppressive therapy or immune modulators within 30
days prior to treatment in this study or is anticipated to need them during the
course of the study.
Note:  Time limited courses of corticosteroids (e.g., for asthma exacerbation) will
be allowed.
 
 
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10. Requires or is anticipated to require any of the following prohibited medications:
 Carbamazepine
 Phenobarbital
 Phenytoin
 Rifabutin
 Rifampin
 Herbal remedies
 St. John’s Wort
 Modafinil
 Bosentan
 Nafcillin
 Pentostatin
Prior/Concurrent Clinical Study Experience
11. Is currently participating in or has participated in an interventional clinical trial
with an investigational compound or device within 30 days of signing informed
consent to participate in this current trial.
Diagnostic assessments
12. Has a documented or known virologic resistance to any approved HIV-1 reverse
transcriptase inhibitor, protease inhibitor, integrase inhibitor, or any study drug, as
demonstrated by any the following resistance substitutions (according to the 2017
IAS-USA drug resistance mutations list [Wensing, A. M., et al 2017]):
a. NRTI resistance substitutions: RT M41L, K65E/N/R, D67N, T69Insert,
K70E/R, L74V, V75I, F77L, Y115F, F116Y, Q151M, M184I/V, L210W,
T215F/Y, K219E/Q. This list includes all resistance substitutions that may
also impact study drugs MK-8591, 3TC, or TDF.
b. NNRTI resistance substitutions: RT L100I, K101E/P, K103N/S, V106A/I/M,
V108I, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188C/H/L, G190A/S, H221Y,
P225H, F227C/L/V, M230I/L, L234I, P236L, or Y318F. This list includes all
resistance substitutions that may also impact study drug DOR.
c. Protease inhibitor resistance substitutions:  Protease D30N, V32I, M46I/L,
I47A/V, G48V, I50L/V, I54L/M, Q58E, T74P, L76V, V82A/F/L/S/T, N83D,
I84V, N88S, orL90M
d. Integrase inhibitor resistance substitutions: Integrase T66I, E92Q, F121Y,
143C/H/R, S147G, Q148H/K/R, or N155H.
Note:  This exclusionary list is for the purpose of this study and includes
major (or primary) resistance substitutions but not substitutions that are minor
and found as naturally occurring polymorphisms.
 
 
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13. Has active hepatitis C virus (HCV) coinfection (defined as detectable HCV RNA)
or HBV co-infection (defined as hepatitis B surface antigen [HBsAg]-positive)
(completed by the central laboratory).  Participants with prior/inactive HCV
infection (defined as undetectable HCV RNA) or past HBV infection (defined as
HBsAg-negative and positive for antibody against HBsAg) may be enrolled
14. Has a current (active) diagnosis of acute hepatitis due to any cause.
Other Exclusions
15. Has previously been randomized in a study and received MK-8591, DOR,
MK-1439A, or 3TC.
16. 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
trial.
Lifestyle Restrictions
No restrictions are required.
Meals and Dietary Restrictions
Study medications may be administered without regard to meals (Section 7.5).
Caffeine, Alcohol, and Tobacco
Participants should be questioned about their estimated daily intake of alcohol and about
substance abuse during the screening evaluation of eligibility.  Any participant who in the
opinion of the investigator has an excessive intake of any of these substances which might
interfere with participation in the trial must be excluded from the study.
Activity
It is recommended that participants abstain from strenuous exercise (e.g., beginning new
weight lifting, running, bicycling, regimens, etc.) for 24 hours before each blood collection
for clinical laboratory tests to minimize abnormal results due to physical exertion.
Abstinence from strenuous exercise should be documented by the participant in the study
diary or by the site in another source document. 
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but
are not subsequently randomized in the study.  A minimal set of screen failure information is
required to ensure transparent reporting of screen failure participants to meet the
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to
respond to queries from regulatory authorities. Minimal information includes demography,
screen failure details, eligibility criteria, and any adverse events or serious adverse events
(SAE) meeting reporting requirements as outlined in the entry guidelines.
 
 
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Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the trial will not be
replaced.
7. Treatments
Study treatment is defined as any investigational treatment(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 treatment(s) provided by the Sponsor] will be packaged to support
enrollment as required. Clinical supplies will be affixed with a clinical label in accordance
with regulatory requirements.
Treatments Administered
The study treatments to be used in this trial are outlined below in Table 1.
Table 1 
Study Treatments
Study
Treatment
Name:
MK-8591
Placebo
for
MK-8591
DOR
(MK-
1439)
Placebo
for
DOR
(MK-
1439) 
3TC  
Placebo
for
3TC  MK-1439A
Placebo
for
MK-
1439A
MK-
8591A
Dosage
Formulation:
Capsule Capsule 
Tablet 
Tablet 
Tablet 
Tablet 
Tablet 
Tablet 
Tablet
Unit Dose
Strength(s):
0.25 mg
0.75 mg 
2.25 mg
0 mg 
100 mg 
0 mg 
300 mg 
0 mg
DOR
100 mg +
3TC
300 mg +
TDF
300 mg
0 mg
0.75 mg/
100 mg
Dosage Level(s):
QD  
QD  
QD  
QD  
QD  
QD  
QD  
QD  
QD
Route of
Administration:
Oral 
Oral 
Oral 
Oral 
Oral 
Oral 
Oral 
Oral 
Oral
Sourcing: 
Central 
Central
Central
or Local
Central Central Central
Central or
Local
Central 
Central
3TC=lamivudine; DOR=doravirine; MK-1439A=doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil
fumarate 300 mg; MK-8591A=MK-8591 0.75 mg/DOR 100 mg; QD=once daily; TDF=tenofovir disoproxil
fumarate.
All placebos were created by the Sponsor to match the active product.
All supplies indicated in Table 1 will be provided per the ‘Sourcing’ row depending upon
local country operational requirements.  Every attempt should be made to source these
supplies from a single lot/batch number. The trial site is responsible for recording the lot
number, manufacturer, and expiry date for any locally purchased product as per local
guidelines unless otherwise instructed by the Sponsor.
 
 
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Refer to Section 9.1.8 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other)
No dose modification of MK-8591 (or placebo), DOR (or placebo), 3TC (or placebo),
MK-1439A (or placebo), or MK-8591A is allowed during the trial, beyond the protocol
specified switch to open-label study medication.
Decisions to temporarily withhold study treatment because of an AE will be reviewed on a
case-by-case basis by the investigator.  Interruptions from the protocol-specified treatment
plan that are expected to be 7 days or longer require consultation between the investigator
and the Sponsor and written documentation of the collaborative decision on participant
management.
The investigator should consider temporarily withholding study treatment if the
severity of the AE is Grade 3 or above and/or if clinically indicated.  Guidelines for
grading the severity of laboratory AEs for the purposes of participant care are based on
Division of Acquired Immunodeficiency Syndrome (DAIDS) Criteria for Grading Severity
of Adverse Events (Appendix 2A). The decision to interrupt study treatment should take
into account the participant’s baseline laboratory values and any concomitant
medication or comorbidities that could be contributory.  At the discretion of the
investigator, study treatment may generally be reinitiated when AEs resolve (i.e., laboratory
parameters return to near normal or baseline values).  See Appendix 4 for instructions if a
rechallenge is planned for an AE that was serious and which may have been caused by the
study medication or poses a significant risk to the participant.
If there is a recurrence of the AE after re-initiation of study treatment, consideration should
be given to permanently discontinuing all study treatment.  In general, when an AE occurs
which requires interruption of study treatment, all study medications should be interrupted to
avoid having a participant receive suboptimal therapy, which may predispose them to the
development of drug resistance. In general, all study medications should be restarted
concomitantly at full dose.
Method of Treatment Assignment
Treatment allocation/randomization will occur centrally using an interactive voice response
system / integrated web response system (IVRS/IWRS).  There are 4 study treatment arms. 
Participants will be assigned randomly in a 1:1:1:1 ratio to the treatment groups as shown
below. 
Group 1:  MK-8591 (0.25 mg) + DOR (100 mg) + 3TC (300 mg) QD + placebo for MK-
1439A
Group 2:  MK-8591 (0.75 mg) + DOR (100 mg) + 3TC (300 mg) QD + placebo for MK-
1439A
Group 3:  MK-8591 (2.25 mg) + DOR (100 mg) + 3TC (300 mg) QD + placebo for MK-
1439A
Group 4:  MK-1439A QD + placebo for DOR + placebo for 3TC +  placebo for MK-8591
As described in Section 5.1 and Section 9.10, after at least 24 weeks of treatment on the 3-
drug regimen all participants who are virologically suppressed and have not met viral failure
 
 
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criteria (Section 5.4.1.1.1), will be switched to Part 2.  In Part 2, the doses of MK-8591 will
remain blinded, DOR and MK-1439A will be provided as open-label supplies and the 3TC
will be dropped. Participants will be assigned study medication via Interactive Voice/Web
Response System (IVRS/IWRS) as follows:
Group 1:  MK-8591 (0.25 mg) + DOR (100 mg) 
Group 2:  MK-8591 (0.75 mg) + DOR (100 mg) 
Group 3:  MK-8591 (2.25 mg) + DOR (100 mg) 
Group 4:  MK-1439A QD
After all participants have received 48 weeks of study therapy (Part 1 + Part 2), a dose of
MK-8591 will be selected.  Following dose selection and site notification (Week 60 or
beyond), participants in Groups 1 to 3 will be switched to the selected dose of MK-8591
administered with DOR provided as open-label supplies in Part 3. Participants in Group 4
will continue to receive open-label MK-1439A.  Participants will be assigned study
medication via IVRS/IWRS as follows:
Groups 1 to 3:  MK-8591 selected dose + DOR (100 mg) 
Group 4:          MK-1439A QD
In Part 4, all participants will receive open-label MK-8591A.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
 Screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).
Blinding
In Part 1 of the trial, a double-blinding technique with in-house blinding will be used for
MK-8591, DOR, 3TC, and MK-1439A.  The participant, the investigator, and Sponsor
personnel or delegate(s) who are involved in the study treatment administration or clinical
evaluation of the participants will be unaware of the group assignments.  During the double-
blind portion of the trial, all active drug treatments will be packaged identically relative to
their matching placebos.
In Part 2, when participants are switched to the 2-drug dose-ranging/maintenance regimen
(Section 5.1 and Section 9.10), the dose of MK-8591 will remain blinded, however, the DOR
(Groups 1 to 3) and MK-1439A (Group 4) will be provided as open-label supplies; matching
placebos will not be administered.
Once the MK-8591 dose is selected and sites are notified (Part 3), all study treatments will be
provided as open-label supplies. Matching placebos will not be administered (Section
9.1.8.1).  In Part 4, MK-8591A will be provided as open-label supplies.
See Section 9.1.10 for a description of the method of unblinding a participant during the trial,
should such action be warranted.
 
 
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Preparation/Handling/Storage/Accountability
Dose Preparation
The rationale for selection of doses to be used in this trial is provided in Section 3.2.  There
are no specific calculations or evaluations required to be performed in order to administer the
proper dose to each participant.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study treatment received and any discrepancies are reported
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site
staff may supply or administer study treatment. All study treatments 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 treatment accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
For all trial 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 trial site is responsible for recording the lot number, manufacturer, and expiry date for
any locally purchased product 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
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
Study Medication Diary Cards completed by the participants will be used to document drug
compliance.  Study medication diary cards will be provided to the participants at the visits
specified in the SoA (Section 2).  The investigator/study coordinator will be responsible for
entering the identification number (allocation number), visit number, next visit date, and
indicating if the visit is fasting or a PK visit (if applicable) before giving the diary card to the
participant. Participants will be instructed to record dates/times and the number of tablets or
capsules of study drug taken on the diary card daily and return the completed diary at each
visit.  Only the participant should enter information onto the diary card.  At visits when
used/unused study medications are returned, site personnel must verify the accuracy of the
dosing diary by comparing entries with amounts of returned study medication.  If a
discrepancy is noted, investigator/study coordinator must discuss the discrepancy with the
 
 
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participant, and the explanation must be documented. Only the participant shall make any
changes to the entries on the diary card. The investigator/study coordinator will be
responsible for transferring the appropriate information from the diary card onto the
appropriate case report form.
Interruptions from the protocol specified treatment plan for ≥7 days require consultation
between the investigator and the Sponsor and written documentation of the collaborative
decision on participant management.
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the
ongoing trial.  If there is a clinical indication for any medication specifically prohibited
during the trial, discontinuation from trial therapy may be required.  The investigator should
discuss any questions regarding this with the Sponsor Clinical Director.  The final decision
on any supportive therapy rests with the investigator and/or the participant's primary
physician.  However, the decision to continue the participant on study treatment requires the
mutual agreement of the investigator, the Sponsor and the participant.
Listed below are specific restrictions for concomitant therapy during the course of the trial:
 The medications and/or substances below are prohibited in this study because they are
moderate or potent broad inducers of CYP3A4 and their co-administration with DOR
could possibly result in reduced drug levels of DOR, or they have the potential for
additional DDIs.
Since this list is not comprehensive, the investigator should use his/her medical
judgment when a participant presents with a medication not on the list or call the
Sponsor Clinical Director or designee for clarification.
 Carbamazepine
 Phenobarbital
 Phenytoin
 Rifabutin
 Rifampin
 Herbal remedies
 St. John’s Wort
 Modafinil
 Bosentan
 Nafcillin
 Enzalutamide
 Mitotane
 Oxcarbazepine
 
 
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 Rifapentine
 The following medication is prohibited as it is a known adenosine deaminase
inhibitor which may increase MK-8591 levels:
 Pentostatin
 Investigational agents are not permitted. Investigational agents must be discontinued
30 days prior to receiving study therapy.
 Concomitant use of immune therapy agents, immune modulators, or other
immunosuppressive therapy is not allowed within 30 days prior to treatment or during
the course of the study with the following exceptions:
 Short courses of corticosteroids (e.g., as for asthma exacerbation)
 If a participant develops a malignancy (e.g., lymphoma) after randomization,
the participant may receive chemotherapy and remain in the study if, in the
opinion of the investigator, the benefits outweigh the risks.  Depending on the
type of chemotherapy, study medication may need to be interrupted until
completion of the chemotherapy.
 Treatment for participants with newly diagnosed HCV should be deferred until study
completion when possible.  Treatment options are dependent upon which part of the
trial a participant is in:
 For participants in Part 1 and those receiving MK-8591 in the dose-ranging
arms in Part 2:  Participants who require treatment must be discontinued from
treatment and complete the early discontinuation and end oftrial phone and
site follow-up visits.
 For participants in Group 4 (open-label MK-1439A) in Part 2 and all
participants in Part 3 and in Part 4:  A consultation with the Sponsor Clinical
Director is required for participants who require treatment during this part of
the trial. After consultation, participants may be allowed to receive treatment
and remain in the study if, in the opinion of the investigator, the benefits
outweigh the risks.
 Other antiretroviral therapies beyond those described in the study (MK-8591, DOR,
3TC, MK-1439A, or MK-8591A) are not permitted during the course of the study.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Treatment After the End of the Study
Provided that development of MK-8591 is continuing, there will be a mechanism for all
participants who are virologically suppressed to receive treatment with MK-8591A, after
completing the study and without interruption, until it becomes commercially available.
Participants eligible for this mechanism will be those who have completed the last scheduled
study visit, who are considered by the investigator to have derived benefit from study
 
 
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participation (regardless of treatment group assigned) and for whom further treatment with
MK-8591 + DOR is considered clinically appropriate.
Clinical Supplies Disclosure
In Part 1, all study supplies will be double-blinded; therefore, the participant, the trial site
personnel, the Sponsor and/or designee will be blinded.  In Part 2, DOR and MK-1439A will
be provided as open-label supplies; the doses of MK-8591 will be blinded. In Parts 3 and 4,
the trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or
designee are not blinded. Study treatment (name, strength or potency) is included in the label
text; random code/disclosure envelopes or lists are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the
trial to unblind participants and to unmask study treatment identity. The emergency
unblinding call center should only be used in cases of emergency (see Section 9.1.10). In the
event that the emergency unblinding call center is not available for a given site in this trial,
the central electronic treatment allocation/randomization system (IVRS/IWRS) should be
used in order to unblind participants and to unmask study treatment identity.  The Sponsor
will not provide random code/disclosure envelopes or lists with the clinical supplies.
See Section 9.1.10, Participant Blinding/Unblinding, for a description of the method of
unblinding a participant during the trial, should such action be warranted.
8. Discontinuation/Withdrawal Criteria
Discontinuation of Study Treatment
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment.  Therefore, all participants who
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in the SoA (Section 2) by
participating in the Early Discontinuation and End of Trial Site Follow-Up visit.
Participants may discontinue study treatment at any time for any reason or be dropped from
the study treatment at the discretion of the investigator should any untoward effect occur.  In
addition, a participant may be discontinued from study treatment by the investigator or the
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative
and/or other safety reasons.  Specific details regarding procedures to be performed at study
treatment discontinuation are provided in Section 9.1.9.
A participant must be discontinued from study treatment for any of the following reasons:
 The participant or participant’s legally acceptable representative requests to
discontinue study treatment.
 The participant has a medical condition or personal circumstance which, in the
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk
from continued administration of study treatment.
 
 
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 The participant has a confirmed positive serum pregnancy test (See Section 9.3.6).
Note: Infants born to participants who become pregnant while receiving study
intervention will have follow-up data collected up to approximately 1 year after birth
(See Section 9.5.6).
 The participant experiences a severe skin or hypersensitivity reaction.
 The participant has a Clcr of <50 mL/min based on the Cockcroft-Gault equation
(Section 6.1, #5):
Note:  Creatinine clearance should be confirmed by repeat analysis prior to
discontinuing treatment.
 The participant has been diagnosed with HBV infection.
 Prior to Amendment 03, the participant has met 1 of the virologic failure criteria
(Section 5.4.1.1.1).
 As of Amendment 03, the participant has confirmed HIV-1 virologic rebound as
defined in Section 5.4.1.1.2.
 Participants in Part 1 or participants in the MK-8591 dose-ranging groups in Part 2
who are newly diagnosed with HCV and require treatment. See Section 7.7 for
instruction regarding participants in other treatment groups or parts of the trial.
NOTE: Participants who are discontinued from study treatment should be switched as
soon as possible to another ART regimen, which will not be provided by the Sponsor, in
order to avoid potential exposure to MK-8591 monotherapy due to the long half-life of
MK-8591.
For participants who are discontinued from study treatment but continue to be monitored in
the trial, see the Early Discontinuation and End of Trial Site Follow-up visits, as outlined in
the SoA (Section 2) for those procedures to be completed at each specified visit.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued,
he/she shall not be allowed to restart study treatment.
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the
study, as well as specific details regarding withdrawal from Future Biomedical Research are
outlined in Section 9.1.9.  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 8.3.
 
 
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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, phone 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 amount of missing data for the participant will be
managed via the pre-specified data handling and analysis guidelines.
9. 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.
 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.
The maximum amount of blood collected from each participant over the duration of the
study, including any extra assessments that may be required, will not exceed approximately
867 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with
the samples.
Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential
participant or each participant’s legally acceptable representative prior to participating in a
clinical trial or Future Biomedical Research. If there are changes to the participant’s status
during the trial (eg, health or age of majority requirements), the investigator or qualified
designee must ensure the appropriate consent is in place.
 
 
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General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s
legally acceptable representative’s dated signature on a consent form along with the dated
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before
participation in the trial.
The initial ICF, any subsequent revised written ICF and any written information provided to
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. 
The participant or his/her legally acceptable representative should be informed in a timely
manner if new information becomes available that may be relevant to the participant’s
willingness to continue participation in the trial.  The communication of this information will
be provided and documented via a revised consent form or addendum to the original consent
form that captures the participant’s dated signature or by the participant’s legally acceptable
representative’s dated signature.
Specifics about a trial and the trial 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.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent
to the participant, answer all of his/her questions, and obtain written informed consent before
performing any procedure related to Future Biomedical Research.  A copy of the informed
consent will be given to the participant.
Consent for Infant Safety Follow-up
Depending on applicable laws and regulations, a separate informed consent may be required
for participation in the infant safety follow-up period (Section 9.5.6). If a separate consent is
required, the investigator or medically qualified designee will explain the infant safety
follow-up consent to the participant, answer all questions, and obtain written informed
consent before collecting any data related to the infant follow-up. A copy of the informed
consent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee
to ensure that the participant qualifies for the trial.  Refer to Appendix 2 for list of specific
laboratory tests.
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as
participants in a research trial. The card will contain trial site contact information (including
direct telephone numbers) to be utilized in the event of an emergency. The investigator or
qualified designee will provide the participant with a Participant Identification Card
 
 
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immediately after the participant provides written informed consent. At the time of treatment
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
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical
history should include information pertaining to the diagnosis of HIV-1 infection and AIDS
(if applicable) and the year diagnosed.  In addition, the participants’ history of smoking
should be obtained and recorded on the appropriate electronic case report form (eCRF) as
relevant for calculating cardiovascular risk.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use and record prior
medication taken by the participant within 30 days before Screening and during the screening
period.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant
during the trial once randomization has occurred.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to
identify the participant for all procedures that occur prior to randomization.  Each participant
will be assigned only one screening number.  Screening numbers must not be re-used for
different participants.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a
treatment/randomization number.  The treatment/randomization number identifies the
participant for all procedures occurring after treatment allocation/randomization.  Once a
treatment/randomization number is assigned to a participant, it can never be re-assigned to
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Study treatment should begin on the day of treatment allocation/randomization or as close as
possible to the date on which the participant is allocated/assigned.
 
 
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Timing of Dose Administration
All study medications should be administered QD at approximately the same time each day
without regard to food.  The tablets from each container should be taken together (Section
7.5.1).
In Part 1, all participants will take 1 tablet from each of 4 containers, A, B, C and D, QD.
In Part 2, participants in Groups 1 to 3 will take 1 tablet each from Containers E and F QD,
participants in Group 4 will take 1 tablet from Container G QD.
In Part 3, participants in Groups 1 to 3 will take 1 tablet each from Containers H and F QD,
and participants in Group 4 will continue to take 1 tablet from Container G QD.
Study medication will be provided as per Table 2.
If a participant misses a dose of any of the study drugs, the following guidance should be
followed:
 If it is ≤12 hours before the next dose, the missed dose should be skipped and the
normal dosing schedule resumed. The subject should not double the next dose in
order to compensate for what has been missed
 If it is >12 hours before the next dose, the missed dose should be taken and the
normal dosing schedule resumed
Table 2 
Study Medication Labeling
Container Label
Medication Label 
Blinding
Part 1 –Double Blind
All Groups
A
MK-8591 0.25 mg, 0.75 mg, or 2.25 mg or placebo 
Blinded
B1
MK-1439 100 mg or placebo
Blinded
C
Lamivudine 300 mg or placebo
Blinded
D
MK-1439A (MK-1439 100 mg/lamivudine
300 mg/tenofovir disoproxil fumarate 300 mg) or placebo
Blinded
Part 2 –Site Blinded to MK-8591 Dose
Groups 1 -3
E
MK-8591 0.25 mg, 0.75 mg, or 2.25 mg
Dose blinded
F1
MK-1439 100 mg
Open-label
Group 4
G
MK-1439A (MK-1439 100 mg/ lamivudine 300 mg/
tenofovir disoproxil fumarate 300 mg)
Open-label
 
 
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Container Label
Medication Label 
Blinding
Part 3 –Open-label
Groups 1 –3
H
MK-8591 Selected dose (0.25 mg, 0.75 mg, or 2.25 mg) 
Open-label
F1, 2
MK-1439 100 mg
Open-label
Group 4
G2
MK-1439A (MK-1439 100 mg/ lamivudine 300 mg/
tenofovir disoproxil fumarate 300 mg)
Open-label
Part 4 –Open-label
Groups 1 –4
J
MK-8591A (MK-8591 0.75 mg/DOR 100 mg) 
Open-label
1 Tablets must be kept in the original container prior to taking study medication.
2  Iflocally sourced, container labels F and G will not apply.
Centrally sourced study medication containers will contain enough study drug for 35 days
while locally sourced study medication containers will contain enough study drug for 30
days. All study medication should be dispensed 1 container for each 4-week visit interval.
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the trial, all applicable activities
scheduled for the Early Discontinuation Visit should be performed at the time of withdrawal. 
Any adverse events which are present at the time of withdrawal should be followed in
accordance with the safety requirements outlined in Section 9.3 - Adverse Events.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants may
withdraw consent at any time by contacting the principal investigator for the main trial.  If
medical records for the main trial 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 trial data and
results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the
investigator is no longer required by regulatory authorities to retain the main trial records) or
the specimens have been completely anonymized, there will no longer be a link between the
 
 
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participant’s personal information and their specimens.  In this situation, the request for
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY
EFFORT SHOULD BE MADE NOT TO UNBLIND THE PARTICIPANT UNLESS
NECESSARY.
For emergency situations where the investigator or delegate needs to identify the drug used
by a participant and/or the dosage administered, he/she will contact the emergency
unblinding call center by telephone and make a request for emergency unblinding.  As
requested by the investigator or delegate the emergency unblinding call center will provide
the information to him/her promptly and report unblinding to the sponsor. Prior to contacting
the emergency unblinding call center to request unblinding of a participant’s treatment
assignment, the investigator or delegate must enter the intensity of the adverse events
observed, the relation to study drug, the reason thereof, etc., in the medical chart etc.
Participants whose treatment assignment has been unblinded by the investigator/delegate
and/or non-study treating physician should continue to be monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the
IVRS system to update drug disposition.  In the event that the emergency unblinding call
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency
unblinding in the event that this is required for participant safety.
Study treatment identification information is to be unmasked ONLY if necessary for the
welfare of the participant.  Every effort should be made not to unblind the participant unless
necessary.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date,
reason and person performing the unblinding) must be documented promptly, and the
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has
taken place, the principal investigator, site personnel, and Sponsor personnel may be
unblinded so that the appropriate follow-up medical care can be provided to the participant.
As noted, Part 1 is double-blind (operating under in-house blinding procedures) in which the
participant enrolled; the trial investigator, study center personnel, and the Sponsor are
blinded to which study drugs, MK-8591, DOR, 3TC, and MK-1439A, are received. In Part
2, DOR and MK-1439A will be provided as open-label supplies, the dose of MK-8591 will
continue to be blinded.  In Parts 3 and 4, all study medications will be provided and
dispensed as open-label supplies.  Matching placebos will no longer be provided/dispensed in
Parts 2 - 4.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or
instrument used for a clinical evaluation/test during a clinical study that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible.
 
 
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Documentation of equipment calibration must be retained as source documentation at the
study site.
Efficacy Assessments
The primary efficacy measurement is HIV-1 RNA.  Additional blood samples will be
collected as indicated in the SoA (Section 2) to explore single-copy HIV-1 RNA.  Additional
efficacy measurements include CD4+ T-cell counts and viral resistance testing.  Blood will
be collected to evaluate CD4+ T-cell counts and viral resistance as indicated in the SoA
(Section 2).
HIV-1 RNA
Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real
time polymerase chain reaction (PCR) assay with a lower limit of detection of 40 copies/mL. 
Exploratory measurements of HIV-1 RNA will be assessed at certain time points. The
single-copy HIV-1 RNA assay will only be performed at the visits specified in the SoA
(Section 2) when the HIV-RNA is below the lower limit of detection for the HIV-1 RNA
assay.
Management of Study Participants with Viremia
When viremia (HIV-1 RNA ≥50 copies/mL) is detected (Section 5.4.1.1.2), the investigator
should query the participant regarding adherence to study therapy, intercurrent illness, or
recent immunization. All cases of viremia must be confirmed, and the participant should
continue to take the full assigned dosage of study medication while awaiting confirmation.
Viremia Confirmation
Confirmation of viremia requires 2 consecutive plasma HIV-1 RNA results of ≥50 copies/mL
(Section 5.4.1.1.2) with the second sample collected at a “Viremia Confirmation” visit at
least 2 weeks but not more than 4 weeks from the date of the initial sample. This timeframe
may be extended if study medication is interrupted for 1 of the following circumstances:
 Intercurrent illness: redraw 2 to 4 weeks following resolution of the illness, during
which time the participant should continue to receive the assigned dosage of study
medication(s) without interruption;
 Immunization: redraw at least 4 weeks following any immunization, during which
time the participant should continue to receive the assigned dosage of study
medication(s) without interruption;
 Toxicity management, noncompliance, or other reason: redraw 2 to 4 weeks
following resuming the assigned dosage of study medication(s).
Participants With Clinically Significant Confirmed Viremia (≥200 copies/mL)
Study participants with confirmed HIV-1 RNA of ≥200 copies/mL will be assessed for
development of viral drug resistance (Section 9.2.4) and discontinuation from study
intervention (Section 8.1). Once it is determined that study intervention discontinuation is
 
 
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appropriate, Early Discontinuation and End of Treatment visit procedures should be
completed (Section 2.3 and Section 9.10.4) and the participant managed by the investigator
per local standard-of-care.
Participants With Low-Level Viremia (≥50 and 200 copies/mL)
Study participants with confirmed HIV-1 RNA of ≥50 and <200 copies/mL should continue
study medication and all regularly scheduled study visits during which HIV-1 RNA levels
will be monitored per the SoA (approximately every 3 months). Additional visits may be
conducted to monitor HIV-1 RNA levels more frequently than every 3 months, if
appropriate, after discussion with the Sponsor.
Investigators should use their clinical judgment regarding the most appropriate clinical
management of participants, if more stringent local guidelines apply, and may contact the
Sponsor’s Clinical Director to discuss questions on clinical management of individual
participants.
CD4+ T-cell Counts
CD4+ T-cell counts (absolute and percentage) will be performed at the central laboratory.
Viral Resistance Testing
Participants with HIV-1 RNA ≥200 copies/mL at any time during the study will be assessed
for development of viral drug resistance.
Blood samples will be collected for phenotypic and genotypic HIV-1 drug resistance testing
to determine resistance to MK-8591, DOR, 3TC, and TDF per the SoA (Section 2).  An extra
sample of blood is being collected at the screening visit, which may be used in the event the
first sample is not evaluable and needs to be repeated.  Resistance testing will be performed
by the central laboratory.
Adverse Events, Serious Adverse Events and Other Reportable Safety Events
The definitions of an adverse event (AE) or serious adverse event (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 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative).
The investigator, who is a qualified physician, and any designees are responsible for
detecting, assessing, documenting, and reporting events that meet the definition of an AE or
SAE as well as other reportable safety events. Investigators remain responsible for following
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
 
 
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Time Period and Frequency for Collecting AE, SAE and Other Reportable
Safety Event Information
All AEs, SAEs and other reportable safety events that occur after the consent form is signed
but before treatment allocation/randomization must be reported by the investigator if the
participant is receiving placebo run-in or other run-in treatment, if the event cause the
participant to be excluded from the trial, or is the result of a protocol-specified intervention,
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
From the time of treatment allocation/randomization through 42 days following cessation of
treatment, all AEs, SAEs and other reportable safety events must be reported by the
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the
time period specified in the previous paragraph must be reported immediately to the Sponsor
if the event is considered to be drug-related.
For infants born to participants who become pregnant while receiving study intervention and
consent to infant follow-up, SAEs occurring (in these infants) from the time of birth through
1-year of age must be reported by the investigator to the Sponsor within 24 hours of learning
of the event.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events
in former study participants. However, if the investigator learns of any SAE, including a
death, at any time after a participant has been discharged from the study, and he/she
considers the event to be reasonably related to the study treatment 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 timeframes as indicated in Table 3.
 
 
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Table 3 
Reporting Time Periods and Timeframes for Adverse Events and Other
Reportable Safety Events
Type of Event 
Reporting Time
Period:
Consent to
Randomization/
Allocation
Reporting Time
Period:
Randomization/
Allocation
through Protocol-
Specified Follow-
up Period
Reporting Time
Period:
After the Protocol
Specified Follow-
up Period
Timeframe to
Report Event
and Follow-up
Information to
SPONSOR:
Serious
Adverse Event
(SAE)
Report if: 
- due to protocol-
specified
intervention
- causes exclusion
- subject 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
Non-Serious
Adverse Event
(NSAE)
Report if: 
- due to protocol-
specified
intervention
- causes exclusion
- subject is
receiving placebo
run-in or other run-
in treatment
Report all
Not required 
Per data entry
guidelines
Overdose 
Report if: 
- receiving placebo
run-in or other run-
in medication
Report all
Not required
Within 5 days of
learning of event
Event of Clinical
Interest (require
regulatory
reporting)
Report if:
- due to
intervention
- causes exclusion
Report 
- Potential DILI
- Require
regulatory
reporting
Not required
Within 24 hours
of learning of
event
Event of Clinical
Interest (Do not
require regulatory
reporting)
Report if:
- due to
intervention
- causes exclusion
Report 
- non-DILI ECIs
and those not
requiring
regulatory
reporting
Not required
Within 5 days of
learning of event
Cancer
Report if: 
- due to
intervention
- causes exclusion
Report all
Not required 
Within 5 days of
learning of event
Pregnancy/
Lactation
Exposure
Report if: 
- due to
intervention
- causes exclusion
Report all
Previously reported
–Follow to
completion/terminat
ion; report outcome
Within 24 hours
of learning of
event
 
 
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Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable
safety events. Open-ended and non-leading verbal questioning of the participant is the
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be
followed until resolution, stabilization, until the event is otherwise explained, or the
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will
make every attempt to follow all non-serious AEs that occur in randomized participants for
outcome.  Further information on follow-up procedures is given in Appendix 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 treatment 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 treatment under clinical
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs
and investigators in accordance with all applicable global laws and regulations, i.e., per
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
 Investigator safety reports must be prepared for suspected unexpected serious adverse
reactions (SUSAR) according to local regulatory requirements and sponsor policy and
forwarded to investigators as necessary.
 An investigator who receives an investigator safety report describing a SAE or other
specific safety information (eg, summary or listing of SAE) from the sponsor will file it
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
This section is not applicable to the trial.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously
reported to the investigator or their designee) that occurs during the trial 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,
 
 
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blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as
serious events (Important Medical Events). If the pregnancy continues to term, the outcome
(health of infant) must also be reported.
For infants born to participants who become pregnant while receiving study intervention and
consent to infant follow-up, SAEs occurring (in these infants) from the time of birth through
1-year of age must be reported by the investigator to the Sponsor within 24 hours of learning
of the event.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include:
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X
the upper limit of normal and, at the same time, an alkaline phosphatase lab value
that is less than 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may
require an additional evaluation for an underlying etiology. The trial site guidance
for assessment and follow up of these criteria can be found in the Investigator Trial
File Binder (or equivalent).
Treatment of Overdose
In this trial, an overdose is any dose greater than 2×the protocol-specified dose(s) in a
calendar day of MK-8591, DOR, 3TC, MK-1439A, or MK-8591A.
No specific information is available on the treatment of overdose.
Decisions regarding dose interruptions will be made by the investigator in consultation with
the Merck Clinical Director or designee based on the clinical evaluation of the participant. 
No dose modification of MK-8591, DOR, 3TC, MK-1439A, or MK-8591A is allowed during
the trial (Section 7.2).
Safety
One of the primary endpoints of this trial is to evaluate the safety and tolerability of the
different doses of MK-8591 + DOR.  Details regarding specific safety
procedures/assessments to be performed in this trial are provided below.
Participants should be in a fasted state (at least 8 hours) for collection of the blood samples
for safety assessment at Day 1 and at Weeks 24, 36, 48, 72, 96, 120, 144, and 192.
The approximate blood volumes drawn/collected by assessment can be found in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
 
 
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Physical Examinations
The complete physical examination will be conducted as per institutional standard.  The full
physical examination will include examination of body systems (including, but not limited to,
general appearance, skin, neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, back,
lymph nodes, extremities, and nervous system).
The directed physical examination will be conducted as per institutional standard, sign- and
symptom-directed, and based on the participant’s condition and circumstances. The
investigator should note any changes in the participant’s condition (body systems) since the
last examination.  This does not preclude examination of any of the body systems as
clinically indicated.
Weight and height will be measured at the visits specified in SoA (Section 2).
Investigators should pay special attention to clinical signs related to previous serious
illnesses.
Vital Signs
Vital signs will include temperature, pulse, respiratory rate, and systolic and diastolic blood
pressure. The participant should be in a rested state for 10 minutes prior to measurement.
Any lying position during rest and measurement (eg, supine, semi-supine, semi-recumbent) is
acceptable.
Note:  Oral temperatures should be taken. If an oral temperature measurement is not
possible, a tympanic, rectal, or axillary temperature measurement may be taken and should
be recorded appropriately.
Electrocardiograms
Special care must be taken for proper lead placement by qualified personnel. Skin should be
clean and dry prior to lead placement.  Subjects may need to be shaved to ensure proper lead
placement.  Female participants may need to remove their bra. Participants should be in a
rested state for 10 minutes prior to measurement. Any lying position during rest and
measurement (eg, supine, semi-supine, semi-recumbent) is acceptable.
The correction formula to be used for the corrected QT interval is Fridericia.
Procedures for printing, archiving, and review of ECGs will be specified by the central
laboratory vendor.
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 must review the laboratory report, document this review, and record
any clinically relevant changes occurring during the study in the AE section of the
CRF. The laboratory reports must be filed with the source documents. Clinically
significant abnormal laboratory findings are those which are not associated with the
underlying disease, unless judged by the investigator to be more severe than expected
for the participant's condition.
 
 
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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 non-protocol 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 42 days after the last dose of study
treatment, 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.
DEXA Assessments
Decreases in BMD and lipodystrophy have been reported in HIV-1-infected patients taking
ART [AIDS info 2017], particularly with the use of certain NRTIs.  Lipodystrophy includes
the buildup of body fat and the loss of body fat.
An assessment of BMD as well as peripheral and visceral fat will be conducted by utilizing
DEXA scans per the SoA (Section 2) to assess if these changes are seen with the use of the
different doses of MK-8591 and considered in context of historical data for other agents. 
Only those participants who are confirmed eligible to be randomized will undergo total body
DEXA scans for BMD of the spine and hip as well as peripheral fat and trunk fat.  Dual-
energy x-ray absorptiometry images will be evaluated by a central imaging reader.
If a subject fractures the hip being examined during the study, no further DEXA scans of
either hip will be required.
Refer to the Site Imaging Manual for additional details regarding DEXA procedures,
including participant preparation instructions to be considered prior to DEXA imaging.
Infant Safety Follow-up Assessments
Infants, born to participants who become pregnant while receiving study intervention and
consent to infant follow-up, will have safety follow-up through approximately 1-year of age
as outlined in Table 4.  This infant safety follow-up data may be collected by phone call. 
Length, weight, and head circumference measurements will be collected at birth and at 1-
year of age. Infant SAEs, including congenital anomalies identifiable on physical
examination at birth or shortly after birth, will be collected as per Section 9.3.1.
 
 
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Table 4 
Infant Safety Follow-up: Data Collection Through 1-Year of Age
Study Period
Infant Safety Follow-up
Scheduled Day
At Birth
1-Year After Birth1
Data Collection Window
+90 days
+90 days
Administrative and Safety Procedures
Informed Consent (if applicable)2
X
Review Pregnancy Outcome3
X
Length
X
X
Weight
X
X
Head Circumference
X
X
Review Infant Serious Adverse Events4
X ----------------------------- X
1
If a participant withdraws from the study, data from 1-Year After Birth should be collected at the time of withdrawal.
2
Depending on applicable laws and regulations, a separate informed consent may be required (Section 9.1.1.3).
3
Collect and report pregnancy outcome (health of infant), per Section 9.3.6.
4
Collect SAEs, including any congenital anomalies, per Section 9.3.1.
Pharmacokinetics
Population PK samples will be collected from all participants as outlined in Table 5.  The
exact time the dose of study medication was taken prior to the sample collection will be
recorded on the appropriate eCRF.  The type of meal (i.e., no, light, medium, or full)
consumed 2 hours before or 2 hours after the dose of study medication, as per the sampling
time point outlined in Table 5, will also be recorded on the appropriate eCRF.  The type of
meal is defined as follows:
 No meal –the participant did not have a meal
 Light meal –the participant consumed a snack (less than 250 calories)
 Medium meal –the participant consumed a small meal (from 250 to 750 calories)
 Full meal –the participant consumed a large meal (greater than 750 calories)
 
 
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Table 5 
Timing for Collection of Population Pharmacokinetics Samples
Study Day/Week
Time Relative to Container “A” Dose
(MK-8591 or placebo)
Day 1
Sample to be collected predose
Week 4 
Sample to be collected predose and within 0.5 and 2 hours postdose*
Week 8 
Sample to be collected predose and within 0.5 and 2 hours postdose*
Week 12
Sample to be collected irrespective of time of dose (time of last dose and
time of PK sample collection must be documented)
Week 16
Sample to be collected irrespective of time of dose (time of last dose and
time of PK sample collection must be documented)
Week 48
Sample to be collected irrespective of time of dose (time of last dose and
time of PK sample collection must be documented)
PK = pharmacokinetic
* For participants who take their dose during the day, samples should be collected predose and postdose.  For participants
who take their medication in the evening, only a post-dose sample should be collected the following day irrespective of
time of dose (time of last dose and time of PK sample collection must be documented).
Venous blood samples will be collected for measurement of MK-8591.  Sample collection,
storage and shipment instructions for samples will be provided in the operations/laboratory
manual.
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
 DNA for Future Biomedical Research
Refer to Section 9.8 for further description of the Future Biomedical Research sample.
 
 
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Biomarkers
Laboratory Markers Associated with Clinical Outcome
Interleukin-6, D-dimer, and soluble CD163 have been shown to be predictive of the risk for
both short- and long-term mortality [Baker, J. V., et al 2011] [Knudsen, T. B., et al 2016]
[Wang, H., et al 2016].  The causes of persistent inflammation and thrombotic activity in
HIV-1-infected patients remain the subject of debate and ongoing research.  Blood samples
will be collected to evaluate the inflammatory and thrombotic response as measured by the
following laboratory markers as indicated in the SoA (Section 2):
 Interleukin-6
 D-dimer
 Soluble CD163
Decreases in renal function have been noted with the use of certain NRTIs.  Urine samples
will be collected to evaluate renal function as measured by the following urinary analytes and
calculations:
 Albumin
 Protein
 Beta-2-microglobulin/creatinine ratio
 Retinol binding protein/creatinine ratio
Planned Genetic Analysis Sample Collection
The “Blood for Genetic Analysis” sample should be drawn for planned analysis of the
association between genetic variants in DNA and drug response. This sample will not be
collected at the site if there is either a local law or regulation prohibiting collection, or if the
IRB/IEC does not approve the collection of the sample for these purposes. If the sample is
collected, leftover extracted DNA will be stored for FBR if the participant signs the informed
consent for FBR. If the planned genetic analysis is not approved, but FBR is approved and
informed consent for FBR is given, this sample will be collected for the purpose of FBR.
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples
will be provided in the operations/laboratory manual.
Visit Requirements
Visit requirements are outlined in Section 2 –Schedule of Activities (SoA).  Specific
procedure-related details are provided above in Section 9 –Study Assessments and
Procedures.
Switch from Part 1 (3-drug Dose Ranging) to Part 2
After 24 weeks of dosing in Part 1, participants who are virologically suppressed (i.e., HIV-1
RNA <50 copies/mL) at the Week 20 visit and have not met any viral failure criteria
(Section 5.4.1.1.1) will switch to Part 2 of the trial at Week 24 after other visit procedures
 
 
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have been completed. Participants who have met the viral failure criteria (Section 5.4.1.1.1)
will not be eligible to continue to Part 2 and should be discontinued from treatment and
complete the early discontinuation and end of trial phone and site follow-up visits. In Part 2,
the 3TC and/or matching placebos will be dropped from the regimen and participants will be
unblinded as to whether they are receiving 1 of the MK-8591 doses or the control,
MK-1439A. The doses of MK-8591 will remain blinded, but the DOR and MK-1439A will
be provided in an open-label fashion.  Upon confirmation of eligibility, site personnel will
contact the IVRS/IWRS in order to dispense the supplies.
Participants who have HIV-1 RNA levels ≥50 copies/mL at Week 20 will continue to receive
the 3-drug regimen (Part 1) until the HIV-1 RNA is <50 copies/mL and they have not met
any of the viral failure criteria (Section 5.4.1.1.1).  The participant will then switch to the 2-
drug regimen or open-label MK-1439A in Part 2 of the trial at the next visit after all other
visit procedures have been completed as outlined in Table 6.
Table 6 
Guidelines for Switching to Part 2 Beginning at the Week 24 Visit
Treatment
Week
(Visit)
Prior
Treatment
Week
(Visit)
HIV-1 RNA Result from
Prior Treatment Week
Action
Week 24
(Visit 9)
Week 20
(Visit 8)
<50 copies/mL 
Switch to Part 2 at Week 24
≥50 copies/mL 
Continue with 3-drug regimen
Week 28
(Visit 10)
Week 24
(Visit 9)
<50 copies/mL 
Switch to Part 2 at Week 28
≥50 and <200 copies/mL1 
Continue with 3-drug regimen
Week 32
(Visit 11)
Week 28
(Visit 10)
<50 copies/mL 
Switch to Part 2 at Week 32
≥50 and <200 copies/mL1 
Continue with 3-drug regimen
Week 36
(Visit 12)
Week 32
(Visit 11)
<50 copies/mL 
Switch to Part 2 at Week 36
≥50 and <200 copies/mL1 
Continue with 3-drug regimen
Week 40
(Visit 13)
Week 36
(Visit 12)
<50 copies/mL 
Switch to Part 2 at Week 40
≥50 and <200 copies/mL1 
Continue with 3-drug regimen
Week 44
(Visit 14)
Week 40
(Visit 13)
<50 copies/mL 
Switch to Part 2 at Week 44
≥50 and <200 copies/mL1 
Continue with 3-drug regimen
Week 48
(Visit 15)
Week 44
(Visit 14)
<50 copies/mL 
Switch to Part 2 at Week 48
≥50 and <200 copies/mL1 
Continue with 3-drug regimen
Week 48
(Visit 15)
<50 copies/mL 
Switch to Part 2 at Week 52
≥50 copies/mL 
Conduct Viral Failure
Confirmation visit >7 days and
≤14 days from Week 48:
 
Switch to Part 2 at Week 52
if <50 copies/mL, or
 
Discontinue treatment if ≥50
copies/mL
HIV-1 = human immunodeficiency virus type 1; RNA = ribonucleic acid
1  If the HIV-1 RNA result obtained at the Week 24 visit through the Week 44 visit is ≥200 copies/mL, a viral
failure confirmation visit is required to be conducted as noted in Section 9.10.4 and Section 2.  If HIV-1 RNA
is confirmed ≥200 copies/mL, the participant should be discontinued from treatment and complete the early
discontinuation and end oftrial phone and site follow-up visits (Section 5.4.1.1.1).
 
 
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For participants who have continued to receive study medication in Part 1 through Week 48,
the HIV-1 RNA results from Week 48 should be reviewed immediately upon receipt.  If the
Week 48 HIV-1 RNA results are ≥50 copies/mL, per Section 2 and Section 5.4.1.1.1, the
participant should continue the Part 1 regimen and a virologic failure confirmation visit
should be conducted within 7 to 14 days (e.g., no greater than Week 50).  If the HIV-1 results
from the viral failure confirmation visit are <50 copies/mL, the participant should return at
Week 52 and be switched to Part 2.  If the results from the viral failure confirmation visit are
≥50 copies/mL, the participant may not be switched and should be discontinued from
treatment and complete the early discontinuation and end of trial phone and site follow up
visits (Section 8.1).
In addition to the routine sample collections noted in the SoA (Section 2.1), blood should be
collected for a hepatitis screen (HBV surface antigen and HCV antibody/HCV RNA per
Appendix 2) beginning at Week 20.  This screen will be performed only for subjects with
HIV-1 RNA <50 copies/mL (those participants eligible to switch to Part 2).  The hepatitis
screen blood sample should continue to be collected at the Treatment Week Visits until a
participant is transitioned from Part 1 to Part 2 or discontinued.  If the results indicate that the
participant is positive for HBV infection, the participant should be discontinued from study
treatment (Section 8.1, Section 2.3).  If the participant is positive for HCV and treatment for
HCV is required, see Section 8.1 regarding discontinuation of study treatment.
Transition from Part 2 to Part 3
Once the MK-8591 dose selection has occurred and has been communicated by the Sponsor,
participants who are receiving MK-8591 will be switched to the selected dose (provided as
open-label supplies) at the next visit.  Participants in the control group will continue to
receive open-label MK-1439A.  Site personnel will contact the IVR/IWR in order to dispense
the open-label supplies as well as conduct all other assessments noted for the visit in the SoA
(Section 2).
Transition from Part 3 to Part 4
Participants will be reconsented on or before the scheduled Week 144 visit, prior to
performing any Part 4 procedures as per the SoA (Section 2). All participants (those
receiving the selected dose of MK-8591 in combination with DOR [Groups 1-3] or MK-
1439A in the control group [Group 4]) who consent to continue in Part 4 will be switched to
MK-8591A (provided as open-label supplies) at the Week 144 visit. Site personnel will
contact the IVRS/IWRS in order to dispense the open-label supplies as well as conduct all
other assessments noted for the visit in the SoA (Section 2).
Participants who received MK-1439A in the control group (Group 4) and do not consent to
continue in Part 4 will complete Week 144 and subsequent Day 42 post-study visit. These
participants will be converted to a locally approved antiretroviral regimen at the discretion of
the investigator.
 
 
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Viremia Confirmation Visit
Prior to Amendment 03, if a participant met the criteria for viral failure (Section 5.4.1.1.1),
the viral failure confirmation visit was to be conducted within 7 to 14 days (cannot be
conducted <7 days) as outlined in the SoA (Section 2).
As of Amendment 03, if a participant has a viral load of ≥50 copies/mL at any time during
the study, a Viremia Confirmation visit must be conducted within 2 to 4 weeks of the initial
HIV-1 viremia (Sections 2.3 and 5.4.1.1.2).
If a scheduled visit is to occur within the timeframe that a participant would return for a
viremia confirmation visit, the assessments for the scheduled visit should be conducted and
the viral resistance sample from the viremia confirmation visit must be collected.  Refer to
Section 8.1 for the discontinuation of study treatment criteria.
End of Treatment Follow-up Visit
Participants in all Groups who discontinue study medication at any time prior to the
Week 192 visit will have an End of Treatment safety follow-up visit in-clinic approximately
42 days after the last dose of study intervention. Assessments for this visit are outlined in
Section 2.3.
10. Statistical Analysis Plan
This section outlines the statistical analysis strategy and procedures for the trial.  Changes to
analyses made after the protocol has been finalized will be documented in a supplemental
Statistical Analysis Plan (sSAP) and referenced in the Clinical Study Report (CSR) for the
study.  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan
is provided in Sections 10.2 to 10.12.
Study Design Overview  
A Phase 2B, Randomized, Double-Blind, Active-Comparator-Controlled,
Dose-Ranging Clinical Trial to Evaluate the Safety, Tolerability,
Antiretroviral Activity, and Pharmacokinetics of MK-8591 Given in
Combination with Doravirine (DOR) and Lamivudine (3TC) in HIV-1-
Infected Treatment-Naïve Adults
 
 
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Treatment Assignment 
In Part 1, ~ 120 participants will be randomized in a 1:1:1:1 ratio to receive
1 of 3 doses of MK-8591 (0.25 mg, 0.75 mg, or 2.25 mg) given in
combination with DOR and 3TC (and placebo for MK-1439A), or MK-
1439A (and placebo for MK-8591 + placebo for DOR + placebo for 3TC). 
Participants will be stratified by screening HIV-1 RNA value (≤100,000 or
>100,000 copies/mL).
After at least 24 weeks in Part 1, participants who were on 1 of the MK-
8591 + DOR + 3TC treatment groups and are virologically suppressed
(<50 copies/mL) will be switched to the 2-drug regimen of MK-8591 +
DOR, where MK-8591 will be at the same dose to which the participant
was randomized.  Participants who were on MK-1439A will remain on this
same regimen, but MK-1439A will be provided in an open-label fashion in
Part 2.  The participants and investigators will remain blinded to the dose
of MK-8591.  Sponsor personnel will be unblinded to all treatment
assignments at Week 24 to assess the safety and efficacy objectives for the
3-drug regimen.
When participants have reached Week 48 in the study, regardless of length
of time on Part 2, analyses for dose selection of MK-8591 will be
conducted by the Sponsor.  Once a dose is selected, all participants on the
MK-8591 treatment groups will continue in the trial (Part 3, open-label) on
the selected dose of MK-8591 + DOR, while participants on MK-1439A
will remain on this regimen.  In Part 4, all participants will be switched to
open-label MK-8591A.
Analysis Populations
Efficacy:  Treatment Full Analysis Set (FAS)
Safety:  All Participants as Treated (APaT)
Primary Endpoint(s)
1. Proportion of participants with HIV-1 RNA <50 copies/mL at Week 24
and at Week 48
2. Number of participants experiencing AEs, and discontinuing study drug
due to AEs
Key Secondary Endpoints 
1. Proportion of participants on the selected dose of MK-8591 with HIV-1
RNA <50 copies/mL 24 and 48 weeks after switching to the 2-drug
regimen
2. Change from baseline in CD4+ T-cell count at Week 24, Week 48,
Week 96, and Week 144
Statistical Methods for Key
Efficacy/Immunogenicity/
Pharmacokinetic Analyses
The primary objective will be assessed using 2-sided 95% CIs for the
difference between treatment groups in the proportion of participants (MK-
8591 treatment group minus MK-1439A) achieving HIV-1 RNA <50
copies/mL at Week 24 and at Week 48.  At Week 48, the participants in the
MK-8591 treatment groups could have varying durations on the 3-drug
regimen (MK-8591 + DOR + 3TC) and on the 2-drug regimen (MK-8591
+ DOR), but it is expected that the majority will enter Part 2 at Week 24. 
The CIs will be based on stratum-adjusted Mantel-Haenszel method
[Mantel, N. and Haenszel, W. 1959] with the difference weighted by the
harmonic mean of the sample size per treatment group for each stratum.
Statistical Methods for Key
Safety Analyses
Point estimates and 95% CIs will be provided using the Miettinen and
Nurminen method [Miettinen, O. and Nurminen, M. 1985] for the
difference between treatment groups in the proportion of participants (MK-
8591 treatment group minus MK-1439A) in the broad AE categories
consisting of the percentage of participants with any AE, with a drug-
related AE, with an SAE, with an AE that is both drug-related and serious,
and who discontinued due to an AE. 
 
 
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Interim Analyses
When all participants have reached Week 24 or have discontinued prior to
this, analyses will be performed by the Sponsor to assess safety and efficacy
objectives for the 3-drug regimen.  When all participants have reached Week
48 or have discontinued prior to this, Sponsor personnel will conduct dose
selection analyses.  Throughout the trial, an external unblinded statistician
will perform analyses for periodic safety reviews by an eDMC, as well as ad
hoc reviews as needed.  Details are provided in Section 10.7.
 
Week 24 interim analysis (to be conducted by the Sponsor and results
shared with the eDMC) to assess the safety and efficacy objectives for
the 3-drug regimen
 
Week 48 dose selection analyses (to be conducted by the Sponsor and
results shared with the eDMC)
 
Week 96 interim analysis to be conducted by the Sponsor and results
shared with the eDMC
 
Periodic safety reviews (eDMC reviews) to be performed every 4 to 6
months or as specified in the DMC charter
 
Participants who meet the protocol-defined virologic failure criteria in
Part 1 (Section 5.4.1.1.1) will be communicated to the unblinded
statistician. If 3 or more participants (10% or more out of 30 expected
participants) in any treatment group are observed to have virologic
failure by the unblinded statistician, this will be reported to the
eDMC. The eDMC may recommend dropping a treatment group on
the basis of this criterion.
Multiplicity
No multiplicity adjustment is planned in this Phase 2B trial. 
Sample Size and Power 
The planned sample size is 120 participants.  With 30 participants in each
treatment group, the trial has 80% power to obtain a 2-sided 95% CI for the
treatment difference in the proportions of participants achieving HIV-1
RNA <50 copies/mL that would exclude a ≥33.0% treatment difference
when the true proportions are, in fact, equal to 85% in each treatment
group. This power statement applies to the 3 treatment differences
corresponding to the difference between each specific MK-8591 treatment
group and the MK-1439A control group, at both Week 24 and Week 48. 
Detailed information is in Section 10.9.1.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this trial will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
Part 1 of this trial will be conducted as a double-blind trial under in-house blinding
procedures.  Participants on the MK-8591 treatment groups who meet criteria for moving
into Part 2 of the trial after at least 24 weeks in Part 1 will switch to the 2-drug regimen (MK-
8591 + DOR), where the dose of MK-8591 will be at the same dose to which the participant
was randomized in Part 1. The participants and investigators will remain blinded to the dose
of MK-8591.  Participants randomized to MK-1439A in Part 1 who meet criteria for moving
into Part 2 will remain on MK-1439A, which will now be provided in an open-label fashion. 
When all participants have reached Week 24 or discontinued prior to this, Sponsor personnel
will be unblinded to treatment assignment, including the dose of MK-8591, to assess safety
 
 
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and efficacy objectives for the 3-drug regimen. However, the participants and investigators
will remain blinded with respect to the dose of MK-8591 in Part 2.
When all participants have reached Week 48 or discontinued prior to this, analyses will be
performed by Sponsor personnel to select a dose for MK-8591.  Following dose selection,
participants previously on 1 of the MK-8591 dose groups will be switched to the selected
dose of MK-8591 + DOR (Part 3).  In Part 3, all study treatment will be provided in an open-
label fashion and participants will be given either open-label MK-8591 at the selected dose
and DOR or MK-1439A at their next scheduled visit.
The detailed results of the Week 24, Week 48, and Week 96 analyses will be shared with the
eDMC; the selected MK-8591 dose will be communicated to the sites.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for
study treatment assignment.  Randomization will be implemented in an IVRS/IWRS.
Interim analyses are described in Section 10.7.  Treatment-level results of periodic safety
analyses to be reviewed by the eDMC will be provided by an external unblinded statistician. 
Moreover, the unblinded statistician will be informed of participants who meet the protocol-
defined virologic failure criteria in Part 1 (Section 5.4.1.1.1), and if 3 or more participants in
any treatment group are observed to have virologic failure by the unblinded statistician, this
will be reported to the eDMC.  The eDMC may make recommendations for discontinuation
of the trial or for modifications to the trial to the EOC of the Sponsor.  If the eDMC
recommends modifications to the design of the protocol or discontinuation of the trial, the
EOC may be unblinded (if prior to unblinding) to results at the treatment level in order to act
on these recommendations.  Limited additional Sponsor personnel may also be unblinded to
the treatment level results assessed by the eDMC, if required, in order to act on the
recommendations of the eDMC.  The extent to which individuals are unblinded with respect
to results of the periodic safety analyses will be documented by the unblinded statistician.
Additional logistical details will be provided in the DMC Charter.  Key aspects of the interim
analyses are described in Section 10.7.
The unblinded statistician will not be involved in any discussions regarding modifications to
the protocol, statistical methods, identification of protocol deviations, or data validation
efforts.
Hypotheses/Estimation
There are no hypotheses to be tested in this trial.  Objectives of the trial are stated in
Section 4.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and between-treatment
differences are listed below.  Details in this section apply to all Parts in the trial.
 
 
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Efficacy/Pharmacokinetic Endpoints
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 4.
Proportions of Participants with Virologic Responses
A real time PCR assay with a reliable lower limit of quantification of 40 copies/mL will be
used to measure the HIV-1 RNA level in blood samples obtained at each visit.  The primary
objectives will be assessed based upon the proportions of participants achieving HIV-1 RNA
<50 copies/mL at Week 24 and at Week 48.
At the Week 48 time point, it is expected that the majority ofparticipants will have had 24
weeks of treatment on the 3-drug regimen and 24 weeks of treatment on the 2-drug regimen. 
However, it is possible that some participants may take longer to meet the criterion to switch
to the 2-drug regimen and may have received treatment for more than 24 weeks on the 3-drug
regimen and less than 24 weeks on the 2-drug regimen at Week 48.  It is also possible that
some participants may have received treatment on the 3-drug regimen for all 48 weeks. 
For the secondary objective that will be assessed on the basis of the proportion of participants
achieving HIV-1 RNA <50 copies/mL 24 and 48 weeks after switching to the 2-drug
regimen, the participants may have varying durations of time in the trial.  It is expected that
the majority of the participants will switch to Part 2 at Week 24, so 24 weeks after the switch
will be Week 48.  However, some participants may switch as late as Week 48, so 24 weeks
after the switch could be as late as Week 72 in terms of time in the trial.  Likewise, 48 weeks
after switching is expected to be Week 72 for most participants but could be as late as Week
96 for some participants.
Change from Baseline in CD4+ T-cell Count
Change from baseline in CD4+ T-cell count will be estimated at each time point at which
CD4+ T-cell count is collected, with a key interest at Week 24 and Week 48.
For the calculations of change from baseline, baseline measurements are defined as the
Day 1 value for each participant.  In the rare event when data for this visit are missing, the
value obtained at the most recent screening visit will be used as baseline.  This rule will also
be applied to define the baseline measurements for other laboratory tests.
Time to Loss Of Virologic Response (TLOVR)
For participants who achieve HIV-1 RNA <50 copies/mL and subsequently have 2
consecutive HIV-1 RNA values (measured at least 1 week apart) ≥50 copies/mL, TLOVR is
the time between Day 1 and the date of the first of the 2 consecutive HIV-1 RNA values ≥50
copies/mL.  For participants who achieve and sustain HIV-1 RNA <50 copies/mL, TLOVR
is censored at the time of the last available measurement.  For participants who do not
achieve HIV-1 RNA values <50 copies/mL, TLOVR is 0 weeks.
 
 
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Protocol-defined Virologic Failure (PDVF) (prior to Amendment 03) and Clinically
Significant Confirmed Viremia (as of Amendment 03)
Participants with PDVF as defined in Section 5.4.1.1.1 and with clinically significant
confirmed viremia as defined in Section 5.4.1.1.2 will be identified and summarized for each
treatment group.
Resistance
Participants with PDVF (prior to Amendment 03, Section 5.4.1.1.1), participants with
clinically significant confirmed viremia (as of Amendment 03, Section 5.4.1.1.2), and those
who discontinue for any reason, who have blood samples available and potentially
amplifiable (HIV-1 RNA 200 copies/mL) for resistance testing, will be assessed for
resistance to study drugs.  Resistance data from these participants will be summarized.
Pharmacokinetic Endpoints
A population PK model will be developed utilizing the sparse PK data and PK data from
Phase 2 studies in order to assess individual exposure to MK-8591 (AUC, Cmax, and C24, if
feasible) and to predict MK-8591 triphosphate concentrations in PBMCs.
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Adverse Events
The following AEs will be summarized:  1) participants with at least 1 AE; 2) participants
with at least 1 drug-related AE; 3) participants with at least 1 SAE; 4) participants with at
least 1 serious and drug-related AE; and 5) participants who discontinued due to an AE.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory tests, participants must have both a baseline and post-
randomization on-treatment measurement to be included.  Participants’ laboratory values
(based on their most abnormal laboratory test values, in the direction of interest, while on
study treatment) will be classified as to whether or not they fall outside of the pre-defined
limit of change (PDLC) and are worse in grade (i.e., more abnormal in the direction of
interest) than at baseline.  The criteria are adapted from DAIDS Table for Grading the
Severity of Adult and Pediatric Adverse Events, November 2014, Version 2.0 (Appendix
2A).  A listing of the participants who meet the criteria will also be provided.
Analysis Populations
Details in this section apply across all Parts of the trial.
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis
of efficacy data in this trial.  The FAS population consists of all randomized participants
who:
 Receive at least 1 dose of study treatment
 
 
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 Have baseline data for those analyses that require baseline data
Participants will be included in the treatment group to which they are randomized for the
analyses of efficacy data using the FAS population.  Details on the approach to handling
missing data are provided in Section 10.6.
Safety Analysis Population
The All Participants as Treated (APaT) population will be used for the analysis of safety data
in this trial.  The APaT population consists of all randomized participants who received at
least 1 dose of study treatment. Participants will be included in the treatment group
corresponding to the study treatment they actually received for the analysis of safety data
using the APaT population.  For most participants, this will be the treatment group to which
they are randomized.  Participants who take incorrect study treatment for the entire treatment
period will be included in the treatment group corresponding to the study treatment actually
received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of
study treatment is required for inclusion in the analysis of each specific parameter.  To assess
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in
Section 10.6.
Statistical Methods
This trial will use an estimation approach to provide data on antiviral activity and general
tolerability of the MK-8591 treatment groups.
Results from Part 1 will be used to determine if a participant meets the criterion (virologic
suppression) to enter Part 2 of the trial.  If the participant was on 1 of the MK-8591 treatment
groups and enters Part 2, the participant will be switched to a 2-drug regimen. Participants
on MK-1439A will remain on this regimen in Part 2 but will be on open-label medication. 
When all participants have reached Week 24 or have discontinued prior to this, Sponsor
personnel will be unblinded to treatment assignment to assess safety and efficacy objectives
for the 3-drug regimen.
When all participants have reached Week 48 or discontinued prior to this, the Sponsor will
perform analyses to select a dose of MK-8591.  Participants randomized to the other doses of
MK-8591 will be switched to the selected dose of MK-8591 + DOR following dose selection
in Part 3.  Participants in the MK-1439A group will remain in that regimen.  In Part 4, all
participants will be switched to open-label MK-8591A.
Statistical inference for safety analyses are described in Section 10.6.2.  Nominal p-values
may be computed but should be interpreted with caution due to potential issues of
multiplicity, sample size, etc.  Unless otherwise stated, all statistical assessments will be
conducted at the α=0.05 (2-sided) level.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary
objectives.  Methods related to exploratory objectives will be described in the sSAP.
 
 
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Time Window
Table 7 lists the definition of time windows and the target relative day for the scheduled
visits for the trial that will be used for all analyses by time point. The measurement closest to
the target date within a window will be used for analyses at a specific time point.  Results
from additional time points beyond Week 96 may be summarized, and day-range rules will
follow the same pattern where the ranges start and end at the mid-points between target days.
Table 7 
Definitions of Study Time Points
Treatment Phase 
Treatment Period
Visit 
Day-Range Rules 
Target Daya
Pretreatment 
Baseline
Day1 
≤1 
1
Treatment
Week 2 
≥2 and ≤21 
15
Double-blind with in-
house blinding to dose
of MK-8591
Week 4 
≥22 and ≤42 
29
Week 8 
≥43 and ≤70 
57
Week 12 
≥71 and ≤98 
85
Week 16 
≥99 and ≤126 
113
Week 20 
≥127 and ≤154 
141
Week 24 
≥155 and ≤182 
169
Site Blind to MK-8591
dose, MK-1439A open-
label, and without in-
house blinding to dose
of MK-8591b
Week 28 
≥183 and ≤210 
197
Week 32 
≥211 and ≤238 
225
Week 36 
≥239 and ≤266 
253
Week 40 
≥267 and ≤294 
281
Week 44 
≥295 and ≤322 
309
Week 48 
≥323 and ≤350 
337
Week 52 
≥351 and ≤406 
365
Week 60 
≥407 and ≤462 
421
Open-labelc
Week 72 
≥463 and ≤546 
505
Week 84 
≥547 and ≤630 
589
Week 96 
≥631 and ≤714 
673
Week 108 
≥715 and ≤798 
757
Week 120 
≥799 and ≤882 
841
Week 132 
≥883 and ≤966 
925
Week 144 
≥967 and ≤1022 
1009
MK-8591A FDCd
Week 148 
≥1023 and ≤1064 
1037
Week 156 
≥1065 and ≤1134  
1093
Week 168 
≥1135 and ≤1218 
1177
Week 180 
≥1219 and ≤1302 
1261
Week 192 
≥1303 and ≤1351 
1345
DOR=doravirine; FDC=fixed-dose combination.
a. Relative days and target days are counted from the first day of study medication.
b. After entering Part 2, participants will be switched to 2-drug MK-8591 + DOR maintenance (dose of MK-8591
blinded) or control (MK-1439A) provided in an open-label fashion.
c. After MK-8591 dose selection, participants will be switched to the selected dose (open-label) at their next scheduled
visit which may occur at different time points during this time period.
d MK-8591A administered during open-label dosing in Part 4 of the trial.
 
 
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Missing Values
There are 3 types of missing values:
 Intermittent missing values due to a missed or skipped visit or due to an inadequate
sample;
 Non-intermittent missing values due to premature discontinuations because of
treatment-related reasons such as, “adverse event” (regardless of relationship to study
treatment), and “withdrew based on HIV-1 RNA results”;
 Non-intermittent missing values due to premature discontinuations because of other
reasons which are not related to treatment such as loss to follow-up, protocol
violation, participant withdrew consent, etc.
Two approaches will be used to handle missing values (Table 8). The primary approach for
the analysis of the proportion of participants achieving HIV-1 RNA <50 copies/mL is the
Non-Completer=Failure (NC=F) approach as defined by the FDA “snapshot” approach
[Food and Drug Administration 2013].  Under this approach, only those participants who 1)
are on study assigned treatment; 2) have HIV-1 RNA measurement(s) within the time
window specified in Table 7; and 3) have the measurement closest to the target date of the
time point <50 copies/mL, can be classified as virologic success at that time point.  The other
participants, either with HIV-1 RNA measurement of ≥50 copies/mL or no virologic data
within the time window due to intermittent missing or premature discontinuation regardless
of reasons, will be considered as treatment failures in the analyses of the proportion of
participants achieving HIV-1 RNA <50 copies/mL at that time point.
A second approach, the Observed Failure (OF) approach will be performed as a sensitivity
analysis for the proportion of participants achieving HIV-1 RNA<50 copies/mL.  Under this
approach, participants with non-intermittent missing data who prematurely discontinued
assigned treatment due to lack of efficacy are considered as failures at time points thereafter. 
Participants with other reasons for missing data will be excluded from the analyses.
These approaches will also be used for the secondary analyses ofthe proportion of
participants achieving HIV-1 RNA <50 copies/mL 24 and 48 weeks after switching to the 2-
drug regimen.  Participants who were discontinued for virologic failure and did not switch to
the 2-drug regimen will be considered treatment failures in these analyses.  Moreover, to
assess the continued viral suppression of participants who were able to switch to the 2-drug
regimen, separate analyses will also be conducted at these time points only on participants
who were able to be switched.  Participants who were not eligible to be switched would not
be included in these additional analyses.
 
 
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Table 8 
Summary of the Two Approaches to Handle Missing Values
Approaches
Intermittent
Missing
Non-intermittentMissing Not Related
to Treatment
Non-intermittentMissing
Related to Treatment
Success at Study
Therapy
Discontinuation
Failure at Study
Therapy
Discontinuation
Study Therapy
Discontinuation Due
to
Clinical/Laboratory
Adverse event
Study Therapy
Discontinuation
Due to Lack of
Efficacy
OF
Excluded  
Excluded
Failures
Excluded
Failures
NC=F
Failures 
Failures
Failures
Failures
Failures
NC=F = Non-Completer=Failure; OF = Observed Failure
Proportion of Participants Achieving HIV-1 RNA <50 copies/mL
In this estimation study, the treatment difference in the proportion of participants achieving
HIV-1 RNA <50 copies/mL (MK-8591 treatment group minus MK-1439A) and the
associated 2-sided 95% CIs will be calculated using the stratum-adjusted Mantel-Haenszel
method with the difference weighted by the harmonic mean of the sample size per treatment
group for each stratum.  These will be provided for each dose of MK-8591, and for each time
point of interest, with primary interest in Week 24 and Week 48.
The NC=F  approach  as defined by FDA “snapshot” approach  will be used as the primary
approach to analysis with respect to the proportion ofparticipants with virologic response
(HIV-1 RNA <50 copies/mL) [Food and Drug Administration 2013].  All participants with
missing data will be treated as failures regardless of the reason.
To provide a full picture ofvirologic outcome at a time point, participants who are not
classified as virologic success will be further categorized as virologic failure (HIV-1 RNA
≥50 copies/mL) or as having no virologic data in the time window with reasons of 1)
discontinued trial due to an AE, 2) discontinued trial for other reasons (includes withdraw
consent, loss to follow-up, moved, etc.), or 3) on trial but missing data in window. The full
categorization of virologic outcome at each time point of interest will be summarized by
treatment group.
A sensitivity analysis will be performed using the OF  approach  under which participants
with non-intermittent missing data who prematurely  discontinued assigned treatment due
to lack  of efficacy  are considered as failures at time points thereafter.
For the secondary endpoints of the proportion of participants achieving HIV-1 RNA <50
copies/mL 24 and 48 weeks after switching to the 2-drug regimen, results of participants
from all 4 treatment groups will be reported on the basis of their original randomized groups,
but the focus for the MK-8591 dose groups will be on participants who were on the selected
dose throughout the trial.  Since most participants are expected to switch to the 2-drug
regimen at Week 24, it is anticipated that most participants will be at Week 48 and Week 72
in the trial when they reach 24 and 48 weeks in the 2-drug regimen, respectively.  However,
some participants may have switched after Week 24, and will be in the trial longer than
others when they reach 24 and 48 weeks in the 2-drug regimen. 
 
 
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Change from Baseline in CD4+ T-cell Count
Change from baseline in CD4+ T-cell count will be summarized by treatment group at each
time point at which CD4+ T-cell count is collected, with a key interest at Week 48.  The
treatment difference in changes from baseline in CD4+ T-cell count at each time point will
be estimated (MK-8591 treatment group minus MK-1439A).  However, these estimates will
not be evaluated based on an absolute criterion for similarity.  The clinical interpretation of
the treatment difference is dependent upon the absolute value at baseline, and the magnitude
and direction of the changes in CD4+ T-cell counts seen in each treatment group.
The OF approach will be used for the calculations of change from baseline in CD4+ T-cell
count.  Under this approach, baseline values will be carried forward for participants who
discontinue due to lack of efficacy.
Table 9 summarizes the key efficacy analyses of the trial.  The strategy to address
multiplicity issues with regard to multiple treatment comparisons, multiple efficacy
endpoints, multiple time points, and interim analyses is described in Section 10.7 and
Section 10.8.
Table 9 
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs.
Supportive
Approach 
Statistical Method
Analysis
Population
Missing Data
Approach
Primary:
Proportion of participants
with HIV-1 RNA <50
copies/mL at Week 24 and
at Week 48
P
Stratum-adjusted
Mantel-Haenszela 
FAS  
NC=F
Proportion of participants
with HIV-1 RNA <50
copies/mL at Week 24 and
at Week 48
S
Stratum-adjusted
Mantel-Haenszela 
FAS  
OF
Secondary:
Proportion of participants
with HIV-1 RNA <50
copies/mL 24 and 48 weeks
after starting Part 2
P
Stratum-adjusted
Mantel-Haenszela 
FAS  
NC=F
Change from baseline in
CD4+ T-cell counts at
Week 24,Week 48, Week
96, Week 144, Week 168
and Week 192
P
Descriptive
statisticsb
FAS  
OF assuming
baseline carried
forward
CI=confidence interval; FAS=Full Analysis Set; HIV-1=human immunodeficiency virus Type 1
NC=F=Non-Completer=Failure; OF=Observed Failure; P=Primary approach; RNA=ribonucleic acid;
S=Secondary approach; TLOVR=time to loss of virologic response
a.
Stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of the
sample size per treatment group for each stratum.
b
Mean and two-sided 95% CI.
 
 
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Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach (Table 10).  The tiers differ with
respect to the analyses that will be performed.  Safety parameters or AEs of special interest
that are identified a priori as “Tier 1” safety endpoints will be subject to inferential testing for
statistical significance with p-values and 2-sided 95% CIs provided for between-group
comparisons.  Other safety parameters will be considered Tier 2 or Tier 3.  Tier 2 parameters
will be assessed using point estimates and 95% CIs for between-group comparisons; only
point estimates will be provided by treatment group for Tier 3 safety parameters.
There are no a priori clinical events of concern that have been identified; therefore, there are
no events defined as Tier 1 in this trial.  The broad categories consisting of the percentage of
participants with any AE, with a drug-related AE, with an SAE, with an AE that is both drug-
related and serious, and who discontinued due to an AE will be considered Tier 2 endpoints.
The 95% CIs will be provided for treatment differences (MK-8591 treatment groups minus
MK-1439A) in the percentage of participants with these events; these analyses will be
performed using the Miettinen and Nurminen method [Miettinen, O. and Nurminen, M.
1985], an unconditional, asymptotic method.  No stratification factor will be included.
Adverse events (preferred terms and system organ class terms) and PDLCs in laboratory
parameters will be classified as belonging to "Tier 2" or "Tier 3", based on the number of
events observed.  Membership in Tier 2 requires that at least 4 participants in at least 1
treatment group exhibit the event; all other AEs and PDLCs will belong to Tier 3.
The threshold of at least 4 events prior to dose selection was chosen because the 95% CI for
the between-group difference in percent incidence will include zero when treatment groups
of equal size each have less than 4 events and thus, would add little to the interpretation of
potentially meaningful differences. Because many 95% CIs may be provided without
adjustment for multiplicity, the CIs should be regarded as a helpful descriptive measure to be
used in review, not a formal method for assessing the statistical significance of the between-
group differences in adverse events and predefined limits of change. 
Continuous measures such as changes from baseline in laboratory and vital signs parameters
will be considered Tier 3 safety parameters.  Summary statistics for baseline, on-treatment,
and change from baseline values will be provided by treatment group.
 
 
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Table 10 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for
Treatment
Comparison
Descriptive
Statistics
Tier 2
Proportion of participants:
(1) With at least one AE
(2) With a drug-related AE
(3) With a serious AE
(4) With serious and drug-related AE
(5) Who discontinued due to an AE
Specific AEs (preferred terms), System Organ Classes, or
PDLCs (incidence of ≥4 participants in one of the
treatment groups)
X 
X
Tier 3 
Specific AEs (preferred terms), System Organ Classes, or
PDLCs (incidence of <4 participants in all of the treatment
groups)
Change from baseline in laboratory measurements and vital
signs
X
AE = adverse event; CI = confidence interval; PDLC = pre-defined limit of change
The key periods of interest for safety analyses are Day 1 through Week 24 and Day 1 through
Week 48. 
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by
the use of descriptive statistics.  No statistical hypothesis tests will be performed on these
characteristics.  The number and percentage of participants screened, randomized, the
primary reasons for screening failure, and the primary reason for discontinuation will be
displayed.  Demographic variables (age, gender, race, region, etc.), baseline characteristics,
primary and secondary diagnoses, and prior and concomitant therapies will be summarized
by treatment group using descriptive statistics for continuous or categorical variables, as
appropriate.  Summary statistics for baseline disease characteristics to be used as efficacy
measures such as HIV-1 RNA and CD4+ T-cell count will also be provided by treatment.
Population PK and PK/PD Analyses
PK samples will be used to develop a population PK model and to explore the exposure-
response relationship of MK-8591 in the trial population.  Association between efficacy
responses and PK parameters predicted from the population PK model will be graphically
explored.
 
 
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Interim Analyses
The analyses described in Sections 10.7.4 and 10.7.5 will be performed by an external
unblinded statistician and reviewed by the eDMC.  Details regarding the eDMC will be
described in a DMC Charter.  Analyses described in Sections 10.7.1, 10.7.2, and 10.7.3 will
be performed by the Sponsor.
Interim Analysis at Week 24
When all participants have reached Week 24 or have discontinued prior to Week 24, the
Sponsor will be unblinded to treatment assignment to assess the safety and efficacy
objectives for the 3-drug regimen.  Details of these analyses will be shared with the eDMC.
Interim Analysis at Week 48
When all participants have reached Week 48 or have discontinued prior to Week 48, the
Sponsor will conduct analyses for selecting a dose of MK-8591. Safety and efficacy results
will be assessed, and details will be shared with the eDMC.
Interim Analysis at Week 96
Analysis will be conducted when all participants have reached Week 96 or have discontinued
prior to Week 96.  Safety and efficacy results will be assessed, and details will be shared with
the eDMC.
Periodic Safety Assessments
To supplement the routine safety monitoring outlined in this protocol, the eDMC will
monitor ongoing safety data and provide recommendations to ensure the safety of study
participants and the integrity of the trial to the EOC (Appendix 3).  HIV-1 RNA data may be
included as part of the reviews.  The eDMC will monitor the trial with suggested periodic
reviews to occur every ~ 4 to 6 months or as specified in the DMC charter.
Virologic Failure Assessments
Participants who meet the protocol-defined virologic failure criteria in Part 1 (Section
5.4.1.1.1) will be communicated to the unblinded statistician.  If 3 or more participants (10%
or more out of 30 expected participants) in any treatment group are observed to have
virologic failure by the unblinded statistician, this will be reported to the eDMC.  The eDMC
may recommend dropping a treatment group on the basis of this criterion.
Multiplicity
No multiplicity adjustment will be made as this is a Phase 2 dose-selection trial and there are
no hypotheses for this trial.
 
 
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Sample Size and Power Calculations
Sample Size and Power for Efficacy Analyses
This trial will include ~120 participants randomized to receive 1 of 3 MK-8591 treatment
groups or MK-1439A. Table 11 displays the differences in proportions (MK-8591 treatment
group minus MK-1439A group) that can be ruled out with 80% power and 30 participants
per group.  The power calculation is based on an asymptotic method proposed by Farrington
and Manning [Farrington, C. P. and Manning, G. 1990].
Table 11 
Difference in Efficacy Proportions (MK-8591 Treatment Group minus
MK-1439A Group) That Can Be Ruled Out With 80% Power and 95%
Confidence with 30 Participants Per Group
Response Rate (%) in
the Comparator
Group (MK-1439A)
True Difference in Response Ratesa
(Experimental [MK-8591 Treatment Group] –Comparator [MK-1439A]
Group)
-10
Percentage
Points
-5
Percentage
Points
0
Percentage
Points
5
Percentage
Points
10
Percentage
Points
60
25.7
30.4
35.0
42.6
43.8
65
25.7
30.6
35.4
40.1
44.5
70
25.3
30.5
35.5
40.2
44.9
75
24.6
30.0
35.1
40.0
44.9
80
23.5
29.0
34.3
39.4
44.4
85
21.7
27.4
33.0
38.3
43.5
90
19.2
25.2
30.9
36.5
41.9
a. Calculated using SAS v9.4.
It is anticipated that ~85% of participants will achieve <50 copies/mL at Weeks 24 and 48.
With 30 participants per group, the trial has 80% power to declare with 95% confidence that
the difference in the proportions of participants achieving HIV-1 RNA <50 copies/mL at
Week 24 and at Week 48 between a MK-8591 treatment group and MK-1439A group will be
no more than 33.0%, when the true proportions are in fact equal to 85% in each treatment
group (Table 11).
Sample Size and Power for Safety Analyses
The probability of observing at least 1 of a particular type of AE in this trial depends on the
number of participants treated and the underlying percentage of participants with that AE in
the study population.
If the underlying incidence of a particular AE is 1% (1 of every 100 participants receiving
study treatment), there is a 26.0% chance of observing at least 1 AE among 30 participants in
any treatment group. If no AE of that type is observed among the 30 participants in any
 
 
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treatment group, this trial will provide 95% confidence that the underlying percentage of
participants with that particular AE is <11.6% for that treatment group.
The estimate of, and the upper bound of the 95% CI for, the underlying percentage of
participants with an AE given various hypothetical observed number of participants with the
AE within each treatment group are provided in Table 12. These calculations are based on
the exact binomial method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E.
S. 1934].
Table 12 
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on
Hypothetical Number of Participants with AEs Among 30 Participants in Each
Treatment Group
Hypothetical Number of 
Participants With Adverse Event 
Estimate of
Incidence 
95% Upper Confidence Bounda
0
0.0%
11.6%
1
3.3%
17.2%
2
6.7%
22.1%
5
16.7%
34.7%
7
23.3%
42.3%
10
33.3%
52.8%
AE=adverse event
a. Based on the 2-tailed exact confidence interval of a binomial proportion [Clopper, C. J. and Pearson, E. S.
1934].
Table 13 gives the difference in the incidence of AEs (MK-8591 treatment group minus
MK-1439A group) that can be ruled out with different power levels and 95% confidence
when there are 30 participants in each treatment group.  The underlying incidence of AEs is
assumed to be the same for the treatment groups. For an AE that occurs in 10% of
participants in 1 of the MK-8591 treatment groups or the control group, the trial has 80%
power to declare with 95% confidence that the true difference between the treatment groups
is no more than 21.7 percentage points. The calculations are based on an asymptotic method
proposed by Farrington and Manning [Farrington, C. P. and Manning, G. 1990].
 
 
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Table 13 
Difference in Incidence of AEs (MK-8591 treatment group minus MK-1439A)
That Can Be Ruled Out With 30 Participants in Each Treatment Group
Differencea in Percentage Points That Can Be Ruled Out with Target Power
Assuming the Underlying Incidence of the AE is:
Target Power 
10%
20%
30%
40%
50%
80
21.7
28.9
33.1
35.4
36.2
85
23.2
30.9
35.5
37.9
38.7
90
25.1
33.5
38.4
41.0
41.8
95
27.9
37.2
42.7
45.6
46.5
AE = adverse event
a. The upper bound of the 2-sided 95% confidence interval [Farrington, C. P. and Manning, G. 1990] for the
difference in AE incidences (MK-8591 treatment group minus MK-1439A) assuming the incidences are the
same.
Subgroup Analyses
To assess the consistency of the treatment effect across various subgroups, the estimate of the
between-group treatment effect for the primary endpoint will be assessed and plotted within
each category of the following classification variables:
 Age category (≤median, >median)
 Sex (female, male)
 Region
 Race (White, Black, Asian, Other)
 Ethnicity (Hispanic/Latino, not Hispanic/Latino)
 Screening HIV-1 RNA categories (HIV-1 RNA ≤100,000 copies/mL, HIV-1 RNA
>100,000 copies/mL)
 Baseline HIV-1 RNA categories (HIV-1 RNA ≤100,000 copies/mL, HIV-1 RNA
>100,000 copies/mL)
The OF approach will be used to handle missing values in these subgroup analyses.  Nominal
2-sided 95% CIs will be calculated for variables with a sufficient number of participants in
each treatment group.  No stratification will be used in these analyses.
Compliance (Medication Adherence)
Study Medication Diary Cards will be used to ensure and document drug compliance.
Participants are to take 1 pill QD from each container of study medication. A day within the
trial will be considered an “On-Therapy” day if the participant takes the required number of
tablets from all containers provided for this trial (as noted in Section 7.5.1).
For a participant who is followed for the entire trial period, the “Number of Days Should be
on Therapy” is the total number of days from Day 1 to the last scheduled day for treatment
 
 
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administration for that participant. For a participant who discontinued from the trial
permanently, the “Number of Days Should be on Therapy” is the total number of days from
Day 1 to the date of the last dose of study medication.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the FAS
population.
Data from the study medication diary, rather than the returned pill-count, will serve as the
primary data for compliance.
Extent of Exposure
The extent of exposure to study therapy for all randomized and treated participants will be
summarized. The number of participants exposed to various doses (actual total daily dose)
for defined periods of time will be listed, along with a summary of the mean (range) duration
participants were exposed to various doses.
11. References
[AIDS info 2016]
AIDS info. Guidelines for the use of
antiretroviral agents in HIV-1-infected
adults and adolescents [Internet].
Rockville: U.S. Department of Health &
Human Services; 2016. Available from:
http://aidsinfo.nih.gov/guidelines.
[04DK0G]
[AIDS info 2017]
AIDS info. Guidelines for the use of
antiretroviral agents in HIV-1-Infected
adults and adolescents [Internet].
Rockville, MD: AIDS info; 2017.
Available from:
http://aidsinfo.nih.gov/guidelines.
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[Baker, J. V., et al 2011] 
Baker JV, Neuhaus J, Duprez D, Kuller 
LH, Tracy R, Belloso WH, De Wit S. et al.
Changes in inflammatory and coagulation
biomarkers: a randomized comparison of
immediate versus deferred antiretroviral
therapy in patients with HIV infection. J
Acquir Immune Defic Syndr. 2011 Jan
1;56(1):36-43.
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[Charpentier, C., et al
2014]
Charpentier C, Choquet M, Joly V, Yeni P, 
Visseaux B, Caseris M, et al. Virological
outcome at week 48 of three recommended
first-line regimens using ultrasensitive viral
load and plasma drug assay. J Antimicrob
Chemother. 2014 Oct;69(10):2819-25.
[04PYMQ]
[Clopper, 
C. 
J. 
and
Pearson, E. S. 1934]
Clopper CJ, Pearson ES. The use of 
confidence or fiducial limits illustrated in
the case of the binomial. Biometrika
1934;26(4):404-13.
[00V5VX]
[Farrington, C. P. and
Manning, G. 1990]
Farrington CP, Manning G. Test statistics 
and sample size formulae for comparative
binomial trials with null hypothesis of non-
zero risk difference or non-unity relative
risk. Stat Med 1990;9:1447-54.
[00TGPS]
[Food 
and 
Drug
Administration 2013]
Food and Drug Administration. Guidance 
for industry: human immunodeficiency
virus-1 infection: developing antiretroviral
drugs for treatment, Jun-2013.
[03WNQX]
[Gill, V. S., et al 2010] 
Gill VS, Lima VD, Zhang W, Wynhoven 
B, Yip B, Hogg RS, et al. Improved
virological outcomes in British Columbia
concomitant with decreasing incidence of
HIV type 1 drug resistance detection. Clin
Infect Dis. 2010 Jan 1;50(1):98-105.
[04LV4H]
[Knudsen, T. B., et al
2016]
Knudsen TB, Ertner G, Petersen J, Moller 
HJ, Moestrup SK, Eugen-Olsen J. et al.
Plasma Soluble CD163 Level
Independently Predicts All-Cause
Mortality in HIV-1-Infected Individuals. J
Infect Dis. 2016 Oct 15;214(8):1198-204.
[04MWL7]
[Lee, F. J., et al 2014] 
Lee FJ, Amin J, Carr A. Efficacy of initial 
antiretroviral therapy for HIV-1 infection
in adults: a systematic review and meta-
analysis of 114 studies with up to 144
weeks' follow-up. PLoS One. 2014 May
15;9(5):e97482.
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[Mantel, N. and Haenszel,
W. 1959]
Mantel N, Haenszel W. Statistical aspects 
of the analysis of data from retrospective
studies of disease. J Natl Cancer Inst
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[Michailidis E 2014] 
Michailidis E, et al. 4-Ethynyl-2-fluoro-2- 
deoxyadenosine (EFdA) Inhibits HIV-1
Reverse Transcriptase with Multiple
Mechanisms. J Biol Chem 2014;
289(35):24533-24548.
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[Miettinen, 
O. 
and
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative
analysis of two rates. Statist Med
1985;4:213-26.
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[Moore, R. D. 2011] 
Moore RD, Bartlett JG. Dramatic decline 
in the HIV-1 RNA level over calendar time
in a large urban HIV practice. Clin Infect
Dis. 2011 Sep;53(6):600-4.
[04LV4P]
[National 
Institute 
of
Allergy and Infectious
Diseases 2017]
National Institute of Allergy and Infectious 
Diseases. Division of AIDS (DAIDS) table
for grading the severity of adult and
pediatric adverse events, corrected version
2.1 [Internet]. Bethesda, MD: NIAID;
2017. Available from: https://rsc.tech-
res.com/docs/default-
source/safety/division-of-aids-(daids)-
table-for-grading-the-severity-of-adult-
and-pediatric-adverse-events-corrected-v-
2-1.pdf?sfvrsn=2.
[04R7PK]
[Panel on Antiretroviral
Guidelines for Adults and
Adolescents 2018]
Panel on Antiretroviral Guidelines for 
Adults and Adolescents. Guidelines for the
use of antiretroviral agents in adults and
adolescents living with HIV: Oct 2018.
Washington (DC): U.S. Department of
Health and Human Services (HHS); [last
updated: 2018 Oct 25]. 331 p.
[053CRN]
[Vandenhende, M. A., et
al 2015]
Vandenhende MA, Ingle S, May M, Chene 
G, Zangerle R, Van Sighem A, et al.
Impact of low-level viremia on clinical and
virological outcomes in treated HIV-1-
infected patients. AIDS. 2015;29(3):373-
83.
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[Wang, H., et al 2016] 
Wang H, Lu X, Yang X, Xu N. The 
efficacy and safety of tenofovir
alafenamide versus tenofovir disoproxil
fumarate in antiretroviral regimens for
HIV-1 therapy: Meta-analysis. Medicine
(Baltimore). 2016 Oct;95(41):e5146.
[04MWLQ]
[Wensing, A. M., et al
2017]
Wensing AM, Calvez V, Gunthard HF,
Johnson VA, Paredes R, Pillay D, et al.
2017 update of the drug resistance
mutations in HIV-1. Top Antivir Med.
2017 Dec/Jan;24(4):132-41.
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12. Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation
Definition
3TC
lamivudine
AE
adverse event
AIDS
acquired immune deficiency syndrome
ALT
alanine aminotransferase
APaT
All Participants as Treated
ART
anti-retroviral therapy
AST
aspartate aminotransferase
BMD
bone mineral density
C24
concentration after 24 hours
CD4+
CD4-positive
CI
confidence interval
Clcr
creatinine clearance
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CSR
clinical study report
Ctrough
lowest concentration reached by a drug before the next dose is
administered
CYP
cytochrome P450
DAIDS
Division of Acquired Immunodeficiency Syndrome
DDI
drug-drug interaction
DEXA
dual-energy x-ray absorptiometry
DMC
Data Monitoring Committee
DOR
doravirine (MK-1439)
DRV
darunavir
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic case report form
eDMC
external Data Monitoring Committee
EFV
Efavirenz
eGFR
estimated glomerular filtration rate
EOC
Executive Oversight Committee
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDC
fixed-dose combination
FSH
follicle-stimulating hormone
 
 
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Abbreviation
Definition
FTC
emtricitabine
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV-1
human immunodeficiency virus type 1
HRT
hormonal replacement therapy
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
IEC
Independent Ethics Committee
IL-6
interleukin-6
InSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
IRB
Institutional Review Board
IVRS/IWRS
Interactive Voice/Web Response System
MK-1439
doravirine
MK-1439A
doravirine + lamivudine + tenofovir disoproxil fumarate
NC=F
Non Completer=Failure
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitors
NRTTI
nucleoside reverse transcriptase translocation inhibitor
OF
observed failure
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PDLC
pre-defined limit of change
PDVF
protocol-defined virologic failure
PI
protease inhibitor
PK
pharmacokinetic
QD
once daily
r
ritonavir
RNA
ribonucleic acid
RT
reverse transcriptase
SAE
serious adverse event
SoA
Schedule of Activities
sSAP
supplemental statistical analysis plan
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate
 
 
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Abbreviation
Definition
TLOVR
time to loss of virologic response
TP
triphosphate
ULN
upper limit of normal
WOCBP
woman of childbearing potential
 
 
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Appendix 2: Clinical Laboratory Tests
 Clinical laboratory tests detailed in Table 14 will be performed by a central
laboratory.
 Local laboratory results are only required when central laboratory results are not
available in time for either study treatment administration and/or response evaluation. 
If a local sample is required, it is important that the sample for central analysis is
obtained at the same time.  Additionally, if local laboratory results are used to make
either a study treatment decision or response evaluation, the results must be entered
into the case report form (CRF).
 The investigator must document his/her review of each laboratory safety report.
 Protocol-specific requirements for inclusion or exclusion of participants are detailed
in Section 6 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.
 Clinical laboratory test results will be graded according to criteria adapted from the
DAIDS Laboratory Tables for Grading the Severity of Adult and Pediatric Adverse
Events, Publish Date:  November 2014 Version 2 (Appendix 2A).
Table 14 Protocol-Required Laboratory Assessments and Approximate Blood Draw
Volumes
Laboratory Assessments
Parameters
Approximate Blood
Volume (mL)
Pregnancy
Serum -human chorionic gonadotropin (hCG) test
2
Urine -human chorionic gonadotropin (hCG) test
Not applicable
Hematology
Hematocrit
4
Hemoglobin
Platelet count
Red blood cell count
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Red cell distribution width
White blood cell count (total and differential)
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
CD4% and absolute CD4/lymphocytes
2
CD8% and absolute CD8/lymphocytes
CD4/CD8 ratio
 
 
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Laboratory Assessments
Parameters
Approximate Blood
Volume (mL)
Chemistry (non-fasting)
Aspartate aminotransferase (AST)
8.5
Alanine aminotransferase (ALT)
Alkaline phosphatase
Creatine kinase
Total bilirubin
Direct bilirubin
Indirect bilirubin
Amylase
Lipase
Blood urea nitrogen
Creatinine
Calcium
Phosphorus
Magnesium
Protein
Albumin
Sodium
Potassium
Chloride
Bicarbonate
Glucose, non-fasting
Chemistry (fasting for at
least 8 h)
Glucose, fasting
8.5
High-density lipoprotein cholesterol (HDL)
Low-density lipoprotein cholesterol (LDL-C)
Triglycerides
Total cholesterol
Urinalysis 
Specific gravity
Not Applicable
pH
Glucose
Protein
Blood
Ketones
Bilirubin
Urobilinogen
Nitrite
Leukocytes
Erythrocytes
Urinary analytes
Albumin
Protein
Beta-2-microglobulin/creatinine ratio (B-2M/Cr)
Not Applicable
Retinol binding protein/creatinine ratio (RBP/Cr)
Renal function
Estimated glomerular filtration rate (eGFR) by MDRD
equation
Not Applicable
Hemostatic function
Prothrombin test (PT)
4.5
Activated partial thromboplastin time (APTT)
International normalized ratio (INR)
 
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Laboratory Assessments 
Parameters
Approximate Blood
Volume (mL)
Hepatitis screen
(Screening)
Hepatitis B virus surface antigen
Hepatitis B virus surface antibody
Hepatitis C antibody  (if positive perform plasma
hepatitis C virus PCR quantitative test)
5
Hepatitis screen
(Post randomization)
Hepatitis B virus surface antigen
Hepatitis C antibody (if positive perform plasma
hepatitis C virus PCR quantitative test)
5
HIV-1 Screen  
Enzyme immunoassay HIV-1 antibody  
5
Virology  
HIV-1 viral RNA quantification (real time PCR) 
5
HIV-1 viral resistance 
15
HIV-1 RNA single-copy assay  
20
PK and inflammatory 
markers 
MK-8591 PK  
4
D-dimer 
2
IL-6 
2
Soluble CD163 
2
Blood for Genetic Analysis 
8.5
Blood (plasma) for repeat HIV-1 viral resistance or PK  
4
CD=cluster of differentiation; HIV-1=human immunodeficiency virus type 1; IL-6=interleukin-6;
MDRD=Modification of Diet in Renal Disease; PCR=polymerase chain reaction; PK=pharmacokinetics;
RNA=ribonucleic acid; U=unscheduled.
 
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12.2 Appendix 2A: Division of AIDS (DAIDS) Tables for Grading the Severity of
Adult and Pediatric Adverse Events
 
 
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Source: [National Institute of Allergy and Infectious Diseases 2017]
 
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Appendix 3: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I. Introduction
A. Purpose
Merck, 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 participant safety is the overriding concern
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine
participant preferences, etc. 
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud,
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary,
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and
data disclosed accordingly.
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice
guidelines. 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.  Merck funding of a trial will be acknowledged in publications.
 
 
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III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site. 
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC
approval. For each site, the IRB/IEC and Merck 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.  Participants are never denied access to
appropriate medical care based on participation in a Merck clinical trial.
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent
for participation.  Participants may withdraw from a Merck 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
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential
medical records that might identify the research participant by name. 
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring
institution) in a fair manner for the work performed in support of Merck trials.  Merck 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.
Merck does not pay for participant referrals.  However, Merck 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 Merck, and that the investigator or sponsoring
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above,
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical
Association (AMA).
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
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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.
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 which 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.
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 institutional review board, ethics review committee (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 trial 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.
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 trial documents in
order to verify worksheet/case report form data.  By signing the consent form, the participant
agrees to this process.  If trial documents will be photocopied during the process of verifying
worksheet/case report form information, the participant will be identified by unique code
only; full names/initials will be masked prior to transmission to the Sponsor.
 
 
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By signing this protocol, the investigator agrees to treat all participant data used and
disclosed in connection with this trial in accordance with all applicable privacy laws, rules
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and
approves this trial.  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.
Committees Structure
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior
Management.  The EOC will receive and decide upon any recommendations made by the
DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting
members of the committee are external to the Sponsor.  The members of the DMC must not
be involved with the trial in any other way (eg, they cannot be trial investigators) and must
have no competing interests that could affect their roles with respect to the trial.
The DMC will make recommendations to the EOC regarding steps to ensure both participant
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim
Analyses) and recommend to the EOC if the trial should continue in accordance with the
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles
and responsibilities of the various members and the Sponsor protocol team; meeting
facilitation; the trial governance structure; and requirements for and proper documentation of
DMC reports, minutes, and recommendations will be described in the DMC charter that is
reviewed and approved by all the DMC members.
A DMC recommendation will be communicated to the Sponsor as agreed to in the DMC
Charter.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor
will comply with the requirements for publication of study results. In accordance with
standard editorial and ethical practice, the sponsor will generally support publication of
multicenter studies only in their entirety and not as individual site data. In this case, a
coordinating investigator will be designated by mutual agreement.
 
 
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If publication activity is not directed by the sponsor, the investigator agrees to submit all
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect
proprietary information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International Committee
of Medical Journal Editors authorship requirements.
Compliance with Trial 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 trial is solely responsible for determining whether the trial and its results are subject to
the requirements for submission to http://www.clinicaltrials.gov,
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will
review this protocol and submit the information necessary to fulfill these requirements.
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate trials for their
disease conditions and pursue participation by calling a central contact number for further
information on appropriate trial locations and trial 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 trial or its results to those
registries.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and
diligent manner and in conformance with this protocol; generally accepted standards of Good
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated
Guideline and other generally accepted standards of good clinical practice); and all
applicable federal, state and local laws, rules and regulations relating to the conduct of the
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and
scientific conduct of clinical investigations sponsored by Merck, is provided in this appendix
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance
providers or from government programs for procedures included as part of the trial
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection
observations/findings to allow the Sponsor to assist in responding to any citations resulting
from regulatory authority inspection, and will provide the Sponsor with a copy of the
proposed response for consultation before submission to the regulatory authority.
 
 
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Persons debarred from conducting or working on clinical trials by any court or regulatory
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator
will immediately disclose in writing to the Sponsor if any person who is involved in
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best
of the investigator’s knowledge, threatened.
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.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator
upon request and also shall be made available at the trial 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 regulatory authority as a result of an audit or inspection to cure
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from
source documents; that the safety and rights of participants are being protected; and that the
study is being conducted in accordance with the currently approved protocol and any other
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period. No records may be destroyed during
the retention period without the written approval of the sponsor. No records may be
transferred to another location or party without written notification to the sponsor.
 
 
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Source Documents
Source documents provide evidence for the existence of the participant and substantiate the
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents
must be consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Study and Site Closure
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 trial site, the Sponsor will
promptly notify that trial site’s IRB/IEC.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
● An AE is any untoward medical occurrence in a patient or clinical study participant,
temporally associated with the use of study treatment, whether or not considered
related to the study treatment.
● 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 treatment.
● NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s
product) includes any pharmaceutical product, biological product, vaccine, device,
diagnostic agent or protocol specified procedure whether investigational (including
placebo or active comparator product) or marketed, manufactured by, licensed by,
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition
● Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or
other safety assessments (eg, ECG, radiological scans, vital signs measurements),
including those that worsen from baseline, 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 treatment 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
treatment or a concomitant medication.
● For all reports of overdose (whether accidental or intentional) with an associated
adverse event, 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 9.3.5 for protocol specific exceptions
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
A 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 a serious adverse event.  A pre-existing condition is a clinical
condition that is diagnosed prior to the use of a Merck product and is documented in
the patient’s medical history.
d. Results in persistent or significant disability/incapacity
● The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.
● This definition is not intended to include experiences of relatively minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.
 
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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 one of the other
outcomes listed in the above definition. These events should usually be considered
serious.
Examples of such events include invasive or malignant cancers, intensive treatment in
an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency or
drug abuse.
Additional Events reported
Additional Events which require reporting
● In addition to the above criteria, adverse events 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.
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 Adverse Event
case report forms/worksheets at each examination.
● It is not acceptable for the investigator to send photocopies of the participant’s medical
records to the Sponsor in lieu of completion of the AE CRF page.
● There may be instances when copies of medical records for certain cases are requested
by the Sponsor. In this case, all participant identifiers, with the exception of the
participant number, will be blinded on the copies of the medical records before
submission to the Sponsor.
● The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. In such cases, the diagnosis (not the
individual signs/symptoms) will be documented as the AE/SAE.
 
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Assessment of Intensity
● An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as
described in the definition of an SAE, NOT when it is rated as severe.
● The investigator will make an assessment of intensity for each AE and SAE (and other
reportable safety event) reported during the study and assign it to 1 of the following
categories:
● Mild: An event that is easily tolerated by the participant, causing minimal
discomfort and not interfering with everyday activities.  (for pediatric trials,
awareness of symptoms, but easily tolerated)
● Moderate: An event that causes sufficiently discomfort and interferes with normal
everyday activities. (for pediatric trials, 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 utilized for
rating the intensity of an event; and both AE and SAE can be assessed as severe
(for pediatric trials, extremely distressed or unable to do usual activities).
Assessment of Causality
● 
Did the Sponsor's product cause the adverse event?
● The determination of the likelihood that the Sponsor's product caused the adverse
event 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 adverse event 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 adverse event:
● 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 trials with investigational
medicinal product)?
● Likely Cause:  Is the AE not reasonably explained by another etiology such as
 
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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 trial is a single-dose drug trial); or (4) Sponsor's
product(s) is/are only used one time.)
● Rechallenge:  Was the participant re-exposed to the Sponsor's product in this
trial?
● 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 trial is a single-dose drug trial); or (3) Sponsor's
product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH
WAS SERIOUS AND WHICH 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 INSTITUTIONAL REVIEW
BOARD/INDEPENDENT ETHICS COMMITTEE.
● Consistency with Study treatment 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.
 
 
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● 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 one of the criteria used when determining regulatory
reporting requirements
Follow-up of AE and SAE
● The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by Sponsor to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may
include additional laboratory tests or investigations, histopathological examinations, or
consultation with other health care professionals.
● New or updated information will be recorded in the CRF.
● The investigator will submit any updated SAE data to the Sponsor within 24 hours of
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic
Data Collection Tool
● The primary mechanism for reporting to the Sponsor will be the electronic data
collection (EDC) tool. 
● Electronic reporting procedures can be found in the EDC data entry guidelines (or
equivalent).
● If the electronic system is unavailable for more than 24 hours, then the site will use
the paper AE Reporting form. 
● Reference section 9.3.1 –Time Period and Frequency for Collecting AE and
SAE and Other Reportable Safety Event Information for reporting time
requirements
 
 
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● The site will enter the SAE data into the electronic system as soon as it becomes
available.
● After the study is completed at a given site, the electronic data collection 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 electronic data collection 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 Trial File Binder (or
equivalent).
SAE Reporting to the Sponsor via Paper CRF
● If the electronic data collection 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 Trial File Binder (or equivalent).
 
 
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP:
 Premenarchal
 Premenopausal female with 1 of the following:
 Documented hysterectomy
 Documented bilateral salpingectomy
 Documented bilateral oophorectomy
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.
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range
may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy (HRT). However, in the
absence of 12 months of amenorrhea, confirmation with 2 FSH measurements
in the postmenopausal range is required.
 Females on HRT and whose menopausal status is in doubt will be required to use 1 of
the non-hormonal highly effective contraception methods if they wish to continue
their HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use
one of the contraception methods described in Table 15 consistently and correctly during the
protocol-defined time frame in Section 6.1.
 
 
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Table 15 
Contraceptive Methods
Acceptable Contraceptive Methods 
Failure rate of >1% per year when used consistently and correctly.
 Male or female condom with or without spermicide
 Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
 Combined (estrogen- and progestogen-containing ) hormonal contraceptionb,c
○ Oral
○ Intravaginal
○ Transdermal
○ Injectable
 Progestogen-only hormonal contraceptionb,c
○ Oral
○ Injectable
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
 Progestogen-only contraceptive implantb,c
 Intrauterine hormone-releasing system (IUS)b
 Intrauterine device (IUD)
 Bilateral tubal occlusion
 Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the
partner is the sole male sexual partner of the woman of childbearing potential and the
absence of sperm has been confirmed. If not, an additional highly effective method of
contraception should be used.
 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
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the
duration of the study and the preferred and usual lifestyle of the participant.)
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for participants
of clinical studies.
a
Typical use failure rates are higher than perfect-use failure rates (i.e., when used consistently and
correctly).
b
If hormonal contraception efficacy is potentially decreased due to interaction with study treatment,
condoms must be used in addition to the hormonal contraception during the treatment period and for at
least 6 weeks after the last dose of study treatment.
c
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable
hormonal contraceptives are limited to those which inhibit ovulation.
 
 
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Pregnancy Testing
Women of childbearing potential should only be included after a negative highly sensitive
urine or serum pregnancy test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or
when pregnancy is otherwise suspected.
 
 
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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 trial as outlined in Section 9.8 –Future
Biomedical Research Samples will be used in various experiments to understand:
o The biology of how drugs/vaccines work
o Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o Other pathways drugs/vaccines may interact with
o 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 trial will be considered for enrollment in
Future Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained
during screening for protocol enrollment from all participants or legal guardians, at a
trial 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 trial flow chart.  If delayed, present consent at next possible Participant Visit. 
 
 
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Consent forms signed by the participant will be kept at the clinical trial site under
secure storage for regulatory reasons. 
A template of each trial 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 electronic Case Report Forms (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 trial flow chart. 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 trial 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 trial data to the
specimen. The clinical data allow specific analyses to be conducted. Knowing participant
characteristics like gender, age, medical history and treatment outcomes are critical to
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future
Biomedical Research, the Sponsor has developed secure policies and procedures. All
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical trial 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 trial site.  No personal identifiers will
appear on the specimen tube. 
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific
practices.  Analyses utilizing the Future Biomedical Research specimens may be
performed by the Sponsor, or an additional third party (eg, a university investigator)
designated by the Sponsor. The investigator conducting the analysis will follow the
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses
will conform to the specific scope of analysis outlined in future biomedical research
protocol and consent. Future biomedical research specimens remaining with the third
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research and ask that
their biospecimens not be used for Future Biomedical Research.  Participants may
withdraw consent at any time by contacting the principal investigator for the main trial. If
 
 
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medical records for the main trial 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 trial data and results. No new analyses would be generated
after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the
investigator is no longer required by regulatory authorities to retain the main trial
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 trial 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
trial, the trial site will ship directly to the Sponsor-designated biorepository. The
specimens will be stored under strict supervision in a limited access facility which
operates to assure the integrity of the specimens.  Specimens will be destroyed according
to Sponsor policies and procedures and this destruction will be documented in the
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the
authorized Sponsor representatives and the designated trial 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
 
 
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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 trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research
For Future Biomedical Research, risks to the participant have been minimized. No
additional risks to the participant have been identified as no additional specimens are
being collected for Future Biomedical Research (i.e., only leftover samples are being
retained).’
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 e-mailed directly to
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC
DATA AND SAMPLE CODING CATEGORIES - E15;
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. 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. Pharmacogenomics Informational
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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