Phase IIb, Double-Blinded, Multicenter, Randomized Study to Assess the Effect on Central Nervous System (CNS) Toxicity of Switching From ATRIPLA™ (Efavirenz, Tenofovir, Emtricitabine) to MK-1439A (Doravirine, Tenofovir, Lamivudine) in Virologically-Suppressed Subjects.
Phase: PHASE2
Conditions: HIV-1, Central Nervous System
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT Number:  
    NCT02652260
Document Date:           31-Oct-2022
Phase IIb, Double-Blinded, Multicenter, Randomized 
Study to Assess the Effect on Central Nervous System 
(CNS) Toxicity of Switching from ATRIPLA™ (Efavirenz, 
Tenofovir, Emtricitabine) to MK-1439A (Doravirine, 
Tenofovir, Lamivudine) in Virologically-Suppressed 
Subjects

Product:  MK-1439A 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
This protocol amendment is applicable only to South Africa.
SPONSOR:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
Phase IIb, Double-Blinded, Multicenter, Randomized Study to Assess the Effect on Central 
Nervous System (CNS) Toxicity of Switching from ATRIPLA™ (Efavirenz, Tenofovir, 
Emtricitabine) to MK-1439A (Doravirine, Tenofovir, Lamivudine) in Virologically-
Suppressed Subjects
IND NUMBER:  [124, 997]
EudraCT NUMBER:  [2015-003617-18]
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 13
Trial Design ........................................................................................................... 13
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16
Primary Objective(s) & Hypothesis(es).............................................................. 16
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 19
Rationale................................................................................................................ 20
Rationale for the Trial and Selected Subject Population .................................... 20
Rationale for Dose Selection/Regimen/Modification......................................... 22
Rationale for Endpoints ...................................................................................... 24
4.2.3.1
CNS Toxicity Questionnaire........................................................................ 24
4.2.3.2
Efficacy Endpoints....................................................................................... 25
4.2.3.3
Safety Endpoints.......................................................................................... 26
4.2.3.4
Exploratory Endpoints ................................................................................. 26
4.2.3.5
Planned Exploratory Biomarker Research................................................... 27
4.2.3.6
Future Biomedical Research........................................................................ 27
Rationale for Amendment 01.............................................................................. 27
Rationale for Study Extensions........................................................................... 28
Benefit/Risk ........................................................................................................... 29
5.0
METHODOLOGY ................................................................................................... 29
Entry Criteria........................................................................................................ 29
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Diagnosis/Condition for Entry into the Trial...................................................... 29
Subject Inclusion Criteria.................................................................................... 29
Subject Exclusion Criteria .................................................................................. 33
Trial Treatment(s) ................................................................................................ 35
Dose Selection .................................................................................................... 36
5.2.1.1
Dose Selection (Preparation) ....................................................................... 36
5.2.1.2
Dose Modification/Interruption ................................................................... 37
Timing of Dose Administration.......................................................................... 37
Trial Blinding/Masking....................................................................................... 38
Randomization ...................................................................................................... 38
Stratification.......................................................................................................... 38
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 38
Rescue Medications & Supportive Care............................................................. 41
Diet/Activity/Other Considerations..................................................................... 42
Subject Withdrawal/Discontinuation Criteria................................................... 42
Subject Replacement Strategy............................................................................. 44
Beginning and End of the Trial ........................................................................... 44
Clinical Criteria for Early Trial Termination ................................................... 44
6.0
TRIAL FLOW CHART ........................................................................................... 45
Base Study Flow Chart: Screening Through Week 24 (ISG) or 36 
(DSG) Plus 14-Day Follow-up.............................................................................. 45
Study Extension 1 Flow Chart for Immediate Switch Group (ISG): Weeks 
40 Through 120 Plus 14-Day Follow-up ............................................................. 51
Study Extension 1 Flow Chart for Deferred Switch Group (DSG): Weeks 
52 Through 132 Plus 14-Day Follow-up ............................................................. 53
Study Extension 2 Flow Chart for Immediate Switch Group (ISG): Weeks 
136 Through 216 Plus 14-Day Follow-up ........................................................... 55
Study Extension 2 Flow Chart for Deferred Switch Group (DSG): Weeks 
148 Through 228 Plus 14-Day Follow-up ........................................................... 56
Study Extension 3 Flow Chart for Immediate Switch Group (ISG): Weeks 
232 Through 312 Plus 14-Day Follow-up ........................................................... 57
Study Extension 3 Flow Chart for Deferred Switch Group (DSG): Weeks 
244 Through 324 Plus 14-Day Follow-up ........................................................... 58
7.0
TRIAL PROCEDURES ........................................................................................... 59
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Trial Procedures ................................................................................................... 59
Administrative Procedures.................................................................................. 59
7.1.1.1
Informed Consent......................................................................................... 59
7.1.1.1.1
General Informed Consent.................................................................... 59
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 60
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 60
7.1.1.3
Subject Identification Card .......................................................................... 60
7.1.1.4
Medical History ........................................................................................... 60
7.1.1.5
Prior and Concomitant Medications Review............................................... 61
7.1.1.5.1
Prior Medications.................................................................................. 61
7.1.1.5.2
Concomitant Medications..................................................................... 61
7.1.1.6
Assignment of Screening Number............................................................... 61
7.1.1.7
Assignment of Treatment/Randomization Number..................................... 61
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 61
7.1.1.9
Patient-Reported Outcomes ......................................................................... 62
Clinical Procedures/Assessments........................................................................ 63
7.1.2.1
Physical Examination................................................................................... 63
7.1.2.2
Height Assessment....................................................................................... 64
7.1.2.3
Vital Signs and Weight................................................................................ 64
7.1.2.4
12-Lead ECG (performed locally)............................................................... 64
7.1.2.5
Adverse Events ............................................................................................ 65
7.1.2.6
Toxicity Management .................................................................................. 65
7.1.2.7
Birth Control Confirmation.......................................................................... 66
Laboratory Procedures/Assessments .................................................................. 66
7.1.3.1
Serum / Urine Pregnancy Test..................................................................... 66
7.1.3.2
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 66
7.1.3.3
HIV/ Hepatitis Screening............................................................................. 67
7.1.3.4
Virology Test ............................................................................................... 67
7.1.3.5
Viral Resistance Testing .............................................................................. 68
7.1.3.6
CD4 Cell Counts.......................................................................................... 68
7.1.3.7
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 68
7.1.3.7.1
Blood Collection for Plasma MK-1439 and Efavirenz......................... 68
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7.1.3.8
Planned Genetic Analysis Sample Collection.............................................. 69
7.1.3.9
Future Biomedical Research Sample Collection ......................................... 69
Other Procedures................................................................................................. 69
7.1.4.1
Withdrawal/Discontinuation........................................................................ 69
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 69
7.1.4.2
Blinding/Unblinding .................................................................................... 69
7.1.4.3
Calibration of Equipment............................................................................. 70
Visit Requirements.............................................................................................. 70
7.1.5.1
Screening...................................................................................................... 71
7.1.5.2
Rescreening.................................................................................................. 71
7.1.5.3
Treatment Visits........................................................................................... 71
7.1.5.4
Post-Trial...................................................................................................... 80
7.1.5.5
Trial Unblinding........................................................................................... 80
Assessing and Recording Adverse Events .......................................................... 80
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 81
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 82
Immediate Reporting of Adverse Events to the Sponsor.................................... 82
7.2.3.1
Serious Adverse Events ............................................................................... 82
7.2.3.2
Events of Clinical Interest............................................................................ 83
Evaluating Adverse Events................................................................................. 84
Sponsor Responsibility for Reporting Adverse Events ...................................... 87
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 87
Statistical Analysis Plan Summary ..................................................................... 87
Responsibility for Analyses/In-House Blinding ................................................. 89
Hypotheses/Estimation......................................................................................... 89
Analysis Endpoints ............................................................................................... 90
CNS Toxicity Questionnaire............................................................................... 90
Efficacy Endpoints.............................................................................................. 91
Safety Endpoints ................................................................................................. 92
Analysis Populations............................................................................................. 93
Efficacy and CNS Toxicity Questionnaire Analysis Populations....................... 93
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Safety Analysis Populations ............................................................................... 93
Statistical Methods................................................................................................ 93
Statistical Methods for Subject-Reported Outcomes for CNS Toxicity............. 95
Statistical Methods for Efficacy Analyses.......................................................... 97
Statistical Methods for Safety Analyses ............................................................. 99
Statistical Methods for Exploratory Endpoints................................................. 101
Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 101
8.6.5.1
Demographic and Baseline Characteristics ............................................... 101
8.6.5.2
PK Analyses............................................................................................... 101
Interim Analyses ................................................................................................. 102
Multiplicity .......................................................................................................... 102
Sample Size and Power Calculations ................................................................ 102
Sample Size and Power for Primary Analysis to address the Primary 
Hypothesis......................................................................................................... 102
Sample Size and Power for Safety Analyses .................................................... 103
Subgroup Analyses and Effect of Baseline Factors ......................................... 103
Compliance (Medication Adherence)................................................................ 104
Extent of Exposure.............................................................................................. 104
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 105
Investigational Product ...................................................................................... 105
Packaging and Labeling Information ............................................................... 105
Clinical Supplies Disclosure............................................................................... 105
Storage and Handling Requirements................................................................ 106
Discard/Destruction/Returns and Reconciliation ............................................ 106
Standard Policies................................................................................................. 106
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 107
Confidentiality..................................................................................................... 107
Confidentiality of Data ..................................................................................... 107
Confidentiality of Subject Records................................................................... 107
Confidentiality of Investigator Information...................................................... 107
Confidentiality of IRB/IEC Information........................................................... 108
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Compliance with Financial Disclosure Requirements..................................... 108
Compliance with Law, Audit and Debarment ................................................. 108
Compliance with Trial Registration and Results Posting Requirements...... 110
Quality Management System............................................................................. 111
Data Management............................................................................................... 111
Publications ......................................................................................................... 111
11.0
LIST OF REFERENCES....................................................................................... 113
12.0
APPENDICES......................................................................................................... 115
Code of Conduct for Clinical Trials.................................................................. 115
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 118
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 122
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
by Sample Types ................................................................................................. 133
CNS Toxicity Questionnaire .............................................................................. 136
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS, PUBLISH DATE: 
AUGUST 2009 Version 1 ................................................................................... 137
List of Abbreviations and Acronyms ................................................................ 144
13.0
SIGNATURES......................................................................................................... 147
Sponsor's Representative ................................................................................... 147
Investigator.......................................................................................................... 147
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LIST OF TABLES
Table 1
Treatment Regimens During Base Study.............................................................. 35
Table 2
Treatment Regimen During Study Extensions ..................................................... 36
Table 3
Prohibited Medication/Therapy Due to MK-1439 Interaction During the Base 
Study and Study Extensions.................................................................................. 40
Table 4
Prohibited Medication/Therapy Due to ATRIPLA™ Interactions....................... 41
Table 5
Laboratory Tests ................................................................................................... 66
Table 6
Pharmacokinetic Sampling Timepoints................................................................ 68
Table 7
Study Drug Bottle (A, B and C) Components ...................................................... 73
Table 8
Evaluating Adverse Events................................................................................... 85
Table 9
Definition of Study Time Point – Immediate Switch Group................................ 94
Table 10
Definition of Study Time Point – Deferred Switch Group................................... 95
Table 11
Analysis Strategy for CNS Toxicity Questionnaire Variables ............................. 97
Table 12
Analysis Strategy for Key Efficacy Variables...................................................... 99
Table 13
Analysis Strategy for Safety Parameters............................................................. 101
Table 14
Power (%) Under Various Assumptions (With 42 Subjects Randomized in 
Each Treatment Group)....................................................................................... 102
Table 15
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Subjects With AEs Among 84 Subjects 
Randomized ........................................................................................................ 103
Table 16
Product Descriptions........................................................................................... 105
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LIST OF FIGURES
Figure 1
Trial Design: Base Study and Study Extensions................................................... 16
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 05
31-OCT-2022
This is a country-specific amendment for South Africa to inform regarding the Sponsor’s
name and address change and updates that were made to the Code of Conduct in the 
previous amendment.
Note: Amendment 05 supersedes Amendment 04.
Amendment 04
26-AUG-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name 
change and update to the address.
Amendment 04 was not released to sites.
Amendment 03
06-APR-2020

Study extension 3 was added to (1) provide continued access to MK-1439A for 
participants who are deriving benefit from MK-1439A until the drug is available 
locally in the country participating in the trial or for an additional 2 years (whichever 
comes first), and (2) collect key safety information from participants who continue on 
MK-1439A in this study extension.
Amendment 02
08-JUN-2018

Added open-label study extension 2 to provide continued access to MK-1439A until 
the drug is available locally in countries participating in the trial or for an additional 2 
years (whichever comes first).
Amendment 01
30-SEP-2016

Added open-label study extension 1 for 2 years to collect long-term efficacy and 
safety data.

Incorporated changes (including decreasing the number or subjects to be enrolled) to 
facilitate enrollment and ensure trial completion.
Original protocol
07-OCT-2015

Not applicable.
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
Title Page 
South Africa was added to the Title 
Page.
This is a country-specific amendment for South 
Africa to inform regarding the Sponsor’s name 
and address change and updates that were made 
to the Code of Conduct in the previous 
amendment.
Note: Amendment 05 supersedes Amendment 
04.  
The following changes were made in Amendment 04; however, Amendment 04 was not released to sites. These changes are 
summarized here for clarity and implementation in the current country-specific amendment.
12.1
Throughout
Title Page
Code of Conduct for 
Clinical Trials
Sponsor entity name and address 
change.
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name 
change and update to the address.
12.1
Code of Conduct for 
Clinical Trials 
The code of conduct was updated in 
Amendment 04.
To align with the current standard text for the 
Code of Conduct.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
Assess the effect of switching HIV-1 infected subjects with CNS 
toxicity (≥Grade 2) from ATRIPLATM or its components to MK-1439A
Trial Phase
IIb
Clinical Indication
Exploratory trial to assess improvement in CNS toxicity (≥Grade 2) 
after a switch from ATRIPLATM to MK-1439A
Trial Type
Interventional
Type of control
Active control (with double dummy placebo for blinding)
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups
Base Study:
Two treatment groups: 
Immediate Switch Group (ISG): Immediate Switch (at Study Day 1) 
from a baseline regimen of ATRIPLATM or its components to 
MK-1439A (+ a placebo matched to ATRIPLATM to maintain blinding)
for 12 weeks followed by treatment with open-label MK-1439A for an 
additional 12 weeks.  
Deferred Switch Group (DSG): Subjects will receive ATRIPLATM (+ a 
placebo matched to MK-1439A to maintain blinding) for the first 
12 weeks of the study followed by treatment with open-label
MK-1439A for 24 weeks.
Study Extensions:
All subjects: open-label MK-1439A 
Number of trial subjects
Approximately 84 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 103 
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
The study consists of a screening phase of up to 45 days (~6.5 weeks) 
followed by a double-blind base study of either 24 weeks ISG) or 36 
weeks (DSG), 3 open-label study extensions (study extensions 1, 2, and 
3), and a 14-day follow-up period.  The treatment duration of study 
extension 1 is 96 weeks; and the treatment duration of study extensions 2 
and 3 is up to 96 weeks for each, depending on when MK-1439A
becomes locally available (whichever comes first).
The approximate cumulative durations of participation in the trial (from 
informed consent through follow-up) are 32 (ISG) or 44 (DSG) weeks for 
subjects who complete the base study; 128 (ISG) or 140 (DSG) weeks for 
subjects who complete the base study and study extension 1; up to 224 
(ISG) or up to 236 (DSG) weeks for subjects who complete the base study 
and study extensions 1 and 2; and up to 320 (ISG) or up to 332 (DSG) 
weeks for subjects who complete the base study and study extensions 1, 
2, and 3.
Randomization Ratio
1:1.
A list of abbreviations used in this document can be found in Section 12.7.
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2.0 TRIAL DESIGN
Trial Design
This is a multicenter, double-blind (with in-house blinding), randomized, active-controlled 
trial to evaluate a switch from ATRIPLA™, generic ATRIPLA™ or its components (EFV, 
TDF 
plus 
emtricitabine) 
to 
MK-1439A 
in 
virologically 
suppressed, 
human 
immunodeficiency virus type 1 (HIV-1)-infected subjects.  
The study consists of a screening period of approximately 6.5 weeks, a base study of 24 
weeks (ISG) or 36 weeks (DSG) followed by 3 consecutive 96-week open-label study 
extensions (study extensions 1, 2, and 3), and a 14-day post-study follow-up visit after the 
last treatment visit. The treatment duration of the first open-label study extension (study 
extension 1) is 96 weeks; and the treatment duration of the second and third open-label study 
extensions (study extensions 2 and 3, respectively) is up to 96 weeks for each, depending on 
when MK-1439A becomes locally available (whichever comes first).
The study is to be conducted in conformance with Good Clinical Practice. 
MK-1439A is a single-tablet fixed-dose combination (FDC) that combines doravirine (also 
known as MK-1439), a non-nucleoside reverse transcriptase inhibitor (NNRTI), with 
lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), 2 approved and marketed 
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).  As of the date of issuance of 
this protocol amendment, MK-1439A has been approved in multiple markets including the 
US, EU, Canada, Switzerland and Australia for the treatment of HIV-1 infection in adult 
patients. 
A single tablet of MK-1439A contains a full daily HIV treatment regimen of MK-1439 100 
mg + 3TC 300 mg + TDF 300 mg (which is equivalent to 245 mg of tenofovir disoproxil).  
ATRIPLA™ is a single-tablet FDC that combines an approved and marketed NNRTI, 
efavirenz (EFV), with 2 approved and marketed NRTIs, emtricitabine (FTC) and TDF.  A 
single tablet of ATRIPLA™ contains a full daily HIV treatment regimen of efavirenz 600 mg 
+ FTC 200 mg + TDF 300 mg (which is equivalent to 245 mg of tenofovir disoproxil).  
This study will investigate whether switching from ATRIPLA™ to MK-1439A leads to 
improvement in or resolution of CNS toxicity associated with EFV, as measured by the 
presence of Grade 2 or worse CNS AEs, an overall change in CNS toxicity score, and an 
improvement in sleep quality, neurocognitive function, anxiety/depression, and overall 
health-related quality of life.  The study will also investigate whether switching from 
ATRIPLA™ to MK-1439A leads to continued virologic suppression and immunological 
reconstitution.  In a Phase 2 study in treatment-naïve subjects initiating antiretroviral therapy, 
subjects treated with an MK-1439-based regimen had a significantly lower rate of treatment-
emergent CNS events than those treated with an efavirenz-based regimen (26.9% vs. 46.3%, 
p<0.001) while the antiretroviral activity and immunological effect of the 2 regimens was 
comparable after 24 weeks of therapy [1].  Based on these data, subjects in this study are 
expected to benefit from the switch from ATRIPLA™ to MK-1439A.
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Prior to enrolling in the base study and each of the study extensions, the subject must meet 
eligibility criteria (see Sec. 5.1.2) and provide consent.
Further detail for the base study and the 3 study extensions is provided below.
Base Study:
Approximately 84 subjects who meet eligibility criteria will be randomized to either switch 
immediately to MK-1439A (the ISG) or to continue the ATRIPLA™ regimen for 12 weeks 
and then switch to MK-1439A (the DSG). At Study Week 12, all subjects will be given open-
label MK-1439A for the remainder of their study treatment period. At Study Week 24 (for 
ISG) or 36 (for DSG), subjects who meet the criteria defined in Section 5.1.2 will be eligible 
to enter study extension 1, which is approximately 2 years’ duration, such that the total 
treatment period will be approximately 2.5 years.
The total duration of treatment with MK-1439A for subjects who complete the base study is 
24 weeks, regardless of treatment group.
All subjects entering the study extensions will receive open-label treatment with MK-1439A 
(100 mg q.d.).
Study Extension 1:
At Study Week 24 (for ISG) or 36 (for DSG), eligibility into study extension 1 will be 
determined.  Subjects who meet eligibility criteria may receive open-label MK-1439A for an 
additional 96 weeks; the total duration of treatment for subjects who continue into study 
extension 1 is 120 (ISG) or 132 (DSG) weeks.
Long-term efficacy and safety data will be collected during study extension 1 and 
summarized descriptively; an exploratory objective (efficacy and safety) is defined for study 
extension 1.
Study Extension 2:
At Study Week 120 (for ISG) or 132 (for DSG), eligibility into study extension 2 will be 
determined. Subjects who meet eligibility criteria and continue into study extension 2 may 
continue to receive treatment with MK-1439A until it becomes locally available or up to 
approximately 2 years beyond the first extension (whichever comes first).  For subjects who 
continue into study extension 2, the total duration of treatment is dependent on when MK-
1439A becomes locally available, with a maximum total duration of treatment of up to 216 
weeks (ISG) or 228 weeks (DSG).
During study extension 2, pregnancy for female subjects and SAEs for all subjects will be 
monitored and collected. Efficacy data will not be collected for study extension 2. 
Study Extension 3:
At Study Week 216 (for ISG) or 228 (for DSG), eligibility into study extension 3 will be 
determined. Subjects who meet eligibility criteria and continue into study extension 3 may 
continue to receive treatment with MK-1439A until it becomes locally available or up to 
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approximately 2 years beyond the second extension (whichever comes first).  For subjects 
who continue into study extension 3, the total duration of treatment is dependent on when 
MK-1439A becomes locally available, with a maximum total duration of treatment of up to 
312 weeks (ISG) or 324 weeks (DSG).
During study extension 3, pregnancy for female subjects and SAEs for all subjects will be 
monitored and collected. Efficacy data will not be collected for study extension 3. 
Goals of the Study:
The primary goal of the study is to evaluate whether a switch from ATRIPLA™ to 
MK-1439A results in a lower proportion of subjects who have at least one CNS toxicity of at 
least Grade 2 intensity (according to the DAIDS Toxicity Criteria, Section 12.6) at Study 
Week 12 compared with continuation of ATRIPLA™.  The initial double-blind period of the 
study will allow for a blinded comparison of the randomized treatment groups at the primary 
analysis time point, as well as a comparison of overall safety data.  The unblinding to initial 
randomized treatment assignment that occurs at Study Week 16 will reduce complexity and 
allow continued observation of whether a switch from ATRIPLA™ to MK-1439A leads to 
within-subject improvement in or resolution of CNS toxicity associated with EFV at 
consistent timepoints following the switch (Weeks 4, 12, and 24) in both the ISG and DSG.     
An additional exploratory goal of the study is to assess drug levels of both MK-1439 and 
EFV in the weeks following the switch to evaluate the decline in efavirenz plasma 
concentrations and the rise of MK-1439 plasma concentrations in HIV-1 infected subjects 
switching from EFV to MK-1439.  The pharmacokinetic (PK) assessment will occur during 
the blinded period of the study and will require samples to be collected in both groups at 
Study Day 1 (day of randomization) and Study Weeks 1, 2, 3, and 4. Since sampling occurs 
during the blinded period of the study, plasma samples for PK analysis will be collected from 
both treatment groups, but only samples taken from the ISG will be analyzed.  
Randomized subjects who meet virologic failure criteria during the base study or study 
extension 1 (see Section 4.2.3.2) will return to the site for repeat viral RNA testing between 
one and 4 weeks (≥ 1 and ≤ 4 weeks) later (at a virologic failure confirmation visit).  If 
virologic failure is confirmed and the viral load meets the threshold for resistance testing 
(HIV-1 RNA > 400 copies/mL), in the base study or study extension 1, viral resistance 
testing will be performed.  For subjects in the base study with confirmed virologic failure, 
plasma samples collected for resistance testing from the virologic failure visit and from the 
confirmation visit will be sent for resistance testing.  For subjects in study extension 1, the 
plasma sample from the virologic failure confirmation visit will be sent for resistance testing.  
In addition, plasma samples for resistance testing collected at the discontinuation visit from 
subjects who discontinue, from either the base study or study extension 1, for reasons other 
than virologic failure, will be sent for testing.  (Note that if a sample from the discontinuation 
visit is not available, a sample from the last available visit [if available] will be sent.)
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
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Trial Diagram
The trial design is depicted in Figure 1.  
Figure 1
Trial Design: Base Study and Study Extensions
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Base Study: 
In HIV-1-positive subjects who are virologically suppressed on ATRIPLATM and who, at 
both screening and randomization, are experiencing at least one Grade 2 or worse (according 
to the DAIDS Toxicity Criteria) CNS toxicity from the CNS toxicity questionnaire (ie, one of 
the following CNS toxicities: dizziness, depression/low mood, insomnia/sleeplessness, 
anxiety/nervousness, 
confusion, 
impaired 
concentration/attention, 
headache, 
somnolence/daytime sleepiness, aggressive mood/behavior and abnormal dreams).
Primary Objective(s) & Hypothesis(es)
1) Objective:  To evaluate the effect of a switch to MK-1439A compared with
continuation of ATRIPLATM on the incidence of Grade 2 or worse CNS toxicity
(defined as at least one toxicity listed on the CNS toxicity questionnaire) at Week 12. 
Hypothesis: Switching from ATRIPLATM) to MK-1439A results in a lower proportion 
of subjects with at least one CNS toxicity (from the CNS toxicity questionnaire) of at 
least Grade 2 intensity (according to the DAIDS Toxicity Criteria) at Week 12 than
continuation of ATRIPLATM.
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Secondary Objective(s) & Hypothesis(es)
1) Objective: To evaluate the effect of a switch from ATRIPLATM to MK-1439A 
compared with continuation of ATRIPLATM on the incidence of Grade 2 or worse
CNS toxicity at Week 4.
2) Objective: To evaluate the change from baseline (the day of the switch from 
ATRIPLATM to MK-1439A) in the incidence of Grade 2 or worse CNS toxicity in all 
subjects (combining both treatment groups) at 24 weeks after the switch.
3) Objective: To compare the change from baseline (Study Day 1) in CNS toxicity 
scores at Weeks 4 and 12 between subjects switching from ATRIPLATM to MK-
1439A at Study Day 1 and subjects continuing ATRIPLATM.
4) Objective: To evaluate the change from baseline (the day of the switch from 
ATRIPLATM to MK-1439A) in CNS toxicity scores in all subjects (combining both 
treatment groups) at 24 weeks after the switch.
5) Objective: To evaluate the effect of a switch from ATRIPLATM to MK-1439A 
compared with continuation of ATRIPLATM on fasting lipids (LDL, HDL, non-HDL 
cholesterol and triglycerides) as measured by the change from baseline (Study Day 1)
in fasting lipids at Study Week 12.
6) Objective: To evaluate the effect of a switch from ATRIPLATM to MK-1439A on 
fasting lipids (LDL, HDL, non-HDL cholesterol and triglycerides) as measured by the 
change from baseline (the day of the switch from ATRIPLATM to MK-1439A) in 
fasting lipids at 24 weeks after the switch (combining both treatment groups). 
7) Objective: To evaluate the effect of a switch from ATRIPLATM to MK-1439A on 
virologic suppression as measured by the proportion of subjects with HIV-1 RNA 
below the limit of quantification (< 40 copies/mL) and <50 copies/mL at 24 weeks 
after the switch (combining both treatment groups).
8) Objective: To evaluate the effect of a switch from ATRIPLATM to MK-1439A on 
continued immunologic restoration as measured by the change from baseline (the day 
of the switch from ATRIPLATM to MK-1439A) in CD4 cell count at 24 weeks after 
the switch (combining both treatment groups).
9) Objective: To evaluate the safety and tolerability of a switch from ATRIPLATM to 
MK-1439A compared with continuation of ATRIPLATM, as assessed by review of the 
accumulated safety data through Study Week 12.
10) Objective: To evaluate the safety and tolerability of a switch from ATRIPLATM to
MK-1439A, as assessed by review of the accumulated safety data 24 weeks after the 
switch (combining both treatment groups).
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Exploratory Objectives
1) Objective: To compare subjects switching from ATRIPLATM to MK-1439A and
subjects continuing ATRIPLATM with respect to the change from baseline (Study Day 
1) to Study Weeks 4 and 12 in questionnaire scores assessing the following:

Sleep quality

Anxiety and depression

Health-related quality of life.
2) Objective: To evaluate the effect of a switch from ATRIPLATM to MK-1439A on the 
change from baseline (the day of the switch from ATRIPLATM to MK-1439A) to 24 
weeks after the switch (combining both treatment groups) in questionnaire scores 
assessing the following:

Sleep quality

Anxiety and depression

Health-related quality of life.
3) Objective: To compare subjects switching from ATRIPLATM to MK-1439A and 
subjects continuing ATRIPLATM with respect to the change from baseline (Study Day 
1) to Study Weeks 4 and 12 in neurocognitive function as assessed by Cogstate Brief 
Battery (CBB).
4) Objective: To evaluate the effect of a switch from ATRIPLATM to MK-1439A on the 
change from baseline (the day of the switch from ATRIPLATM to MK-1439A) to
24 weeks after the switch (combining both treatment groups) in neurocognitive 
function as assessed by CBB.
5) Objective: To evaluate MK-1439 and efavirenz plasma concentrations in the 
Immediate Switch Group weekly through 4 weeks following the switch from 
ATRIPLATM to MK-1439A. 
6) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study.
7) Objective (Study Extension 1): To assess long-term efficacy and safety of MK-1439A 
administered for up to 120 weeks for each treatment group, the Immediate Switch 
Group and the Deferred Switch Group. 
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-
1439A.
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Pharmaceutical and Therapeutic Background
HIV infection, which causes Acquired Immunodeficiency 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 (cART)
also referred to as highly active antiretroviral therapy (HAART).  Currently, there are more 
than 30 individual drugs and fixed-dose combinations available for the treatment of HIV-1 
infection. 
These agents belong to 5 distinct mechanistic classes known as reverse 
transcriptase inhibitors [nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs) and non-
nucleoside reverse transcriptase inhibitors (NNRTIs)], protease inhibitors (PIs), fusion 
inhibitors, entry inhibitors (CCR5 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 cART is to suppress HIV to 
undetectable levels so that immune function is preserved or restored.  Yet, while cART can 
delay disease progression and death, as well as reduce the risk of HIV transmission, it does 
not cure the infection. As a result, lifelong treatment must be maintained, which may lead to 
therapy fatigue and to non-compliance if the treatment regimen is difficult to adhere to (e.g. 
pill burden, frequency of treatment) and associated with intolerable side-effects.  This can 
potentially lead to treatment failures with possible emergence
of resistant virus.  
Additionally, there is currently still significant concern regarding toxicities of some widely-
used antiretroviral agents, including neuropsychiatric toxicities associated with efavirenz 
(EFV, an NNRTI), gastrointestinal toxicities such as diarrhea associated with multiple 
protease inhibitors (PIs), and serum lipid abnormalities associated with multiple mechanistic 
classes. 
These toxicities can be bothersome enough to cause subjects to switch from
effective therapies to seek more tolerable alternatives. Thus, potent treatment regimens that 
have an excellent safety and tolerability profile and are convenient to take are still highly 
desirable.
In a retrospective chart review of 276 patients initiating cART therapy, EFV was part of 
initial therapy in 61% [2].  In this series, EFV was later discontinued in 54% of patients, and 
the majority of these discontinuations (60%) were due to CNS toxicities such as dizziness, 
abnormal dreams, mood changes and anxiety.  The incidence of discontinuation due to CNS 
toxicities with a non-EFV based regimen was 3% (P< 0.0001).
Clinical trials have been conducted to examine the effect on CNS toxicity of a switch from an 
EFV-based regimen to an alternative antiretroviral regimen and have demonstrated 
significant improvements in various CNS adverse events, sleep quality, and anxiety scores
[3, 4].  One study in particular provides key data supporting the statistical approach used in 
this protocol.  That double-blind study [3] randomized 38 patients with CNS toxicity who 
were virologically suppressed on ATRIPLATM to either an immediate switch to an etravirine-
based regimen at study entry or a delayed switch at Study Week 12.  The primary endpoint 
was the percentage of subjects with Grade 2-4 CNS toxicity at Week 12.  In the immediate 
switch group,  Grade 2-4 CNS events were observed in 90% of subjects at baseline and 60% 
of subjects at Week 12 (p=0.041); in the delayed switch group, CNS Grade 2-4 events were 
observed in 88.9% of subjects at baseline and 81.3% of subjects at Week 12 (p=NS).  In both 
arms combined, the decline in the proportion of subjects with Grade 2-4 CNS events 12 
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weeks after a switch to etravirine was significant for overall CNS events, insomnia, abnormal 
dreams and nervousness (p=0.009, 0.016, 0.001. and 0.046, respectively). 
As of the date of issuance of this protocol amendment, both MK-1439 (DOR) and MK-
1439A (DOR/3TC/TDF) have been approved in multiple markets including the US, EU, 
Canada, Switzerland, and Australia for the treatment of HIV-1 infection in adult patients. 
MK-1439 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 
once-daily dosing.  MK-1439 displays excellent potency against wild type virus with an IC50
of 12 nM in the presence of 100% normal human serum (NHS).  Preclinical studies also 
indicate a favorable in vitro resistance profile that is distinct from other NNRTIs, with IC50’s
of 21, 31, and 55 nM against mutants containing the most frequently transmitted NNRTI 
mutations, K103N, Y181C and G190A, respectively, under the same conditions.  The 
potency against viruses containing the double mutant K103N + Y181C is 33nM.  The
preclinical toxicity profile of MK-1439 is favorable following dosing in rats up to 6 months 
in duration at 3, 30, and 450 mg/kg/day, and in dogs up to 9 months in duration at 1, 10, and 
1000 mg/kg/day. Clinical pharmacology studies indicate that MK-1439 can be dosed once 
daily, without regard to food, and MK-1439 is not a metabolic inducer or inhibitor, reducing 
the likelihood that it will cause significant drug-drug interactions. In an ongoing Phase 2 
study, MK-1439 has been associated with a significantly lower rate of treatment-emergent 
CNS events after 24 weeks of therapy than EFV in treatment-naïve subjects initiating 
antiretroviral therapy (26.9% vs 46.3%, p<0.001)) while achieving similar antiretroviral 
activity and immunological effect [1, 5]. These data provide support for the expectation that 
a study in which subjects switch from ATRIPLATM to MK-1439A that is based on the 
etravirine switch study design, as discussed above, will demonstrate improvement in CNS 
toxicity.
Rationale
Rationale for the Trial and Selected Subject Population
Although ATRIPLATM has recently been reclassified from a recommended /preferred agent to 
an alternative agent for initial antiretroviral therapy in US-DHHS guidelines [6], UK –
BHIVA guidelines [7], and in other national guidelines, it remains in common use at present.
While some HIV therapies have been shown in clinical trials to be superior to EFV-based 
therapies, these apparent efficacy differences have been due to EFV tolerability issues and 
are not caused by inadequate virologic effect, since most analyses consider discontinuations
due to adverse experiences as efficacy failures. Efavirenz CNS toxicity is common within the 
first weeks of therapy and generally resolves. However, some individuals have longer term 
CNS toxicity which is the most common reason patients switch from EFV to alternative 
therapy. 
Minimizing pill burden and managing toxicities are crucial to maintaining adherence and 
thereby minimizing future risk of virologic failure. Therefore, when switching a patient from 
ATRIPLATM to an alternate regimen, maintaining a once-daily FDC with a third agent such 
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as doravirine (while continuing a similar dual N(t)RTI backbone) is likely to optimize 
adherence.  Furthermore, as stated in Section 4.1.1, data from a comparative Phase 2 study of 
MK-1439 and EFV demonstrated a superior CNS toxicity profile for MK-1439 and support 
the hypothesis that subjects experiencing CNS toxicity on an EFV-based regimen may expect 
improvement in their CNS toxicity after switching to a MK-1439-based regimen.
Current UK and European guidelines for switching an ARV regimen due to EFV-associated
toxicity recommend either within-class switches or switches to a boosted protease inhibitor 
(PI), an integrase inhibitor (InSTI) such as raltegravir (RAL), or maraviroc (MVC); US 
guidance is consistent with this in the setting of virologic suppression, provided antiretroviral 
history and antiretroviral resistance data has been considered (DHHS guidelines, February 
2014). While switching to a boosted PI, RAL or MVC may occur in the presence of active 
viral replication, pill burden may become a limiting factor, particularly given the requirement 
for twice-daily dosing with RAL or MVC. Furthermore, introduction of MVC in the setting 
of recent EFV therapy requires an increase in the dose of MVC to 600 mg bid for the first 
week post switch due to clinically significant induction of MVC metabolism. Within-class 
switches are best performed in the setting of virologic suppression due to the CYP3A4 
enzyme-inducing effects of EFV and consequent risk of subtherapeutic drug concentrations 
of the new NNRTI. 
Although MK-1439 is not expected to cause drug-drug interactions, it is metabolized by 
CYP3A4 and, thus, can be a victim of drug-drug interaction with agents that significantly 
induce or inhibit this enzyme, such as rifampin and ritonavir, respectively [4].  EFV is known 
to be a modest inducer of cytochrome metabolism, and therefore, in anticipation of the 
present study, a drug-drug interaction study was performed to examine the effect of 
switching from EFV to MK-1439 on the metabolism of MK-1439 in healthy volunteers [8].   
This was an open-label, 3-period, fixed-sequence, multiple-dose study. In Period 1, MK-
1439 100 mg q.d. was administered for 5 consecutive days, followed by 7 days of washout 
between the last dose of MK-1439 in Period 1 and the first dose of EFV in Period 2.  In 
Period 2, EFV 600 mg q.d. was administered for 14 consecutive days. There was no washout 
between Periods 2 and 3.
In Period 3, MK-1439 100 mg q.d. was administered for 14 
consecutive days. 
Following cessation of EFV treatment, MK-1439 C24 on Days 1 and 14 of q.d. dosing with 
MK-1439 decreased by 85% and 50%, respectively, relative to the MK-1439 C24 observed 
when MK-1439 was given without EFV pre-treatment.  Following pre-treatment with EFV, 
MK-1439 C24 was 93.5 nM on Day 1 and increased to 449 nM on Day 14 compared to single 
dose and steady state C24 values of 625 nM and 902 nM for MK-1439 100 mg administered 
without prior efavirenz treatment.  EFV plasma concentrations declined from 3180 ng/mL on 
Day 1 to 139 ng/mL on Day 15 after cessation of EFV treatment.  The MK-1439 AUC and 
Cmax were also significantly decreased on Day 1, but less of an effect was seen on Day 14, 
consistent with induction of CYP3A4 and resolution of induction during EFV washout.  
While MK-1439 and EFV plasma concentrations on Days 4 – 7 post-switch both fall below 
those evaluated for efficacy in the clinic for either compound, this drug interaction is not 
anticipated to be clinically meaningful considering the PK targets for both compounds based 
on in vitro potency, the additivity of MK-1439 and EFV antiviral activity and the population 
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being studied (ie, patients that are virologically suppressed and receiving combination 
antiretroviral therapy).
These data suggest no dose adjustment is warranted in the present study at the time of switch.   
However, this will be confirmed by obtaining additional sparse sampling from study subjects 
in the ISG over the first 4 weeks following the switch from ATRIPLATM to MK-1439A.  
Note that in the present study, subjects will have received efavirenz for at least 6 months in 
contrast to 14 days in the Phase 1 study described above.
The goal of this study is to demonstrate that a switch from ATRIPLATM to MK-1439A leads 
to improvement in EFV-associated CNS toxicity.  Since all patients who enter the study will
eventually switch to MK-1439A, the 12-week delay before the switch in the DSG is 
considered acceptable, as patients with intolerable (for example, Grade 4 which can be
judged potentially life threatening) CNS toxicity will likely have had their regimens modified 
promptly during routine clinical care and will not be enrolled in this study.  
Standard safety monitoring for treatment-emergent adverse experiences in this study will be 
conducted as per standard MSD safety monitoring.  However, the standard tools to detect 
treatment-emergent signals focus on new or worsening signs and symptoms of toxicity.  
These tools are neither appropriate nor adequate for capturing improvement of toxicity 
already present at baseline, which is the overall objective of this study.  Therefore a number 
of other instruments will be used, such as the CNS toxicity questionnaire (see Section 12.5).  
This questionnaire is based upon the widely used DAIDS Toxicity Grading Criteria 
(DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND
PEDIATRIC ADVERSE EVENTS, PUBLISH DATE: AUGUST 2009 Version 1, Section 
12.6), and, while not validated, has been used as the standard Toxicity Grading Scale in 
many, if not most, studies in the field of HIV-1 infection for more than a decade. The specific
terms contained in this tool are those commonly associated with EFV toxicity.  Furthermore, 
this tool has been effectively used in studies conducted by the St. Stephens AIDS Trust 
network to show improvement in CNS toxicity following a switch from an EFV-based 
regimen (generally ATRIPLATM) to other anchor agents including etravirine [9] and
raltegravir (unpublished). Thus, this network has extensive experience with the CNS toxicity 
questionnaire and has been collaboratively involved with the design of this study.
To characterize the exploratory outcomes of the study, a number of additional patient-
reported outcomes will be assessed by questionnaire.  These questionnaires will assess sleep 
quality, anxiety/depression, health-related quality of life and neurocognitive function.  These 
tools will be administered at multiple time points to examine both between-group changes 
(up to Week 12) and within-patient changes (pre-switch to 24 weeks post switch in both 
groups combined).
Rationale for Dose Selection/Regimen/Modification
The FDC, MK-1439A, contains 100 mg of MK-1439, a potent NNRTI, and standard doses of 
2 commercially-available and commonly-used NRTIs, TDF (300 mg) and lamivudine (300 
mg).  
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A 100 mg dose of MK-1439 was selected for Phase 3 development based on Phase 1b and 2 
data and several other factors.
In a Phase 1b study (Protocol 005), q.d. oral administration of 25 mg and 200 mg of MK-
1439 as monotherapy for 7 days to treatment-naïve HIV-infected patients reduced plasma 
vRNA burden as compared to placebo-treated controls.  The mean change from baseline in 
log10 HIV RNA copies/mL on Day 7 (24 hours post-dose) was -1.52 for the MK-1439 25 mg 
group and was -1.41 for the MK-1439 200 mg group, while that for the placebo group was -
0.15. The mean differences between MK-1439 25 mg and 200 mg versus placebo in change 
from baseline in log10 HIV RNA copies/mL were -1.37 and -1.26, respectively.
Protocol 007 (Part 1) is a Phase 2 study designed to assess MK-1439 at doses of 25, 50, 100 
and 200 mg q.d. versus efavirenz at 600 mg q.d., both in combination with the fixed-dose 
combination of TDF/FTC (TRUVADA™) in treatment-naïve HIV-1 infected subjects. The 
MK-1439 dose range was selected based upon projections from in vitro data as well as the 
Phase 1b data in HIV-1 infected treatment-naïve individuals, which showed comparable 
virologic suppression at the 25 mg and 200 mg doses given once daily for 7 days.
In Protocol 007 (Part 1) 208 treatment-naïve HIV-1 infected subjects were treated with study 
drug (MK-1439 or efavirenz). At Week 24, all MK-1439 doses had rates of virologic 
suppression comparable to efavirenz for the key efficacy endpoints including the proportion 
of subjects with HIV-1 RNA levels < 40 copies/mL (primary) or < 200 copies/mL
(secondary).  All MK-1439 doses showed numerically higher response rates compared to 
efavirenz (80.0%, 76.2%, 71.4%, 78.0% versus 64.3% of patients with < 40 copies/mL for 
the MK-1439 25 mg, 50 mg, 100 mg, 200 mg versus efavirenz arms, respectively) [1]. The 
treatment differences (MK-1439 minus efavirenz) were not significant, and there was no 
dose response for efficacy observed.  Overall 76.4% of patients receiving MK-1439 (at any 
dose) achieved <40 copies/mL compared with 64.3% for efavirenz. In addition, 
approximately 30% of subjects in the study had baseline HIV RNA above 100,000 
copies/mL, and, in this subgroup, MK-1439 at all dosing levels showed virologic responses 
comparable to efavirenz.  It should be acknowledged that this high viral load subgroup was 
relatively small, with approximately 12 subjects per dosing group.  However, the totality of 
these efficacy data strongly support that the dose range studied (25-200 mg daily) was on the 
plateau of the dose response curve.   
Similarly, the data from Protocol 007 showed an overall favorable safety and tolerability 
profile for MK-1439 compared with efavirenz, with no differentiation among MK-1439 
doses (25 mg - 200 mg daily) with regard to safety.  Based upon the 24 week results of 
Protocol 007, MK-1439 at doses ranging from 25-200 mg was generally well-tolerated, with 
no apparent dose related toxicity. Fewer drug-related AEs were observed for MK-1439 than 
for efavirenz (34.9% for MK-1439 overall vs. 57.1% for EFV), and fewer neuropsychiatric 
AEs were reported both at Week 8 and Week 24 (20.5% for MK-1439 overall vs. 33.3% for 
EFV at Week 8 and 23.4% for MK-1439 overall vs. 33.3% for EFV at Week 24).   
Because the safety and efficacy data from Protocol 007 did not distinguish among the doses 
tested, the selection of the MK-1439 100-mg daily dose for study in Part 2 of Protocol 007 
and in the Phase 3 studies has taken into consideration a number of additional factors.  
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Firstly, MK-1439 is a substrate of CYP3A metabolism and is subject to induction and 
inhibition of CYP3A by other concomitant medications.  Consequently, the 100 mg dose is 
more likely than the lower doses to provide adequate MK-1439 exposures even in the setting 
of moderate metabolic inducers, and it allows for a safety margin in the setting of moderate 
metabolic inhibitors (since acceptable safety and tolerability were seen at the 200 mg dose in 
the Phase 2 study as well as at multiple doses and single doses as high as 750 mg and 1200 
mg, respectively, in Phase 1 studies).  Secondly, the 100-mg dose may provide forgiveness in 
the setting of the occasional missed dose.   Thirdly, based on modeling and simulation, the 
100-mg dose is predicted to provide adequate exposures and Ctrough concentrations in the 
setting of certain common NNRTI resistance mutations against which MK-1439 is 
considered to be active in vitro, including the K103N, Y181C, and Y190A mutations, as well 
as the dual K103N/Y181C mutation. 
Patients receiving MK-1439 at 25, 50 or 200 mg in Part 1 of Protocol 007 were switched to 
100 mg after dose selection. An additional 132 patients were randomized in Part 2, 66 to 
receive MK-1439 100 mg and 66 to receive EFV 600 mg. Combining Part 1 and 2, a total of 
108 patients received MK-1439 100 mg, and 108 patients received EFV. By Week 8, at least 
one neuropsychiatric AE was reported in 22.2% of the MK-1439 group and 43.5% of the 
EFV group (p<0.001).  The most commonly-reported neuropsychiatric AEs were dizziness 
(in 9.3% of patients receiving MK-1439 and 27.8% of patients receiving EFV), insomnia (in 
6.5% of patients receiving MK-1439 and 2.8% of patients receiving EFV), abnormal dreams 
(in 5.6% of patients receiving MK-1439 and 16.7% of patients receiving EFV), and 
nightmares (in 5.6% of patients receiving MK-1439 and 8.3% of patients receiving EFV). 
Standard marketed doses of lamivudine and TDF were selected for inclusion in MK-1439A 
because these dose levels have demonstrated efficacy and safety in treatment-naive subjects,
and no antagonism was observed between MK-1439 and either of these drugs in in vitro 
studies.
ATRIPLA™, the active comparator in this study will be administered at the standard 
approved dose of one tablet once daily.  Each tablet contains 600 mg of efavirenz, 200 mg of 
FTC and 300 mg of TDF (which is equivalent to 245 mg of tenofovir disoproxil).
Rationale for Endpoints
4.2.3.1
CNS Toxicity Questionnaire
The CNS toxicity questionnaire (Section 12.5) will be used to solicit for CNS toxicity and 
will include the following events:
1) Dizziness 
2) Depression/low mood 
3) Insomnia/sleeplessness 
4) Anxiety/nervousness 
5) Confusion
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6) Impaired concentration/attention
7) Headache
8) Somnolence/daytime sleepiness
9) Aggressive mood/behavior
10) Abnormal dreams
The primary endpoint is the proportion of subjects with at least one CNS toxicity of at least 
Grade 2 intensity (according to the DAIDS Toxicity Criteria) at Week 12. Based on a 
similarly designed study of a switch from ATRIPLATM to an etravirine-based regimen that 
had the same primary endpoint [3] it was determined that the proportion of subjects with at 
least one CNS toxicity of at least Grade 2 intensity was deemed to be a more clinically 
relevant and statistically powerful an endpoint versus the CNS toxicity score.
Subjects are asked to rate the intensity for each of the events as none (Grade 0), mild (Grade 
1), moderate (Grade 2), or severe (Grade 3).  Mild, moderate and severe are generally 
defined as follows: mild = symptom is noticeable but does not interfere with normal 
activities; moderate = symptom has some impact on normal activities; severe = symptom 
prevents conduct of normal activities.  The CNS toxicity questionnaire will be completed by 
each subject at screening, Study Day 1, and Study Weeks 4 and 12 during the blinded period 
for all subjects in both treatment groups.  During the open-label period of the base study, 
CNS toxicity assessments will also be completed by subjects in the ISG at Study Week 24 
and by subjects in the DSG at Study Weeks 16, 24 and 36 (which correspond to Weeks 4, 12
and 24 post-switch); during study extension 1, the CNS toxicity questionnaire will be 
completed at each treatment visit and, if applicable, at the early discontinuation visit.   
The change from baseline in CNS toxicity scores is a secondary endpoint in the study. The 
CNS toxicity score is a measure of overall CNS toxicity and is calculated from the same CNS 
questionnaire as is used for the primary endpoint.  The ACTG adverse event scale (None=0,
Mild=1, Moderate=2, Severe=3) is applied to the intensity rating for each of the 10 CNS 
toxicities on the questionnaire, and a CNS toxicity score will be calculated for each subject at 
baseline and at each post-baseline visit by summing across all 10 CNS toxicities and 
converting the sum to a percentage of the maximum possible sum of intensities (10 x 3 = 30).
4.2.3.2
Efficacy Endpoints
Efficacy endpoints being used to address the study objectives are commonly accepted 
endpoints in this type of trial.  Maintaining HIV-1 RNA suppression is considered the key 
efficacy endpoint for switch studies of this type.  Secondary and exploratory measurements 
for efficacy include the proportion of subjects maintaining HIV-1 RNA <50 copies/mL 
24 weeks after the switch to MK-1439A, the proportion of subjects maintaining HIV-1 RNA 
<40 copies/ mL 24 weeks after the switch to MK-1439A, the change in CD4 cell counts from 
baseline (immediately pre-switch) to 24 weeks after the switch to MK-1439A, and viral 
resistance for subjects who meet the virologic failure criteria and whose virus can be 
amplified. Plasma HIV RNA and samples for resistance testing will be collected at all study 
visits (except the post-study follow-up visit and Study Weeks 1, 2 and 3 in both treatment 
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groups).  For all confirmed virologic failures, the plasma sample collected for resistance 
testing from the virologic failure visit will be sent for resistance testing provided the viral 
load meets the criteria for resistance testing (HIV-1 RNA > 400 copies/mL); otherwise, the 
plasma sample collected at the confirmation visit will be sent for resistance testing (if HIV-1 
RNA > 400 copies/mL).
Protocol-defined virologic failure (PDVF) is defined as subjects who have 2 consecutive 
measurements of HIV-1 RNA ≥200 copies/mL at least one week apart.  Subjects should be 
discontinued if they meet the protocol-defined virologic failure criteria.  The choice of 
subsequent antiretroviral therapy will be at the discretion of the study investigator or 
subject’s physician.
4.2.3.3
Safety Endpoints
Safety evaluations and data collected are generally typical of this type of trial.  There is 
special emphasis on subject-reported outcomes and other assessments used to assess non-
efficacy related advantages anticipated of the ISG versus the DSG (see Section 4.2.3.1 and 
Section 4.2.3.4).  General safety evaluations in the base study will include physical 
examinations (and vital signs) and laboratory tests (including fasting lipids at designated 
visits) performed at all scheduled study visits (except Study Weeks 1, 2 and 3 since only PK 
samples are being collected at these timepoints and for subjects in the ISG at Study week 16), 
and, for subjects who do not enter study extension 1, a 14-day follow-up visit. For subjects 
who continue into study extension 1, safety evaluations will be performed at each of the 
study visits in the extension (for subjects in the ISG group, at Study Weeks 40, 56, 72, 88, 
104 and 120 and in the DSG group, at Study Weeks 52, 68, 84, 100, 116 and 132) and, if 
applicable, an early discontinuation visit and/or a virologic failure confirmation visit and at a 
14-day follow-up visit.  Adverse experiences will be evaluated at each visit and assessed 
according to the guidelines in Section 7.2. Subjects may be asked to return for unscheduled 
visits in order to perform additional safety monitoring.
During study extension 2, SAEs and pregnancy test results will be collected at each study 
visit (Week 136, 152, 168, 184, 200, and 216 for ISG and Week 148, 164, 180, 196, 212, and 
228 for DSG, as applicable, depending on when MK-1439A is available locally, and, if 
applicable, at early discontinuation visit).
During study extension 3, SAEs and pregnancy test results will be collected at each study 
visit (Week 232, 248, 264, 280, 296, and 312 for ISG and Week 244, 260, 276, 292, 308, and 
324 for DSG, as applicable, depending on when MK-1439A is available locally, and, if 
applicable, at early discontinuation visit).
4.2.3.4
Exploratory Endpoints
Exploratory endpoints, assessed in the base study only, include the changes from baseline in 
sleep quality scores, neurocognitive function as assessed by CBB, anxiety and depression
scores, and health-related quality of life scores.  The Pittsburgh Sleep Quality Index (PSQI) 
will be used to assess sleep quality.  Neurocognitive function will be assessed using CBB 
tests.  The anxiety and depression assessment will be done using the Hospital Anxiety and 
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Depression Scale (HADS), and general health-related quality of life will be assessed using 
the EQ-5D-5L.  The questionnaires are further described in 7.1.1.9.  All 5 questionnaires will 
be administered at Study Day 1, and Study Weeks 4 and 12 during the blinded period for all 
subjects in both treatment groups.  During the open-label period, all 5 questionnaires will 
also be administered in subjects in the ISG at Study Week 24 and in subjects in the DSG at 
Study Weeks 16, 24 and 36 (which correspond to Weeks 4, 12 and 24 post-switch).   
Pharmacokinetic samples will be collected at Study Day 1 (predose) and Study Weeks 1, 2, 
3, and 4 in all subjects in both treatment groups. Although samples will be collected from 
subjects in both treatment groups to maintain blinding, only samples from subjects in the ISG
will be analyzed. These samples will be assayed for MK-1439 and efavirenz plasma 
concentrations and used to evaluate the decline of efavirenz plasma concentrations and the 
rise of MK-1439 plasma concentrations in the 4 weeks post-switch.
4.2.3.5
Planned Exploratory Biomarker Research
Understanding genetic determinants of drug response is an important endeavor during 
medical research.  This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation.  If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.3.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 12.2. Additional 
informational material for institutional review boards/ethics committees (IRBs/ECs) and 
investigational site staff is provided in Appendix 12.3.
Rationale for Amendment 01
The main reasons for the amendment are to provide a study extension to collect long-term 
safety and efficacy data on MK-1439A; to update the inclusion criteria as well as the 
protocol-specific definition of virologic failure to reflect current medical practice and HIV 
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treatment guidelines; and to update the inclusion criteria and revise the sample size to 
facilitate timely completion of the trial.
Because HIV infection is a chronic disease, with treatment generally lasting for years, 
collection of long-term safety and efficacy data on MK-1439A will provide useful 
information; these data will be summarized descriptively and will not be used to test
hypotheses.
Subjects who are virologically suppressed on ATRIPLATM for at least 12 weeks are very 
unlikely to have drug resistance mutations to NRTIs or efavirenz, since complete viral 
suppression would require fully active efavirenz and NRTIs with no resistance.  Therefore, 
the absence of baseline genotype information for subjects switching from an NNRTI-based 
regimen (ie, ATRIPLATM) would not increase the risk of failure on MK-1439A due to NRTI 
resistance.  This justifies the removal of the requirement for genotyping results prior to the 
start of subject’s initial antiretroviral regimen; inclusion criterion #5 (criterion #6 in the 
original protocol, version 00) has been modified such that genotyping is no longer required,  
but if it has been done and documentation is available, it must show no resistance mutations 
to any study drug.
The inclusion criteria are also broadened to include subjects whose initial regimen was not 
ATRIPLA™ or its components, as long as complete viral suppression is demonstrated prior 
to screening.  This is to acknowledge that there are subjects who had to switch from their 
initial antiretroviral therapy to ATRIPLA™ due to tolerability or other reasons.
For consistency with the definition for viral blips in the US Department of Health & Human 
Services (DHHS) ‘Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults 
and Adolescents’ and to prevent unnecessary discontinuation of trial subjects, protocol-
defined virologic failure (PDVF) is defined as subjects who have 2 consecutive 
measurements of HIV-1 RNA ≥200 instead of ≥ 50 copies/mL at least one week apart.
Due to slower than expected enrollment, the number of subjects is being reduced from 106 to 
84 to allow timely completion of the trial, with the power thus reduced from 90% to 80%.  A 
power of 80% is sufficient to test the trial’s primary objective. 
Rationale for Study Extensions
Because HIV infection is chronic, with treatment generally life long, collection of long-term 
safety and efficacy data will provide useful information on MK-1439A.  Thus, after the 
96-week double-blind period to evaluate the key primary and secondary objectives and 
hypotheses, there will be an open-label study extension (“study extension 1”) for an 
additional 96-week period where all eligible subjects can continue to receive an open-label 
MK-1439A regimen.
Study extensions 2 and 3 were added to avoid interruption of treatment with MK-1439 for 
eligible subjects who are deriving benefit from treatment, until MK-1439 becomes locally 
available. This will also reduce the well-recognized, but small, risk of treatment failure 
associated with a change from a successfully suppressive and tolerated cART regimen.
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Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
MK-1439 is a promising new NNRTI 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 NNRTI resistant variants at concentrations achieved with once-daily dosing.  In 
early studies, MK-1439 has been shown to be efficacious in combination with other ARTs in 
treatment-naïve patients.  MK-1439 is not expected to have many of the safety concerns 
associated with EFV (especially neuropsychiatric AEs and dyslipidemia) and thus may offer 
improvement of CNS toxicity associated with EFV.  In addition, MK-1439 is not expected to 
have major drug-drug interactions that would limit its utility in clinical practice.  Therefore, 
MK-1439 could represent a valuable addition to the HIV armamentarium for treatment-naïve 
patients.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects 18 years of age or older who are HIV-1 positive, who have had 
documentation of HIV-1 RNA < 50 copies/mL for at least 12 weeks prior to screening while 
on ATRIPLATM, generic versions of ATRIPLATM, or the components of ATRIPLATM (EFV, 
TDF plus emtricitabine), and at study entry have undetectable HIV-1 RNA, and who have at 
least one EFV-associated CNS toxicity of Grade 2 or worse intensity at the time of screening 
and Study Day 1 (randomization visit) will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. be at least 18 years of age on the day of signing the informed consent.
2. understand the study procedures and voluntarily agree to participate by giving written 
informed consent (or have a legal representative provide written informed consent, if 
considered acceptable by local regulatory agencies and/or ERCs/IRBs) for the trial.  The 
subject or his/her legal representative (if considered acceptable by local regulatory 
agencies and/or ERCs/IRBs) may also provide consent for Future Biomedical Research.  
However, the subject may participate in the main trial without participating in Future 
Biomedical Research.
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3. have had documentation of HIV-1 RNA < 50 copies/mL for at least 12 weeks prior to 
screening while on ATRIPLATM, as evidenced by  
at least one HIV-1 RNA < 50 copies/mL between 3 and 15 months prior to screening. 
Note: Any subsequent HIV-1 RNA values (if performed) before screening must be 
< 50 copies/mL.
4. have plasma HIV-1 RNA levels BLoQ (< 40 copies/mL by the Abbott RealTime HIV-1 
Assay as determined by the central laboratory) at the screening visit.
5. if genotyping was performed at any point prior to screening and the results are available,
the subject must have no known resistance mutations to any of the study agent
components (MK-1439, tenofovir, lamivudine, EFV, or emtricitabine).
6. have at least one EFV-associated CNS toxicity of Grade 2 or worse intensity both at the 
time of screening and at Study Day 1 (BL); at least one of the Grade 2 or worse intensity 
CNS toxicity present at screening must also be present at Study day 1 with Grade 2 or 
worse intensity.
EFV-associated CNS toxicity is defined as one of the following 
conditions listed on the CNS toxicity questionnaire: dizziness, depression/low mood, 
insomnia/sleeplessness, 
anxiety/nervousness, 
confusion, 
impaired 
concentration/attention, 
headache, 
somnolence/daytime 
sleepiness, 
aggressive 
mood/behavior, abnormal dreams. See examples below:
a.
Screen – Grade 2 dizziness,  BL – Grade 2 dizziness = eligible
b. Screen – Grade 3 dizziness,  BL – Grade 2 dizziness = eligible
c.
Screen – Grade 2 dizziness, BL - Grade 1 dizziness = not eligible
d. Screen – Grade 2 dizziness, BL  - Grade 1 dizziness and Grade 2 insomnia = not 
eligible
7. have the following laboratory values at screening:  
a) Alkaline phosphatase ≤ 3.0 x upper limit of normal (ULN) 
b) AST (SGOT) and ALT (SGPT) ≤ 5.0 x ULN 
c) Hemoglobin ≥9.0 g/dL (if female) or ≥10.0 g/dL (if male).  
Note: A single repeat of a laboratory screening test will be allowed for test results 
that are unexpected based on documented prior laboratory results. 
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8. have a calculated creatinine clearance at the time of screening ≥ 50 mL/min based on the 
Cockcroft-Gault equation which is as follows:
For Men:
Clcr (mL/min) =
(140-age) × weight (in kg)
72 × serum creatinine (mg/dL)
For Women:
Clcr (mL/min) =
(140-age) × weight (in kg)
×    0.85
72 × serum creatinine (mg/dL)
9. in the opinion of the investigator, be considered clinically stable with no signs or 
symptoms of active infection at the time of entry into the study (ie, clinical status and all 
chronic medications should be unchanged for at least 2 weeks prior to the start of 
treatment in this study).
10. be highly unlikely to become pregnant or to impregnate a partner since the subject falls 
into at least one of the following categories:
a.
The subject is a male who is not of reproductive potential, defined as a male who 
has azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).
b. The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) is postmenopausal (defined as at least 12 months with no menses in 
women ≥45 years of age); (2) has had a hysterectomy and/or bilateral 
oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 
6 weeks prior to screening; OR (3) has a congenital or acquired condition that 
prevents childbearing.
c.
The subject is a female or a male who is of reproductive potential and agrees to 
avoid becoming pregnant or impregnating a partner while receiving study drug, for 
12 weeks after the last dose of ATRIPLATM on study (this applies to the last dose 
of ATRIPLATM prior to the switch to MK-1439A in both treatment groups), and for 
14 days following the last dose of MK-1439A on study (if subjects discontinue 
prior to receiving 10 weeks of MK-1439A, they will still need to agree to follow 
aforementioned ATRIPLATM requirements) by complying with one of the 
following: (1) practice abstinence† from heterosexual activity OR (2) use (or have 
their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
Combination method (requires use of 2 of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
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•
cervical cap with spermicide (nulliparous women only)
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)↑
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring,
contraceptive rod implanted into the skin or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
↑Use of barrier methods of contraception is strongly encouraged to reduce the risk 
of HIV-1 transmission during sexual contact.
In order to be eligible for participation in study extension 1, the subject must:
11. have completed the Study Week 24 (for ISG) or Study Week 36 (for DSG) visit.
12. be considered, in the opinion of the investigator, to have derived benefit from study
participation through Study Week 24 (for ISG) or Study Week 36 (for DSG).
13. be considered, in the opinion of the investigator, a clinically appropriate candidate for an 
additional 2 years (additional 96 weeks) of treatment with MK-1439A.
14. understand the procedures in study extension 1 and provide written informed consent to 
enter study extension 1, thus continuing for approximately 2 years (96 weeks) beyond the 
base study.
In order to be eligible to continue receiving MK-1439A in study extension 2, the subject 
must:
15. have completed the Study Week 120 (for ISG) or Study Week 132 (for DSG) visit.
16. be considered, in the opinion of the investigator, to have derived benefit from MK-1439A 
by Study Week 120 (for ISG) or Study Week 132 (for DSG).
17. be considered, in the opinion of the investigator, a clinically appropriate candidate for an 
additional 2 years (additional 96 weeks) of treatment with MK-1439A.
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18. understand the procedures in the study extension and provide written informed consent to 
enter study extension 2, thus continuing treatment with MK-1439A until it is locally 
available or for up to approximately 2 years (whichever comes first) beyond study 
extension 1. 
In order to be eligible to continue receiving MK-1439A in study extension 3, the subject 
must:
19. have completed the Study Week 216 (for ISG) or Study Week 228 (for DSG) visit.
20. be considered, in the opinion of the investigator, to have derived benefit from MK-1439A 
by Study Week 216 (for ISG) or Study Week 228 (for DSG).
21. be considered, in the opinion of the investigator, a clinically appropriate candidate for an 
additional 2 years (additional 96 weeks) of treatment with MK-1439A.
22. understand the procedures in the study extension and provide written informed consent to 
enter study extension 3, thus continuing treatment with MK-1439A until it is locally 
available or for up to approximately 2 years (whichever comes first) beyond study 
extension 2. 
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. has a history or current evidence of any condition, therapy, laboratory abnormality or 
other circumstance that might confound the results of the study or interfere with the 
subject’s participation for the full duration of the study, such that it is not in the best 
interest of the subject to participate.
2. is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history of drug or alcohol abuse or dependence.  The nature and potential 
clinical context of the subject's illicit drug use, in relation to their exclusion from this 
trial, will be at the discretion of the Investigator.
3. has ongoing Grade 4 CNS toxicity during screening period that requires a prompt change 
in ART.
4. 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, adefovir, emtricitabine, 
entecavir, lamivudine or tenofovir.  
Note: Subjects may be enrolled if treatment occurred prior to the diagnosis of 
HIV or in the context of their treatment with ATRIPLATM.
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5. has documented or known resistance to study drugs including MK-1439, EFV, 
lamivudine, emtricitabine, and/or tenofovir (based on genotyping performed prior to the 
initiation of treatment with ATRIPLATM) as defined below:
a.
Resistance to MK-1439 or Efavirenz for the purpose of this study includes the 
following NNRTI mutations: L100I, K101E, K101P, K103N, K103S, V106A, 
V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, 
Y181I, Y181V, Y188C, Y188H, Y188L, G190A, G190S, H221Y, L234I, P225H, 
F227C, F227L, F227V, M230L, M230I
b. Resistance to lamivudine, emtricitabine and tenofovir includes the following 
mutations: K65R, M41L, T69S (insertion complex), Q151M, M184I, M184V, 
L210W, T215F, T215Y, K219E, K219Q, D67N, K70R, K70E. 
6. has participated in a study with an investigational compound/device within 30 days prior 
to signing informed consent or anticipates participating in such a study involving an 
investigational compound/device during the course of this study.
7. 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: Short courses of corticosteroids (e.g., as for asthma exacerbation) will be allowed
8. requires or is anticipated to require any of the prohibited medications noted in the 
protocol (refer to Section 5.5).
9. has significant hypersensitivity or other contraindication to any of the components of the 
study drugs as determined by the investigator
10. has a current (active) diagnosis of acute hepatitis due to any cause.
Note: Subjects with chronic hepatitis B and C may enter the study as long as they 
fulfill all entry criteria, have stable liver function tests, and have no significant 
impairment of hepatic synthetic function (significant impairment of hepatic synthetic 
function is defined as a serum albumin <2.8 mg/dL or an INR >1.7 in the absence of 
another explanation for the abnormal laboratory value).  
11. has evidence of decompensated liver disease manifested by the presence of or a history of
ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or
symptoms of advanced liver diseases 
or 
has liver cirrhosis and a Child-Pugh Class C score or Pugh-Turcotte (CPT) score > 9.
Note: To calculate the CPT score and associated Child-Pugh Class, refer to the 
following website: http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality
is pregnant, breastfeeding, or expecting to conceive (at any time during the study).
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12. is pregnant, breastfeeding, or expecting to conceive.
13. is female and is expecting to donate eggs (at any time during the study) or is male and is 
expecting to donate sperm (at any time during the study).
Note: Investigators should provide appropriate guidance to the subjects regarding egg 
and sperm donation after completion of the study treatment. Consistent with the 
recommendations for contraceptive use, it is recommended that all subjects refrain 
from egg or sperm donation for 12 weeks following their last dose of study treatment.
14. is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
The 2 treatment regimens to be used in the base trial are outlined below in Table 1, and the 
treatment regimen to be used in the trial extension is shown in Table 2.
To maintain 
blinding, both drugs will be administered with a placebo matched to the other active drug in 
the study.  Sites should not call IVRS/IWRS for drug administration until the subject has met 
all criteria for the study and is ready to receive the first dose of study medication on Day 1.  
All subjects in this study will switch from ATRIPLATM to MK-1439A and receive 
MK-1439A for 24 weeks.  The 2 treatment groups differ in the timing of the switch and the 
treatment they will receive for the first 12 weeks of the study.  The Immediate Switch Group 
will switch to MK-1439A on Study Day 1.  This group will receive MK-1439A with a 
placebo matched to ATRIPLATM during the first 12 weeks of the trial (the blinded treatment 
period) and will receive MK-1439A alone for 12 additional weeks in the open-label period of 
the trial.  The Deferred Switch Group will receive ATRIPLATM with a placebo matched to
MK-1439A during the first 12 weeks of the trial (the blinded period) and will receive MK-
1439A alone for 24 weeks in the open-label period of the trial.  Blinded trial treatment should 
begin on the day of randomization in both treatment groups.  At Study Week 12, all subjects 
will be given open-label MK-1439A for the remainder of their study treatment period.  No 
further ATRIPLATM or placebo matched to either agent will be used beyond the Week 12
visit.  At Study week 16, all subjects will be unblinded to their initial treatment assignment. 
Table 1
Treatment Regimens During Base Study
Groups
Blinded Period
(Study day 1 – Week 12)
Open-Label Period
(Duration)
Immediate Switch 
N = ~ 42
MK-1439A
Placebo# matched to ATRIPLATM
MK-1439A 
(Week 12-24)
Deferred Switch 
N = ~ 42
ATRIPLATM
Placebo# matched to MK-1439A
MK-1439A 
(Week 12-36)
MK-1439A is a single-tablet FDC containing MK-1439 100 mg, lamivudine 300 mg and TDF 300 mg
(which is equivalent to 245 mg of tenofovir disoproxil).
ATRIPLA™ is a single tablet FDC containing efavirenz 600 mg, emtricitabine 200 mg, and TDF 300 
mg (which is equivalent to 245 mg of tenofovir disoproxil).
# Placebos are used to maintain blinding
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Table 2
Treatment Regimen During Study Extensions
Groups
Open-Label Period
(Duration)
Immediate Switch 
MK-1439A 
(Study Week 24-312)
Deferred Switch 
MK-1439A 
(Study Week 36-324)
MK-1439A is a single-tablet FDC containing MK-1439 100 mg, lamivudine 300 mg and TDF 300 mg
(which is equivalent to 245 mg of tenofovir disoproxil).
Subjects will receive study medication at the Day 1 visit and should take the first dose of 
medication from each bottle (Bottle A and Bottle B) on the same day.
During the double-blind period, MK-1439A and the placebo matched to MK-1439A (Bottle 
A) are to be taken once daily without regard to food at approximately the same time each 
day.
During the double-blind period, ATRIPLA™and the placebo matched to ATRIPLA™
(Bottle B) are to be taken once daily at bedtime on an empty stomach. 
During the open-label period of the base study and during the study extensions, MK-1439A
(Bottle C) should be taken once daily without regard to food at approximately the same time 
each day.
All study medications as indicated in Table 1 and Table 2 above (ATRIPLA™, 
ATRIPLA™-matched placebo, MK-1439A and MK-1439A-matched placebo) for the base 
study and for the study extensions (provided that development of MK-1439A is continuing)
will be provided centrally 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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
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5.2.1.2
Dose Modification/Interruption
Dose Modification:
No dose modification of study therapy is allowed during the base study or the study 
extensions.
Dose Interruption:
Consideration should be given to interrupting study therapy for toxicity management (see 
Section 7.1.2.6).
Interruptions from the protocol-specified treatment plan that are expected to be 7 days or 
greater require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on subject management.
Timing of Dose Administration
From Study Day 1 to the Study Week 12 visit (Blinded Treatment Period):
Bottle A (MK-1439A or placebo):  
Subjects will be instructed to take one tablet from Bottle A once a day (q.d.) orally, with or 
without food at the approximately the same time each day. 
If a subject misses a dose of drug from Bottle A and it is less than 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 
a subject misses a dose and it is greater than 12 hours before the next dose, the missed dose 
should be taken and the normal dosing schedule resumed.
Bottle B (ATRIPLA™ or placebo):  
Subjects will be instructed to take one tablet from Bottle B once a day (q.d.) orally, on an 
empty stomach at bedtime. 
If a subject misses a dose of drug from Bottle B and it is less than 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 
a subject misses a dose and it is greater than 12 hours before the next dose, the missed dose 
should be taken and the normal dosing schedule resumed.
From Study Week 12 to the end of study treatment (Open-Label Treatment Period).
Bottle C (open label MK-1439A):  
Subjects will be instructed to take one tablet from Bottle C once a day (q.d.) orally, with or 
without food at the approximately the same time each day. 
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If a subject misses a dose of drug from Bottle C and it is less than 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 
a subject misses a dose and it is greater than 12 hours before the next dose, the missed dose 
should be taken and the normal dosing schedule resumed.
Trial Blinding/Masking
A double-blind/masking technique will be used. 
MK-1439A, ATRIPLATM and their 
respective placebos will be packaged so that blind/masking is maintained. The subject, the 
investigator and Sponsor personnel or delegate(s) who are involved in the treatment or 
clinical evaluation of the subjects are unaware of the group assignments.
Unblinding Procedures:
A subject will not be unblinded until Study Week 16 visit.  All adverse event data through 
the first 12 weeks of treatment for that subject must be cleaned and reconciled prior to 
unblinding.  
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to either an immediate switch to 
MK-1439A on Study Day 1 (Immediate Switch Group) or to continued treatment with 
ATRIPLATM for 12 weeks in the base study followed by switch to open label MK-1439A
(Deferred Switch Group).  With ~84 subjects enrolled, ~42 subjects will be randomized to 
each group.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
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No medications are to be taken within 30 days prior to the start of treatment in this study 
without the knowledge of the investigator. 
Listed below are specific restrictions for concomitant therapy or vaccination during the 
course of the trial:
Permitted Concomitant Medications/Therapies
The concomitant use of other medications/therapies is allowed unless specifically prohibited 
in the Prohibited Concomitant Medication/Therapies section below. Before placing a subject 
on a specific medication/therapy, it is the responsibility of the investigator to check on 
potential drug-drug interactions between that medication/therapy and ATRIPLA™.
1. Use of oral or other hormonal contraception is permitted. 
2. Newly approved regimens for the treatment of HCV infection are permitted, as long 
as there are no known potential drug-drug interactions between those treatments and 
any of the study medications.  The MSD Clinical Director or designee should be 
contacted if there are any questions about whether there is a potential drug-drug 
interaction with a specific treatment that the Investigator is planning to give the 
subject.
Prohibited Concomitant Medications/Therapies
In general, concomitant use of immune therapy agents or other immunosuppressive therapy,
including interferon-based treatment for hepatitis, is not allowed during the course of the 
study.  Important exceptions to this rule include:

Short courses of corticosteroids (e.g., as for asthma exacerbation) are allowed. 

Intralesional or localized electron beam therapy for cutaneous Kaposi’s sarcoma is 
permitted. 

If a subject develops a malignancy (for example lymphoma) after randomization, the 
subject may receive chemotherapy (including cancer immunotherapy) 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.
Antiretroviral therapies other than MK-1439A and ATRIPLA™are not permitted for use by 
subjects during the course of the study. 
Investigational agents must be discontinued for 30 days prior to treatment in this study and
are also not permitted during the course of the study.
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Prohibited Concomitant Therapy Due to Potential Interactions with MK-1439A
MK-1439 is expected to be eliminated mainly via CYP3A (cytochrome)-mediated oxidation. 
The medications and/or substances below are prohibited in this study because they are 
moderate or potent inducers of CYP3A, and their co-administration with MK-1439A could 
possibly result in reduced drug levels of MK-1439 or has the potential for additional drug-
drug interactions.  Since this list is not comprehensive, the investigator should use his/her 
medical judgment when a subject presents with a medication not on the list or call the 
Sponsor Clinical Director or Designee for clarification. 
Table 3
Prohibited Medication/Therapy Due to MK-1439 Interaction During the Base 
Study and Study Extensions
Carbamazepine
Oxcarbazepine
Enzalutamide
Mitotane
Rifapentine
Phenobarbital
Phenytoin
Rifabutin
Rifampin
St. John’s Wort
Modafinil
Bosentan
Nafcillin
Prohibited Concomitant Therapy Due to Potential Interactions with ATRIPLA™(applicable 
during the blinded treatment period + 4 weeks: Study Day 1 to Study Week 16)
Efavirenz induces CYP3A4 metabolism and may significantly reduce the exposure of 
CYP3A4 substrates.  In addition, there are some medications that may significantly alter the 
metabolism of efavirenz.  In some cases, co-administration of certain drugs with 
ATRIPLA™may lead to significant safety risks.
The following medications are prohibited 
in this study because they: (1) are contraindicated for concomitant use with ATRIPLA™
(according to one or more available ATRIPLA™package circulars), (2) may alter the plasma 
concentration of one or more of the ATRIPLA™components and/or (3) may have significant 
changes in their plasma concentrations when co-dosed with ATRIPLA™that would require 
additional monitoring or dose adjustment, which is not feasible in the setting of a double-
blind trial.  
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Table 4
Prohibited Medication/Therapy Due to ATRIPLA™ Interactions
Artermether
Astemiazole
Bepridil
Boceprevir
Carbamazepine
Cisapride
Clarithromycin
Cyclosporine
Dihydroatenisinin
Ergot derivatives
Itraconazole
Ketoconazole
Lumefantrine 
Midazolam
Phenobarbital
Phenytoin
Pimozide
Rifabutin
Rifampin
Simeprevir
Sirolimus
St. John’s Wort
Tacrolimus
Telaprevir
Terfenadine
Triazolam
Voriconazole
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director.  
Concomitant Therapy to be used With Caution
For complete information, please refer to the ATRIPLA™ package circular available locally
for drugs that are permitted in the protocol but that should be used with caution, since they 
have established drug interactions with ATRIPLA™.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
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Diet/Activity/Other Considerations
Diet:
MK-1439A/placebo can be consumed without regard to food.  MK-1439A/placebo should 
generally be taken at approximately the same time each day.
ATRIPLA™/placebo should be taken once daily at bedtime on an empty stomach. 
Alcohol/Substance Abuse:
Subjects should be questioned about their estimated daily intake of alcohol and about 
substance abuse during the screening evaluation of eligibility.  Any subject who, in the 
opinion of the investigator has an excessive intake of any of these substances must be 
excluded from the study
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
Note:  Please provide additional detail for the reason the subject withdrew consent on 
the Subject Disposition eCRF (electronic case record form).

The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.  These may include, but are not limited to:
o
clinical or laboratory findings suggestive of lactic acidosis or 
pronounced 
hepatotoxicity 
(which 
may 
include 
symptomatic 
hyperlactataemia, metabolic/lactic acidosis, progressive hepatomegaly, 
rapidly elevating aminotransferase levels, and hepatomegaly and 
steatosis even in the absence of marked transaminase elevations).
o
severe rash associated with blistering, desquamation, mucosal 
involvement or fever
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o
severe depression, psychosis or suicidal ideation 

The subject has a confirmed positive serum/urine pregnancy test.
Note: Subjects who become pregnant during the study will be asked to join a 
pregnancy registry which collects information about the outcome of the pregnancy.

The subject fails to comply with the dosing, evaluations, or other requirements of the 
trial.

A physician investigator feels it is in the best interest of the subject to discontinue.

The subject has an adverse experience or tolerability issue related to study medication 
which requires discontinuation of the medication.

The subject has a creatinine clearance of <50 mL/min (confirmed by repeat 
measurement) based on the following Cockcroft-Gault equation:
Male: 
Clcr (mL/min) =
(140-age) × weight (in kg)
72 × serum creatinine (mg/dL)
Female:
Clcr (mL/min) =
(140-age) × weight (in kg)
×    0.85
72 × serum creatinine (mg/dL)
or subject has serum phosphorous <0.32 mmol/l. 
Note:  Subjects with serum phosphorous <0.48 mmol/l should be closely monitored.

Subject requires interferon-based treatment for hepatitis. 

Subjects who participate in study extension 2 or study extension 3 should be 
discontinued at next scheduled visit after MK-1439A becomes locally available.
Subjects should be discontinued regardless of compliance with study therapy if they meet the 
protocol-defined virologic failure criteria in Section 4.2.3.2.
Subjects who require discontinuation of any component of the study therapy must be 
discontinued from the trial.
Subjects who discontinue study therapy prior to the last scheduled treatment visit should 
have an Early Discontinuation visit and 14 day follow-up visit conducted.
Due to the potential for severe acute exacerbations of hepatitis B following discontinuation 
with ATRIPLATM, lamivudine and tenofovir, subjects who are co-infected with hepatitis B 
who stop their assigned study therapy at or prior to the end of the study must be closely 
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monitored for such exacerbations for at least 6 months. This requirement applies to subjects
in both treatment arms. If approved by the Sponsor, a subject can remain on study if they 
cannot make it to regularly scheduled study visits due to unforeseen circumstances but are 
able to remain on study therapy and the Investigator believes it is in the best interest of the 
subject to do so.
Once discontinued from the base study, a subject is not eligible to enter study extension 1.  
Note that a subject who completes the base study and does not elect to participate in study 
extension 1 is considered to have completed the study. Once discontinued from study 
extension 1, a subject is not eligible to enter study extension 2; and once discontinued from 
study extension 2, a subject is not eligible to enter study extension 3.  
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject 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:
Further recruitment in the trial or at a particular trial site(s) may be stopped due to 
insufficient compliance with the protocol, GCP, and/or other applicable regulatory 
requirements, procedure-related problems, or the number of discontinuations for 
administrative reasons is too high.
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6.0 TRIAL FLOW CHART
The flow chart in Section 6.1 applies to the base study from screening through follow-up after the Week 24 or 36 visit.  The flow 
charts in Sections 6.2 and 6.3 apply to ISG and DSG subjects, respectively, continuing into study extension 1, from Week 24 (ISG) or 
Week 36 (DSG) through follow-up after the Week 120 (ISG) or Week 132 (DSG) visit.  The flow charts in Sections 6.4 and 6.5 apply 
to ISG and DSG subjects, respectively, continuing into study extension 2. The flow charts in Sections 6.6 and 6.7 apply to ISG and 
DSG subjects, respectively, continuing into study extension 3.
Base Study Flow Chart: Screening Through Week 24 (ISG) or 36 (DSG) Plus 14-Day Follow-up
Visit number/Title
1
2
Random-
ization
3
4
5
6
7
8
9
10
U
(Virologic
Failure
Confirma-
tion)
U
(Early
Discontin-
uation)
99
Trial Period
Screening
Double-Blind Treatment Periodn
(Both Groups)
Open-Label Treatment Periodn
(By Group)
Post 
treatmento
TRIAL PROCEDURES
by STUDY WEEK
Screen
(45 days)
Fasting
Day 1a
WK 1
WK 2
WK 3
WK 4
Fasting
WK 12
WK 16s
Fasting
WK 24
Fasting
WK 36
(DSG 
ONLY)
1 to 4 
weeks after
initial
virologic
failure
At time of
Discontin-
uation
14-Day 
Follow-
up
Timing relative to switch to MK-1439A
Immediate Switch Group 
(ISG)
Day 1
of Switch
WK 1
Post 
Switch
WK 2
Post 
Switch
WK 3
Post 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 16
Post 
Switch
WK 24
Post 
Switch
NA
Deferred Switch Group 
(DSG)
-12 WKs
(Prior to 
Switch)
-11 WKs
(Prior to 
Switch)
-10 WKs
(Prior to 
Switch)
-9 WKs
(Prior to 
Switch)
-8 WKs
(Prior to 
Switch)
Day 1
of 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 24
Post 
Switch
Administrative 
Procedures
Informed Consent
x
Informed Consent ISG 
(For subjects entering 
study extension only)
xu
Informed Consent DSG
(For subjects entering 
study extension only)
xu
Informed Consent for 
Future Biomedical 
Researchb
x
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Visit number/Title
1
2
Random-
ization
3
4
5
6
7
8
9
10
U
(Virologic
Failure
Confirma-
tion)
U
(Early
Discontin-
uation)
99
Trial Period
Screening
Double-Blind Treatment Periodn
(Both Groups)
Open-Label Treatment Periodn
(By Group)
Post 
treatmento
TRIAL PROCEDURES
by STUDY WEEK
Screen
(45 days)
Fasting
Day 1a
WK 1
WK 2
WK 3
WK 4
Fasting
WK 12
WK 16s
Fasting
WK 24
Fasting
WK 36
(DSG 
ONLY)
1 to 4 
weeks after
initial
virologic
failure
At time of
Discontin-
uation
14-Day 
Follow-
up
Timing relative to switch to MK-1439A
Immediate Switch Group 
(ISG)
Day 1
of Switch
WK 1
Post 
Switch
WK 2
Post 
Switch
WK 3
Post 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 16
Post 
Switch
WK 24
Post 
Switch
NA
Deferred Switch Group 
(DSG)
-12 WKs
(Prior to 
Switch)
-11 WKs
(Prior to 
Switch)
-10 WKs
(Prior to 
Switch)
-9 WKs
(Prior to 
Switch)
-8 WKs
(Prior to 
Switch)
Day 1
of 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 24
Post 
Switch
Inclusion/Exclusion 
Criteria
x
x
Medical Historyc
x
Provide Subject 
Identification Card
x
Concomitant Medication 
Review
x
x
x
x
x
x
x
x
x
Treatment 
Allocation/Randomizatio
n
x
Register Study Visit via 
Interactive Voice/Web 
Response System 
(IVRS/IWRS)
x
x
x
x
x
x
x
x
Dispense Study Therapyd
x
x
x
x
xq
xt
Provide/Review Study 
Medication Diary
x
x
x
x
x
x
x
x
x
x
Unblinding via 
IVRS/IWRSp
x
Clinical Procedures
/Assessments
Full Physical 
Examination
x
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Visit number/Title
1
2
Random-
ization
3
4
5
6
7
8
9
10
U
(Virologic
Failure
Confirma-
tion)
U
(Early
Discontin-
uation)
99
Trial Period
Screening
Double-Blind Treatment Periodn
(Both Groups)
Open-Label Treatment Periodn
(By Group)
Post 
treatmento
TRIAL PROCEDURES
by STUDY WEEK
Screen
(45 days)
Fasting
Day 1a
WK 1
WK 2
WK 3
WK 4
Fasting
WK 12
WK 16s
Fasting
WK 24
Fasting
WK 36
(DSG 
ONLY)
1 to 4 
weeks after
initial
virologic
failure
At time of
Discontin-
uation
14-Day 
Follow-
up
Timing relative to switch to MK-1439A
Immediate Switch Group 
(ISG)
Day 1
of Switch
WK 1
Post 
Switch
WK 2
Post 
Switch
WK 3
Post 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 16
Post 
Switch
WK 24
Post 
Switch
NA
Deferred Switch Group 
(DSG)
-12 WKs
(Prior to 
Switch)
-11 WKs
(Prior to 
Switch)
-10 WKs
(Prior to 
Switch)
-9 WKs
(Prior to 
Switch)
-8 WKs
(Prior to 
Switch)
Day 1
of 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 24
Post 
Switch
Directed Physical 
Examination
x
x
x
x
x
x
x
x
Height
x
Vital Signs (including 
pulse rate, blood 
pressure, respiratory rate, 
and body temperature) 
and weight
x
x
x
x
x
x
x
x
x
Adverse Events 
Monitoring
x
x
x
x
x
x
x
x
x
x
x
Birth Control 
Confirmation
x
x
x
x
x
x
x
x
x
12-Lead 
Electrocardiogram 
(ECG) (local) 
x e m
CNS toxicity 
questionnaire
x
x
x
x
x
x
x
x
Neurocognitive function  
(Cogstate brief battery -
CBB)f
x
x
x
x
x
x
x
Patient-Reported 
Outcomesf
x
x
x
x
x
x
x
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Visit number/Title
1
2
Random-
ization
3
4
5
6
7
8
9
10
U
(Virologic
Failure
Confirma-
tion)
U
(Early
Discontin-
uation)
99
Trial Period
Screening
Double-Blind Treatment Periodn
(Both Groups)
Open-Label Treatment Periodn
(By Group)
Post 
treatmento
TRIAL PROCEDURES
by STUDY WEEK
Screen
(45 days)
Fasting
Day 1a
WK 1
WK 2
WK 3
WK 4
Fasting
WK 12
WK 16s
Fasting
WK 24
Fasting
WK 36
(DSG 
ONLY)
1 to 4 
weeks after
initial
virologic
failure
At time of
Discontin-
uation
14-Day 
Follow-
up
Timing relative to switch to MK-1439A
Immediate Switch Group 
(ISG)
Day 1
of Switch
WK 1
Post 
Switch
WK 2
Post 
Switch
WK 3
Post 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 16
Post 
Switch
WK 24
Post 
Switch
NA
Deferred Switch Group 
(DSG)
-12 WKs
(Prior to 
Switch)
-11 WKs
(Prior to 
Switch)
-10 WKs
(Prior to 
Switch)
-9 WKs
(Prior to 
Switch)
-8 WKs
(Prior to 
Switch)
Day 1
of 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 24
Post 
Switch
Assess Subject 
Eligibility for Study 
Extension 1 (ISG)
xu
Assess Subject 
Eligibility for Extension
Study 1 (DSG)
xu
Laboratory 
Procedures/
Assessments
Collect Blood for Safety 
Laboratory Tests 
(Hematology/
Chemistry)g
x
x
x
x
x
x
x
x
x
x
Serum Pregnancy Testh
x
Urine Pregnancy Test (if 
applicable)h
xe
x
x
x
x
x
x
x
Hemostatic Function 
Testi
x
HIV/Hepatitis Screenj
x
Virology Test Plasma 
HIV viral RNA 
quantification test 
(Abbott Real Time HIV-
1)
x
x
x
x
x
x
x
x
x
x
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Visit number/Title
1
2
Random-
ization
3
4
5
6
7
8
9
10
U
(Virologic
Failure
Confirma-
tion)
U
(Early
Discontin-
uation)
99
Trial Period
Screening
Double-Blind Treatment Periodn
(Both Groups)
Open-Label Treatment Periodn
(By Group)
Post 
treatmento
TRIAL PROCEDURES
by STUDY WEEK
Screen
(45 days)
Fasting
Day 1a
WK 1
WK 2
WK 3
WK 4
Fasting
WK 12
WK 16s
Fasting
WK 24
Fasting
WK 36
(DSG 
ONLY)
1 to 4 
weeks after
initial
virologic
failure
At time of
Discontin-
uation
14-Day 
Follow-
up
Timing relative to switch to MK-1439A
Immediate Switch Group 
(ISG)
Day 1
of Switch
WK 1
Post 
Switch
WK 2
Post 
Switch
WK 3
Post 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 16
Post 
Switch
WK 24
Post 
Switch
NA
Deferred Switch Group 
(DSG)
-12 WKs
(Prior to 
Switch)
-11 WKs
(Prior to 
Switch)
-10 WKs
(Prior to 
Switch)
-9 WKs
(Prior to 
Switch)
-8 WKs
(Prior to 
Switch)
Day 1
of 
Switch
WK 4
Post 
Switch
WK 12
Post 
Switch
WK 24
Post 
Switch
Collect Blood for CD4 
Cell Count
x
x
x
x
Viral Resistance Test 
(Plasma)
x
x
x
x
x
x
x
xk
Collect Blood for 
Genetic Analysisb
x
Collect Plasma for 
Future Biomedical 
Researchr
x
Collect Blood for MK-
1439 and Efavirenz PKl
x
x
x
x
x
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a. Prior to the first dose on Day 1.
b. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response.  If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR 
is approved and consent is given, this sample will be collected for the purpose of FBR.
c. Includes smoking history, historical genotype (if available) and pretreatment HIV RNA.
d. IVRS/IWRS will be used to allocate drug and to manage distribution of study drugs.
e. Results of test must be available prior to randomization and prior to the subject’s first dose of medication.
f. Patient-Reported Outcomes including, for subjects enrolled under the original protocol (version 00), the CBB, will be done on Study Day 1 and Study Weeks 4, 12, and 24 
for the ISG, on Study Day 1 and Study Weeks 4, 12, 16, 24 and 36 for the DSG and at discontinuation (if applicable) for all subjects (Immediate and Deferred Switch 
Treatment Groups). CBB at Study Day 1 will also include a practice. NOTE: Subjects enrolled under Amendment 01 will not use the CBB.  Subjects enrolled under the 
original protocol (version 00) are required to complete the CBB at specified visits in the base study per the study flow chart.  All other PRO questionnaires (CNS Toxicity 
questionnaire, Pittsburgh Sleep Quality Index [PSQI], Hospital Anxiety and Depression Scale [HADS], and the EuroQol Five Dimensional Descriptive System, Five Level 
Version [EQ-5D-5L]) are mandatory for all subjects.
g. Refer to Table 5 for listing of specific blood safety tests.
h. For women of childbearing potential.
i. Hemostatic Function Test includes: Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) and International Normalized Ratio (INR).
j. HIV/Hepatitis Screening Tests include: Enzyme Immunoassay HIV Antibody Screen, Serum Hepatitis B Surface Antigen, Serum Hepatitis B Surface Antibody, Serum 
Hepatitis B e-Antigen and Serum Hepatitis C Antibody. A plasma Hepatitis C virus PCR quantitative test will be performed if the Hepatitis C antibody test is positive.
k. If viral failure or relapse is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for resistance 
does not need to be collected again at the discontinuation visit. All other early discontinuation tests should be performed at the early discontinuation visit.
l. Blood samples will be collected from subjects in both treatment groups due to the blinded nature of the study, even though samples will only be analyzed for subjects 
randomized to the Immediate Switch Group.
m. A local ECG should be performed prior to the subject’s first dose of study medication (at either the Screening visit or the Study Day 1 visit).
n. Visit window periods are approximately: +/- 1 day for the Week 1, 2, and 3 visits; +/- 3 days for the Week 4, 12, 16, 24, and 36 visits. The timing of each visit is relative to 
the randomization (Day 1) visit.  Every attempt must be made to keep subjects on schedule.
o. The visit window period for the Post-study 14 day follow-up visit is approximately – 2 to 0 days. If the post-study visit occurs less than 14 days after the last dose of study 
drug, a subsequent follow-up phone call should be made at 14 days post the last dose of study drug to determine if any adverse events have occurred since the post-study 
clinic visit.  This follow-up assessment applies only to subjects who complete (or discontinue from) the base study and do not enter study extension 1.
p. All adverse events data through the first 12 weeks of treatment for that subject will be cleaned and reconciled prior to unblinding.  
q. At Week 24, subjects in the ISG entering study extension 1 will be dispensed a 16-week supply of study drug (open-label MK-1439A) and subjects in the DSG participating 
in the base study will be dispensed a 12-week supply of study drug (open-label MK-1439A). 
r. Plasma samples for Future Biomedical Research should be collected at Study Day 1 if the subject consents to future biomedical research.
s. For subjects in the ISG only assessments required are AE, concomitant medication and study medication diary review at this visit in addition to unblinding via IVRS/IWRS. 
Subjects in the DSG will have all assessments listed at this visit in addition to unblinding via IVRS/IWRS.  
t. Subjects in the DSG entering the study extension at Week 36 will be dispensed a 16-week supply of study drug (open-label MK-1439A).
u. If the subject is eligible (based on the inclusion criteria relevant to the study extension) and elects to enter the study extension, he/she will be considered to have completed 
the base study and will, after providing informed consent (signed an ICF for the extension), immediately enter the study extension and be dispensed MK-1439A.
NA:  Not applicable
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Study Extension 1 Flow Chart for Immediate Switch Group (ISG): Weeks 40 Through 120 Plus 14-Day Follow-up
Visit Number
11
12
13
14
15
16
TRIAL PROCEDURES by STUDY WEEK
WK 40
WK56
Fasting
WK 72
WK 88
WK 104
Fasting
WK 120
U
(Virologic Failure
Confirmation)
U
(Extension 1
Early
Discontinuation)
99
Trial Period:
Study Extension: Treatmenta,b
1 to 4 
after initial
virologic failure
At time of
Discontinuation
Post
treatment
Weeks post base study
16 WKs 32 WKs
48 WKs
64 WKs
80 WKs
96 WKs
14-Day
Follow-upc
Administrative Procedures
Concomitant Medication Review
x
x
x
x
x
x
x
x
Register Study Visit via Interactive Voice/Web
Response System (IVRS/IWRS)
x
x
x
x
x
x
x
Dispense Study Therapyd
x
x
x
x
x
xe
Provide/ Review Study Medication Diary
x
x
x
x
x
x
x
Clinical Procedures/Assessments
Directed Physical Examination
x
x
x
x
x
x
x
x
Vital Signs (including pulse rate, blood pressure,
respiratory rate, and body temperature) and weight
x
x
x
x
x
x
x
x
Adverse Events Monitoring
x
x
x
x
x
x
x
x
Birth Control Confirmation
x
x
x
x
x
x
x
x
CNS toxicity questionnaire
x
x
x
x
x
x
x
Assess Subject Eligibility for Study Extension 2
xf
Informed Consent for Study Extension 2
xf
Laboratory Procedures/Assessments
Collect Blood for Safety Laboratory Tests
(Hematology/Chemistry)g
x
x
xh
x
x
xh
x
x
x
Urine Pregnancy Test (if applicable)i
x
x
x
x
x
x
x
x
Virology Test Plasma HIV viral RNA quantification
test (Abbott Real Time HIV-1)
x
x
x
x
x
x
x
x
x
Collect Blood for CD4 Cell Count
x
x
Viral Resistance Test (Plasma)
x
xj
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a.
Subjects who enter study extension 1 are considered enrolled in the extension upon providing written informed consent at the Week 24 study visit.
b.
The visit windows are approximately +/- 14 days for all visits from Week 40 through Week 120. The timing of each visit is relative to the randomization (Day 1) visit.  
Every attempt must be made to keep subjects on schedule.
c.
The visit window for the post-study 14-day follow-up visit is approximately – 2 to 0 days.
d. IVRS/IWRS will be used to allocate drug and to manage distribution of MK-1439A.
e.
Study drug for extension 2 will be dispensed at Week 120, if subject is continuing into extension 2.
f.
If the subject is eligible and elects to enter study extension 2, he/she will be considered to have completed study extension 1 and will, after providing informed consent, 
immediately enter study extension 2 and be dispensed MK-1439A. 
g. Refer to Table 5 for listing of specific blood safety tests.
h. Fasting for at least 8 hours.
i.
For women of childbearing potential.
j.
If viral failure or relapse is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for resistance
need not be collected again at the discontinuation visit. All other early discontinuation tests should be performed at the early discontinuation visit.
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Study Extension 1 Flow Chart for Deferred Switch Group (DSG): Weeks 52 Through 132 Plus 14-Day Follow-up
Visit Number
11
12
13
14
15
16
TRIAL PROCEDURES by STUDY WEEK
WK 52
WK68
Fasting
WK 84
WK 100
WK 116
Fasting
WK 132
U
(Virologic
Failure
Confirmation)
U
(Extension 1
Early
Discontinuation)
99
Trial Period:
Study Extension: Treatmenta,b
1 to 4 weeks
after initial
virologic failure
At time of
Discontinuation
Post
treatment
Weeks post base study
16 WKs
32 WKs
48 WKs
64 WKs
80 WKs
96 WKs
14 Day
Follow-upc
Administrative Procedures
Concomitant Medication Review
x
x
x
x
x
x
x
x
Register Study Visit via Interactive Voice/Web
Response System (IVRS/IWRS)
x
x
x
x
x
x
x
Dispense Study Therapyd
x
x
x
x
x
xe
Provide/ Review Study Medication Diary
x
x
x
x
x
x
x
Clinical Procedures/Assessments
Directed Physical Examination
x
x
x
x
x
x
x
x
Vital Signs (including pulse rate, blood pressure,
respiratory rate, and body temperature) and weight
x
x
x
x
x
x
x
x
Adverse Events Monitoring
x
x
x
x
x
x
x
x
Birth Control Confirmation
x
x
x
x
x
x
x
x
CNS toxicity questionnaire
x
x
x
x
x
x
x
Assess Subject Eligibility for Study Extension 2
xf
Informed Consent for Study Extension 2
xf
Laboratory Procedures/Assessments
Collect Blood for Safety Laboratory Tests
(Hematology/Chemistry)g
x
x
xh
x
x
xh
x
x
x
Urine Pregnancy Test (if applicable)i
x
x
x
x
x
x
x
x
Virology Test Plasma HIV viral RNA quantification
test (Abbott Real Time HIV-1)
x
x
x
x
x
x
x
x
x
Collect Blood for CD4 Cell Count
x
x
Viral Resistance Test (Plasma)
x
x j
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a.
Subjects who enter study extension 1 are considered enrolled in the extension upon providing written informed consent at the Week 36 study visit.
b.
The visit windows are approximately +/- 14 days for all visits from Week 52 through Week 132. The timing of each visit is relative to the randomization (Day 1) visit.
Every attempt must be made to keep subjects on schedule.
c.
The visit window for the post-study 14-day follow-up visit is approximately – 2 to 0 days.
d.
IVRS/IWRS will be used to allocate drug and to manage distribution of MK-1439A.
e.
Study drug for extension 2 will be dispensed at Week 132, if subject is continuing into extension 2
f.
If the subject is eligible and elects to enter study extension 2, he/she will be considered to have completed study extension 1 and will, after providing informed consent, 
immediately enter study extension 2 and be dispensed MK-1439A. 
g.
Refer to Table 5 for listing of specific blood safety tests.
h.
Fasting for at least 8 hours. 
i.
For women of childbearing potential.
j.
If viral failure or relapse is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for 
resistance need not be collected again at the discontinuation visit. All other early discontinuation tests should be performed at the early discontinuation visit.
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Study Extension 2 Flow Chart for Immediate Switch Group (ISG): Weeks 136 Through 216 Plus 14-Day Follow-up
Visit Number
17
18
19
20
21
22
TRIAL PROCEDURES by STUDY WEEKa
WK 136
b, c
WK 152
WK 168
WK 184
WK 200
WK 216
U
(Extension 2
Early
Discontinuation)
99
Trial Period:
Study Extension 2: Treatment
At time of
Discontinuation
Post
treatmentd
Weeks post study extension 1
16 WKs
32 WKs
48 WKs
64 WKs
80 WKs
96 WKs
14-Day
Follow-up
Administrative Procedures
Register Study Visit via Interactive Voice/Web
Response System (IVRS/IWRS)
x
x
x
x
x
x
x
Dispense Study Therapy e
x
x
x
x
x
xf
Assess Subject Eligibility for Study Extension 3
xg
Informed Consent for Study Extension 3
xg
Clinical Procedures/Assessments
Serious Adverse Events Monitoring
x
x
x
x
x
x
x
x
Birth Control Confirmation
x
x
x
x
x
x
x
x
Laboratory Procedures/Assessments
Urine Pregnancy Test (if applicable)h
x
x
x
x
x
x
x
x
a.
The total duration is dependent on when MK-1439A becomes locally available, with a maximum total duration of treatment of 216 weeks.  Subjects should discontinue at 
the next scheduled visit after MK-1439A becomes locally available in the market.
b. Subjects who enter study extension 2 are considered enrolled in the extension upon providing written informed consent at the Week 120 study visit.
c.
The visit windows are approximately +/- 14 days for all visits from Week 136 through Week 216.  The timing of each visit is relative to the randomization (Day 1) visit.  
Every attempt must be made to keep subjects on schedule.
d. The visit window for the post-study 14-day follow-up visit is approximately – 2 to 0 days.
e.
IVRS/IWRS will be used to allocate drug and to manage distribution of MK-1439A.
f.
Study drug for extension 3 will be dispensed at Week 216, if subject is continuing into extension 3.
g. If the subject is eligible and elects to enter study extension 3, he/she will be considered to have completed study extension 2 and will, after providing informed consent, 
immediately enter study extension 3 and be dispensed MK-1439A.
h. For women of childbearing potential.
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Study Extension 2 Flow Chart for Deferred Switch Group (DSG): Weeks 148 Through 228 Plus 14-Day Follow-up
Visit Number
17
18
19
20
21
22
TRIAL PROCEDURES by STUDY WEEKa
WK 148
b, c
WK 164
WK 180
WK 196
WK 212
WK 228
U
(Extension 2 Early
Discontinuation)
99
Trial Period:
Study Extension 2: Treatment
At time of
Discontinuation
Post
treatmentd
Weeks post study extension 1
16 WKs
32 WKs
48 WKs
64 WKs
80 WKs
96 WKs
14-Day
Follow-up
Administrative Procedures
Register Study Visit via Interactive Voice/Web
Response System (IVRS/IWRS)
x
x
x
x
x
x
x
Dispense Study Therapy e
x
x
x
x
x
xf
Assess Subject Eligibility for Study Extension 3
xg
Informed Consent for Study Extension 3
xg
Clinical Procedures/Assessments
Serious Adverse Events Monitoring
x
x
x
x
x
x
x
x
Birth Control Confirmation
x
x
x
x
x
x
x
x
Laboratory Procedures/Assessments
Urine Pregnancy Test (if applicable)h
x
x
x
x
x
x
x
x
a.
The total duration is dependent on when MK-1439A becomes locally available, with a maximum total duration of treatment of 228 weeks.  Subjects should discontinue at 
the next scheduled visit after MK-1439A becomes locally available in the market.
b. Subjects who enter study extension 2 are considered enrolled in the extension upon providing written informed consent at the Week 132 study visit.
c.
The visit windows are approximately +/- 14 days for all visits from Week 148 through Week 228.  The timing of each visit is relative to the randomization (Day 1) visit.  
Every attempt must be made to keep subjects on schedule.
d. The visit window for the post-study 14-day follow-up visit is approximately – 2 to 0 days.
e.
IVRS/IWRS will be used to allocate drug and to manage distribution of MK-1439A.
f.
Study drug for extension 3 will be dispensed at Week 228, if subject is continuing into extension
g. If the subject is eligible and elects to enter study extension 3, he/she will be considered to have completed study extension 2 and will, after providing informed consent, 
immediately enter study extension 3 and be dispensed MK-1439A.
h. For women of childbearing potential.
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Study Extension 3 Flow Chart for Immediate Switch Group (ISG): Weeks 232 Through 312 Plus 14-Day Follow-up
Visit Number
23
24
25
26
27
28
TRIAL PROCEDURES by STUDY WEEK a
WK 232
b, c
WK 248
WK 264
WK 280
WK 296
WK 312
U
(Extension 3
Early
Discontinuation)
99
Trial Period:
Study Extension 3: Treatment
At time of
Discontinuation
Post
treatmentd
Weeks post Study Extension 2
16 WKs
32 WKs
48 WKs
64 WKs
80 WKs
96 WKs
14-Day
Follow-up
Administrative Procedures
Register Study Visit via Interactive Voice/Web
Response System (IVRS/IWRS)
x
x
x
x
x
x
x
Dispense Study Therapye
x
x
x
x
x
Clinical Procedures/Assessments
Serious Adverse Events Monitoring
x
x
x
x
x
x
x
x
Birth Control Confirmation
x
x
x
x
x
x
x
x
Laboratory Procedures/Assessments
Urine Pregnancy Test (if applicable)f
x
x
x
x
x
x
x
x
a.
The total duration is dependent on when MK-1439A becomes locally available, with a maximum total duration of treatment of 312 weeks.  Subjects should discontinue at the 
next scheduled visit after MK-1439A becomes locally available in the market.
b. Subjects who enter study extension 3 are considered enrolled in the extension upon providing written informed consent at the Week 216 study visit.
c.
The visit windows are approximately +/- 14 days for all visits from Week 232 through Week 312.  The timing of each visit is relative to the randomization (Day 1) visit.  
Every attempt must be made to keep subjects on schedule.
d. The visit window for the post-study 14-day follow-up visit is approximately – 2 to 0 days.
e.
IVRS/IWRS will be used to allocate drug and to manage distribution of MK-1439A.
f.
For women of childbearing potential.
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Study Extension 3 Flow Chart for Deferred Switch Group (DSG): Weeks 244 Through 324 Plus 14-Day Follow-up
Visit Number
23
24
25
26
27
28
TRIAL PROCEDURES by STUDY WEEKa
WK 244
,b, c
WK 260
WK 276
WK 292
WK 308
WK 324
U
(Extension 3 Early
Discontinuation)
99
Trial Period:
Study Extension 3: Treatment
At time of
Discontinuation
Post
treatmentd
Weeks post extension 2
16 WKs
32 WKs
48 WKs
64 WKs
80 WKs
96 WKs
14-Day
Follow-up
Administrative Procedures
Register Study Visit via Interactive Voice/Web
Response System (IVRS/IWRS)
x
x
x
x
x
x
x
Dispense Study Therapye
x
x
x
x
x
Clinical Procedures/Assessments
Serious Adverse Events Monitoring
x
x
x
x
x
x
x
x
Birth Control Confirmation
x
x
x
x
x
x
x
x
Laboratory Procedures/Assessments
Urine Pregnancy Test (if applicable)f
x
x
x
x
x
x
x
x
a.
The total duration is dependent on when MK-1439A becomes locally available, with a maximum total duration of treatment of 324 weeks.  Subjects should discontinue at 
the next scheduled visit after MK-1439A becomes locally available in the market.
b.
Subjects who enter study extension 3 are considered enrolled in the extension upon providing written informed consent at the Week 228 study visit.
c.
The visit windows are approximately +/- 14 days for all visits from Week 244 through Week 324.  The timing of each visit is relative to the randomization (Day 1) visit.  
Every attempt must be made to keep subjects on schedule.
d.
The visit window for the post-study 14-day follow-up visit is approximately – 2 to 0 days.
e.
IVRS/IWRS will be used to allocate drug and to manage distribution of MK-1439A.
f.
For women of childbearing potential.
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’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 subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’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 subject’s dated signature or 
by the subject’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/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, 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 subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  A review of these criteria should occur at the 
Screening visit and on the Study Day 1 visit (prior to randomization).  For subjects who wish 
to continue into study extension 1, the additional inclusion criteria (11 to 14, Section 5.1.2)
are to be reviewed at the Study Week 24 or Study Week 36 study visit (according to the 
assigned initial treatment group).  For subjects who wish to continue into study extension 2, 
the additional inclusion criteria (Section 5.1.2, 15 through 18) are to be reviewed at the Study 
Week 120 (ISG) or Study Week 132 (DSG) study visit; and for subjects who wish to 
continue into study extension 3, the additional inclusion criteria (Section 5.1.2, 19 through
22) are to be reviewed at the Study Week 216 (ISG) or Study Week 228 (DSG) study visit
7.1.1.3
Subject Identification Card
All subjects will be given a Subject 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 subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee at the Screening 
visit. The medical history should include information pertaining to the diagnosis of HIV 
infection and Acquired Immunodeficiency Syndrome (if applicable) and the year diagnosed.  
If the subject has been previously diagnosed with any Acquired Immunodeficiency 
Syndrome (AIDS) defining conditions or a CD4 cell count < 200, the condition as well as a 
corresponding medical history of Acquired Immunodeficiency Syndrome must be reported.  
Additionally, the subject’s pre-treatment HIV viral load (RNA), historical genotype and
history of smoking should be obtained and recorded on the appropriate eCRF.
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7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use and record all 
medication taken by the subject within 30 days before starting the trial and all prior 
antiretroviral agents taken for the treatment of HIV infection.
Investigational agents must be discontinued for 30 days prior to receiving study therapy.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is rescreened will retain the original screening number assigned at the initial 
screening visit.
The site must access the IVRS/IWRS to register each screened subject.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
The study medication diary will be used to document study drug compliance for the base 
study and study extension 1.
On Study Day 1, the investigator/study coordinator will give the subject a study medication 
diary to be completed during the study period. The investigator/study coordinator will be 
responsible for entering the subject’s identification number (screening and randomization 
number) before giving the study medication diary to the subject.  The subject should follow 
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the instructions on the study medication diary for recording all study drugs.  Aside from the 
initial information entered by the investigator/study coordinator, only the subject should enter 
information on the study medication diary.  The subject is to return the completed study 
medication diary at each scheduled visit.  The investigator/study coordinator will be 
responsible for reviewing the study medication diary for completeness and accuracy with the 
subject.  Only the subject shall make changes to the entries on the diary.  The subject will 
initial the diary to confirm that the information is accurate.  The investigator/study 
coordinator will be responsible for transferring the appropriate information from the diary 
onto the appropriate case report form.
Rigorous monitoring is especially important during the early part of the study, especially
between the Study Day 1 and Study Week 4 visits to ascertain problems with non-
compliance as early as possible, to assess whether subjects are taking study medication as 
directed and to ensure that subjects experiencing difficulties are re-educated, as appropriate.
The Subject Medication Diary will not be used during study extension 2 or study extension 3. 
Sites are responsible for source documentation for drug accountability.
Interruptions from the protocol specified treatment for 7 days or greater require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
7.1.1.9
Patient-Reported Outcomes
There are a total of 4 questionnaires to be completed by subjects in the base study (CNS 
toxicity questionnaire, PSQI, HADS and EQ-5D-5L); subjects enrolled under the original 
protocol (version 00) also complete a CBB questionnaire in the base study.  Only the CNS 
toxicity questionnaire is administered in study extension 1.
Subjects will complete only the CNS toxicity questionnaire at Screening.  However, subjects 
will complete all questionnaires at Study Day 1, Study Weeks 4, 12, 16 (DSG only), 24, and 
36 (DSG only) and the Early Discontinuation visit, if applicable. 
1) CNS Toxicity questionnaire
The CNS toxicity questionnaire is a self-administered questionnaire developed to assess 
CNS toxicities. A 7 day recall period will be used.  
2) Cogstate Brief Battery (CBB)
The Cogstate Brief Battery, while not formally a PRO, has been validated for use in HIV-
infected patients where it has been shown to offer specificity for identifying
neurocognitive function and provides a measure of 4 core cognitive domains: processing 
speed, attention/vigilance, visual recognition memory and working memory [10, 11].  
NOTE: Subjects enrolled under Amendment 01 will not be administered the CBB.  
Subjects enrolled under the original protocol (version 00) are required to complete the 
CBB at specified visits in the base study per the study flow chart.  All other PRO 
questionnaires are mandatory for all subjects.  
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3) Pittsburgh Sleep Quality Index (PSQI)
The PSQI is a validated 19-item questionnaire that was developed to provide a reliable, 
valid, and standardized measure of sleep quality [12]. The PSQI discriminates between 
"good" and "poor" sleepers and provides a brief, clinically useful assessment of a variety 
of sleep disturbances that might affect sleep quality. 
The instrument can be self-
administered and has a four-week recall period. The PSQI has been used in studies of 
HIV-infected patients.
4) Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) measures depression and anxiety in 
and outside of the hospital and in community settings [13, 14]. The HADS is a 14-item 
self-administered instrument that takes 2 to 5 minutes to complete. It has been widely 
used to measure depression and anxiety in adults. Although the term 'hospital' refers to 
the setting in which the instrument was first developed, many studies conducted 
throughout the world have confirmed that it is valid when used in community settings and 
primary care medical practice. The 2 subscales, anxiety and depression, are independent 
measures and can be scored and mapped to 4 ranges: normal, mild, moderate and severe.
5) EuroQol Five Dimensional Descriptive System, Five Level Version (EQ-5D-5L)
The EuroQol EQ-5D-5L is a validated, standardized 5-item health-state questionnaire 
applicable to a wide range of health conditions and treatments and used to assess health 
outcomes [15, 16].
The 5 health state dimensions include: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, and extreme problems.
Administration
Subjects are to complete the questionnaires on their own at the site at the beginning of the 
appropriate study visit (see study flow charts). On Study Day 1, every attempt should be 
made to have the subjects complete the questionnaires prior to receiving study treatment,
prior to discussing any medical conditions with the study personnel, and prior to 
receiving any medical results.  In the base study, the CNS toxicity questionnaire should 
always be administered first and the rest of the questionnaires should be administered in 
the following order: PSQI, HADS, EQ-5D-5L, and, for subjects enrolled under the 
original protocol (version 00), CBB.
During study extension 1, the CNS toxicity
questionnaire will be completed at each treatment visit and, if applicable, at the early 
discontinuation visit.
Clinical Procedures/Assessments
7.1.2.1
Physical Examination
All physical examinations should be performed as indicated in the study flow charts (Section 
6.0). All physical examinations must be performed by the principal investigator or sub-
investigator (physician, physician assistant or nurse practitioner). 
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A complete (full) physical examination (including vital signs [pulse, respiratory rate, blood 
pressure, and body temperature]) must be obtained at the Screening visit. A complete 
physical examination generally includes the following assessments: general appearance, 
head, eyes, ears/nose/throat, neck, lymph nodes, skin, lungs, heart, abdomen, 
musculoskeletal, and neurologic evaluations.  Breast, rectal, and genitourinary/pelvic exams 
should be performed when clinically indicated. 
Physical examinations after the screening visit will be directed exams and will include vital 
signs.  Any significant changes between the screening and Study Day 1 visits should be noted 
on the Medical History eCRF on Study Day 1.  Any significant changes in the physical 
examination after receiving study therapy at Study Day 1 must be reported as adverse events 
and entered on the adverse event eCRF. If the subject is discontinued from the study during 
the treatment period for any reason, every attempt should be made to perform a final physical 
examination.
7.1.2.2
Height Assessment
The subject's height should be assessed as indicated in the study flow charts (Section 6.0). If 
height is measured after the screening visit, the site should indicate whether or not the result 
is clinically significant, and the result should be documented in the subject’s chart. If the 
result is clinically significant, it should be captured as an adverse event on the eCRF.
7.1.2.3
Vital Signs and Weight
Vital signs including pulse rate, respiratory rate, blood pressure and body temperature, 
should be assessed as indicated in the study flow charts (Section 6.0). Subjects should be 
resting in a semi-recumbent position for at least 10 minutes prior to having vital sign 
measurements obtained.
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.
Weight will be collected at all study visits except at Study weeks 1, 2 and 3. 
After the screening visit, the site should indicate whether or not the results are clinically 
significant and document this in the subject's chart. If any result is clinically significant, it
should be captured as an adverse event on the eCRF.
7.1.2.4
12-Lead ECG (performed locally)
As indicated in the flow chart for the base study (Section 6.1), a local 12-Lead 
electrocardiogram (ECG) should be performed prior to the subject’s first dose of study 
medication (at either the Screening visit or the Study Day 1 visit), and any abnormality 
should be documented.  Results must be available prior to subject randomization and prior to 
the subject’s first dose of medication.  Subjects should be resting in a semi-recumbent 
position for at least 10 minutes prior to having ECG readings obtained. Clinically significant 
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findings from the ECG must be documented in the subject's chart and captured on the 
medical history eCRF.
If an ECG is performed for any medical reason while the subject is on study treatment or 
during the follow-up period, any clinically significant change compared with the ECG 
performed prior to the first dose of study medication must be captured as an AE on the eCRF 
and documented in the subject’s chart.
7.1.2.5
Adverse Events
If a subject is diagnosed with an AIDS-defining condition following randomization, the 
condition must be reported as an AE.
Due to the use of lamivudine and ATRIPLATM in this trial, subjects should be monitored for 
symptoms of hyperlactataemia.  
Details on assessing and recording adverse events can be found in Section 7.2.
7.1.2.6
Toxicity Management
Guidelines for grading the severity of laboratory adverse events are based on Division of 
Acquired Immunodeficiency Syndrome (DAIDS) criteria for grading severity of adverse 
events (Appendix 12.6). Decisions to temporarily withhold study therapy because of an 
adverse experience will be reviewed on a case-by-case basis by the investigator. 
The investigator should consider temporarily withholding study therapy if the severity 
of the adverse experience is Grade 3 or above and/or if clinically indicated. The decision 
to interrupt study therapy should take into account the subject’s baseline laboratory 
values and any concomitant medication that could be contributory.  At the discretion of 
the investigator, therapy may generally be reinitiated when laboratory abnormalities or 
clinical adverse events return to near normal or baseline values.
If the adverse experience is considered serious and may have been caused by study 
medication (as defined in Section 7.2.4) or if re-exposure to the test drug poses additional 
potential significant risk to the subject, then the rechallenge must be approved in advance by 
the MSD Clinical Director or Designee and, if required, by the Independent Ethics 
Committee/Institutional Review Board, and a rechallenge consent is needed prior to re-
initiation of study therapy.  If advance approval of rechallenge is not required by local 
regulations, the Independent Ethics Committee/Institutional Review Board will receive 
notification for information only.  If, after re-initiation of study therapy, there is a recurrence 
of the laboratory abnormality or clinical adverse event, consideration should be given to 
permanently discontinuing all study therapy. In general, when a clinical or laboratory adverse 
event occurs which requires interruption of study therapy, all study drugs should be 
interrupted to avoid having a subject receive suboptimal therapy which may predispose them 
to the development of resistance. In general, all study medications should be restarted 
concomitantly at full dose. Whenever study drugs are interrupted, the MSD Clinical 
Director or Designee should be notified.
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7.1.2.7
Birth Control Confirmation
Care must be taken to avoid pregnancy in female subjects of childbearing potential and in the 
female partners of male subjects when the female partners are of childbearing potential.
Site personnel must confirm that subjects and their partner(s) are using acceptable methods 
of contraception. This confirmation must be documented in the subject's chart.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.4.
7.1.3.1
Serum / Urine Pregnancy Test
For women of childbearing potential, a serum pregnancy test is to be done at the screening 
visit, and a urine pregnancy test is to be done at the Study Day 1 visit prior to randomization.  
Urine pregnancy tests must also be subsequently done at the Week 4 visit and at each 
subsequent study visit, including the discontinuation and Follow-Up visits in both the base 
study and the study extensions.  Results must be documented in the subject’s chart.
A 
subject who is pregnant must be discontinued from the study.
7.1.3.2
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests (hematology, chemistry and other) that are to be performed during the base 
study and study extension 1 of the trial are specified in Table 5.
Table 5
Laboratory Tests
Hematology
Chemistry
Other
Hematocrit
Aspartate aminotransferase 
(AST, SGOT)
Prothrombin time (PT)3
Hemoglobin
Alanine aminotransferase 
(ALT, SGPT)
Activated partial thromboplastin time 
(APTT)3
Platelet count
Alkaline phosphatase
International Normalized Ratio (INR)3
Red Blood Cell Count
Creatine Kinase
Hepatitis B Virus surface antigen 3
Erythrocyte Mean corpuscular 
volume
Total Bilirubin  
Hepatitis B Virus surface antibody 3
CD4% and Absolute CD4/ 
Lymphocytes
Direct Bilirubin
Hepatitis B e-Antigen 3
CD8% and Absolute 
CD8/Lymphocytes
Indirect Bilirubin
Hepatitis C Antibody 3
CD4/CD8 ratio
Amylase
Plasma hepatitis C virus PCR quantitative4
White Blood cell Count
Lipase
Enzyme immunoassay HIV antibody (with 
confirmation WB)3
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Hematology
Chemistry
Other
WBC Differential Leukocytes
Glucose, Fasting 1
HIV viral RNA Quantification
Glucose, Non-Fasting 2
Serum -human chorionic gonadotropin 
(hCG) test5
Blood Urea Nitrogen
Urine -human chorionic gonadotropin 
(hCG) test6
Creatinine8
HIV Viral resistance7
Calcium
Phosphorus
Magnesium
Protein
Albumin
Sodium
Potassium
Chloride
Bicarbonate
High-density lipoprotein 
cholesterol (HDL-C) (Fasting1) 
Low-density lipoprotein 
cholesterol (LDL-C) (Fasting1)
Triglycerides (Fasting1)
Total Cholesterol (Fasting1)
1.
Perform at Randomization (Study Day 1), Study Weeks 12, 24 and 36 (DSG only) and, for subjects who continue into 
study extension 1, at the Week 72 (ISG) or 84 (DSG) and Week 120 (ISG) or 132 (DSG) visits.  Subjects should be 
fasting for at least 8 hours. 
2.
Perform at the screening visit and Study Weeks 4 and 16 (DSG only) and, in study extension 1, at the Study Week 40
(ISG) or 52 (DSG), 56 (ISG) or 68 (DSG), 88 (ISG) or 100 (DSG), and 104 (ISG) or 116 (DSG) visits.
3.
Perform at the screening visit only.
4.
If the result of the Hepatitis C Antibody testing is positive, then a plasma hepatitis C virus PCR quantitative test will 
also be performed.
5.
The serum hCG test at the screening visit to be performed by central laboratory.
6.
The urine hCG test is to be performed at the investigator site at Study Day 1 and every study visit thereafter. 
7.
Perform at Study Day 1, all applicable study visits (except Screening, Study Weeks 1, 2, and 3 and Post-Treatment 14-
Day Follow-Up), the Virologic Failure Confirmation visit and the Early Discontinuation visit (if not collected at 
Virologic Failure Confirmation visit).
8.
Creatinine clearance will be computed at every visit by the central laboratory and provided to the site in the report that 
the site receives from the central laboratory.
7.1.3.3
HIV/ Hepatitis Screening
At the screening visit, serum HIV/Hepatitis screening tests will be performed including:  
enzyme immunoassay HIV antibody (with confirmation WB), serum hepatitis B surface 
antigen, serum hepatitis B surface antibody, serum hepatitis B e-antigen and serum hepatitis 
C antibody.  A plasma hepatitis C virus PCR quantitative test will be performed if the 
hepatitis C antibody test is positive.
7.1.3.4
Virology Test
Plasma HIV-1 RNA quantification will be performed at all visits, in the base study and study 
extension 1, except Study Weeks 1, 2, and 3 for all subjects and Study Week 16 for subjects 
in the ISG.
The testing will be performed at the central laboratory using the Abbott 
RealTime HIV-1 assay. 
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7.1.3.5
Viral Resistance Testing
Blood samples will be collected for HIV viral resistance testing at Study Day 1, Study Weeks 
4, 12, 16 (DSG only), 24, and 36 (DSG only), and, in both the base study and study extension
1, at the Virologic Failure Confirmation visit or the Early Discontinuation Visit (if not 
already obtained at Virologic Failure Confirmation visit).  Baseline (Study Day 1) samples 
will be analyzed in cases of virologic failure and/or discontinuation, provided the viral load 
meets the criterion for resistance testing (>400 copies/mL).  All resistance testing in the base 
study and in study extension 1 will be performed by a central laboratory. Amplifiable virus to 
screen for resistance would not be expected for subjects whose viral load was BLoQ at entry.  
7.1.3.6
CD4 Cell Counts
CD4 cell count (absolute and percentage) will be determined at Study Day 1 and at Study 
Weeks 12 and 24.  CD4 cell count (absolute and percentage) will also be determined at Study 
Week 36 for subjects in the DSG only.  For subjects who continue into study extension 1, 
CD4 cell count will also be determined at the Study Week 72 and 120 visits in the ISG and at 
the Study Week 84 and 132 visits in the DSG.  Testing will be performed at the central 
laboratory using a commercially-available assay. 
7.1.3.7
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.7.1 Blood Collection for Plasma MK-1439 and Efavirenz
Samples for MK-1439 and efavirenz PK will be collected from all subjects as outlined in
Table 6.  The exact time the dose of MK-1439A and efavirenz were taken prior to the sample 
collection will be recorded on the appropriate eCRF. On the day of any visit at which a PK 
sample will be collected, the sample must be collected before the subject takes the study 
drug. 
Table 6
Pharmacokinetic Sampling Timepoints
Visit 
Number
Study Day/Week
(for all subjects)
Time Relative to MK-1439A dose
2
Day 1
2 samples to be collected predose
3
Week 1
2 samples to be collected predose
4
Week 2
2 samples to be collected predose
5
Week 3
2 samples to be collected predose
6
Week 4
2 samples to be collected predose
Sample collection, storage and shipment instructions for the PK samples will be provided in 
the operations/laboratory manual.
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7.1.3.8
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
7.1.3.9
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research

Plasma for future research
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Early Discontinuation should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects 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@MSD.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 (e.g., 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 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
Procedures for blinding and unblinding apply only to the base study; treatment during the 
study extensions is open-label.
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STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE SUBJECT. EVERY EFFORT 
SHOULD BE MADE NOT TO UNBLIND THE SUBJECT UNLESS NECESSARY.
For emergency situations where the investigator or sub-investigator needs to identify the drug 
used by a subject and/or the dosage administered in case of emergency, he/she will contact 
the emergency unblinding call center by telephone and make a request for emergency 
unblinding.  As requested by the investigator or sub-investigator the emergency unblinding 
call center will provide the information to him/her promptly and report unblinding to the 
sponsor.  The emergency unblinding call center will make a record promptly however, the 
investigator or sub-investigator must enter the intensity/toxicity grade of the adverse 
experiences observed, their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  
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 subject safety.
Study treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the subject. Every effort should be made not to unblind the subject 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 subject.
7.1.4.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Please refer to the central laboratory manuals for equipment requirements and necessary
maintenance or calibration.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
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7.1.5.1
Screening
Written informed consent/assent must be obtained from the subject prior to performing any 
study-specific procedures. Potential subjects will be evaluated to determine if they fulfill the 
inclusion/exclusion entry requirements set forth in Section 5.1.  The investigator will discuss 
the study, its requirements, and its restrictions with each potential subject.  The study 
screening period is 30 days.

All procedures listed for the screening visit (Visit 1) in the Study Flow Chart (Section 
6.1) must be completed and the subjects eligibility confirmed by the investigator prior to 
the subject’s randomization and drug administration on Study Day 1.

Blood will be collected for safety laboratory evaluations, hemostatic function tests, an 
HIV/hepatitis screen, and HIV-1 RNA quantification.  These samples will be sent to the 
appropriate central laboratory(ies) following the procedure(s) set forth in the manual(s).

Female subjects of childbearing potential will have a serum pregnancy test (hCG) 
conducted at the screening visit.  Women who are pregnant will be excluded from the 
study.

Subjects will be instructed to complete the CNS toxicity questionnaire, as noted in the 
Study Flow Chart (Section 6.1).  Subjects are to complete the questionnaire on their own 
at the site.

Subjects will be instructed about the restrictions for concomitant medications, as noted in 
Section 5.5.

Subjects will be given a study participation identification card.  The card will contain 
contact information (including direct telephone numbers) to be utilized in the event of an 
emergency.
7.1.5.2
Rescreening
Subjects who have previously completed the screening visit (Visit 1) and were deemed 
eligible for randomization into this study, but failed to be randomized within the 45 day 
window, may be rescreened to re-evaluate study eligibility.  To reconfirm the subject's 
eligibility, safety evaluations and HIV RNA test should be repeated. In addition, the serum 
pregnancy test for female participants of childbearing potential should be repeated, 
Rescreening of a patient will require approval from the SPONSOR. 
7.1.5.3
Treatment Visits
Randomization - Study Day 1 (Visit 2)

Procedures listed for Study Day 1 (Visit 2) on the Study Flow Chart (Section 6.1) should 
be performed prior to the subject’s randomization and drug administration on Study Day 
1, unless otherwise specified.
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
For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at the site prior to study drug initiation. If the urine pregnancy test result is 
negative and the subject meets the other eligibility criteria, the subject will be eligible for 
randomization and the remainder of the pretreatment (Study Day 1) testing/procedures 
will be performed.  If the urine pregnancy test result is positive, the subject must not be 
randomized. 

Fasting blood will be collected for genetic analysis, safety laboratory evaluations, HIV-1 
RNA quantification, CD4 cell counts, HIV viral resistance and PK measurements.  
Subjects will be required to fast for at least 8 hours prior to the study visit.
These 
samples will be sent to the appropriate central laboratory(ies) following the procedure(s) 
set forth in the manual(s).

Plasma samples for future biomedical research will be also collected from all subjects 
from whom appropriate consent has been obtained. 

Subjects will be instructed to complete the CNS toxicity questionnaire to confirm 
presence of at least one CNS toxicity noted at the screening visit as noted in the Study 
Flow Chart (Section 6.1).  Subjects are to complete the questionnaire on their own at the 
site.

Following completion of the Study Day 1 pretreatment procedures and confirmation of 
eligibility, the site staff will access the IVRS/IWRS for assignment of the drug to be 
administered.  Site staff should not access IVRS/IWRS for drug administration until the 
subject has met all criteria for the study and are ready to receive the first dose of study 
medication.

Subjects will be instructed to complete the CBB (including practice) and other PRO 
questionnaires, as noted in the Study Flow Chart (Section 6.0).  Subjects are to complete 
the questionnaires on their own at the site.

Subjects randomized to both treatment groups will receive a 4-week supply of study 
medication on Study Day 1 (Visit 2). Subjects will be instructed to take their first dose of 
study medication on the same day as the Study Day 1 visit.

The investigator/study coordinator will give a study medication diary to all subjects in 
both treatment groups. Subjects will start the diary on Study Day 1 and continue to 
complete the diary throughout the treatment period.  The site must ensure that the subject 
is properly trained and comfortable with completing the medication diary prior to the 
subject leaving the clinic.
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Drug Administration
Subjects will be dispensed study drug as outlined in Table 7.
Table 7
Study Drug Bottle (A, B and C) Components  
Bottle Label
Component
Bottle A
MK-1439A or placebo
Bottle B
ATRIPLA™ or placebo
Bottle C
MK-1439A (open label)
Subjects will be instructed to take the study medication as follows:
All Subjects will take one tablet once-daily from each of the bottles as follows:
Bottle A (MK-1439A or placebo):  
Subjects will be instructed to take one tablet from Bottle A q.d. orally, with or without food 
at approximately the same time each day.  Tablets from Bottle A must be kept in the bottle 
prior to taking study medication since the formulation being used in this study is moisture 
sensitive.
Bottle B (ATRIPLA™or placebo):  
Subjects will be instructed to take one tablet from Bottle B q.d. orally, at bedtime, on an 
empty stomach. 
Note: Study medication should be taken directly from the study bottle.  
Study Week 1 (Visit 3) to Study Week 3 (Visit 5)

All procedures for Study Week 1 (Visit 3) to Study Week 3 (Visit 5) listed on the Study 
Flow Chart (Section 6.1) should be performed. 

Blood will be collected for PK measurements (see section 7.1.3.7.1 for details) at the time 
points specified on the Study Flow Chart.  These samples will be sent to the appropriate 
central laboratory(ies) following the procedure(s) set forth in the manual(s).

At each study visit, the study coordinator and subject will review the study medication 
diary information. 
Study Week 4 (Visit 6) and Study Week 12 (Visit 7)

All procedures for Study Week 4 (Visit 6) and Study Week 12 (Visit 7) listed on the 
Study Flow Chart (Section 6.1) should be performed. 

Blood will be collected for safety laboratory evaluations, HIV-1 RNA quantification and
HIV viral resistance at the time points specified on the Study Flow Chart.  Blood will be 
collected for the CD4 cell count at Study Week 12 (Visit 7) only.  These samples will be 
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sent to the appropriate central laboratory(ies) following the procedure(s) set forth in the 
manual(s).

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed.  If the urine pregnancy test result is positive, the subject must be 
discontinued. 

Subjects will be instructed to complete the CNS toxicity questionnaire, the CBB and the 
other PRO questionnaires, as listed on the Study Flow Chart (Section 6.0).  Subjects are 
to complete the questionnaires on their own at the site.

For all subjects, blood samples for PK measurements will be collected at Study Week 4 
only (see section 7.1.3.7.1 for details). 

All bottles of study drug will be returned to the study coordinator at each study visit, at 
which time the drug supplies for the following time period will be dispensed.  The 
number of tablets remaining in the bottle will be counted and recorded in the source 
documentation.  The primary source of adherence data, however, will be the subject’s 
study medication diary.

At each study visit, the study coordinator and subject will review the study medication 
diary information. 

Site staff will access the IVRS/IWRS for assignment of the drug to be administered and 
for registration of visits. 

Subjects will receive an 8-week supply of study drug at Study Week 4 (Visit 6).

Subjects will receive 4-week supply of open-label study drug (Bottle C) at Study week 12 
(Visit 7). 

At Study Week 12, subjects will be assigned a new medication diary (for the open-label 
period) and the previous diary (for the blinded period) will be collected. 
Study Week 16 (Visit 8)

Subject Unblinding: All adverse events data through the first 12 weeks of treatment for 
that subject will be cleaned and reconciled prior to unblinding. Site should have received 
confirmation from the sponsor study team prior to calling IVRS/IWRS to unblind.  Site 
staff will access IVRS/IWRS for assignment of the drug to be administered, for 
registration of the visit and unblinding. 

After unblinding, all subjects will receive an 8-week supply of study drug (Bottle C). 

For subjects in the ISG group, the only assessments required are AE, concomitant 
medication and study medication diary review. 

For subjects in the DSG group all procedures for Study Week 16 (Visit 8) listed on the 
Study Flow Chart (Section 6.1) should be performed.

For subjects in the DSG group blood will be collected for safety laboratory evaluations, 
HIV-1 RNA quantification and HIV viral resistance at the time points specified on the 
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Study Flow Chart.  These samples will be sent to the appropriate central laboratory(ies) 
following the procedure(s) set forth in the manual(s).

For subjects in the DSG group for a female subject who is of childbearing potential, a 
urine pregnancy test will be performed.  If the urine pregnancy test result is positive, the 
subject must be discontinued. 

Subjects in the DSG group will be instructed to complete the CNS toxicity questionnaire, 
the CBB and the other PRO questionnaires, as listed on the Study Flow Chart (Section 
6.0).  Subjects are to complete the questionnaires on their own at the site.

All bottles of study drug will be returned to the study coordinator at the visit, at which 
time the drug supplies for the following time period will be dispensed.  The number of 
tablets remaining in the bottle will be counted and recorded in the source documentation.  
The primary source of adherence data, however, will be the subject’s study medication 
diary.
Study Week 24 (Visit 9)

All procedures for Study Week 24 (Visit 9) listed on the Study Flow Chart (Section 6.1) 
should be performed. 

Subjects will be required to fast for at least 8 hours prior to the study visit.  Blood will be 
collected for safety laboratory evaluations, HIV-1 RNA quantification, CD4 cell count
and HIV viral resistance at the time points specified on the Study Flow Chart.  These 
samples will be sent to the appropriate central laboratory(ies) following the procedure(s) 
set forth in the manual(s).

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at all study visits.  If the urine pregnancy test result is positive, the subject 
must be discontinued. 

Subjects will be instructed to complete the CNS toxicity questionnaire, the CBB and the 
other PRO questionnaires, as listed on the Study Flow Chart (Section 6.0).  Subjects are 
to complete the questionnaires on their own at the site.

All bottles of study drug will be returned to the study coordinator at the visit.  The 
number of tablets remaining in the bottle will be counted and recorded in the source 
documentation.  The primary source of adherence data, however, will be the subject’s 
study medication diary.

Site staff will access the IVRS/IWRS for assignment of the drug to be administered and 
for registration of the visit. Only subjects assigned to the DSG will receive a 12-week 
supply of study drug at Study Week 24 (Visit 9).  Subjects in the ISG who are considered 
eligible and elect to enter the study extension will receive a 16-week supply of study drug 
at Study Week 24 (Visit 9).  For subjects in the ISG who do not enter the study extension, 
no study drug will be dispensed, as Study Week 24 (Visit 9) will be the last treatment 
visit for subjects in the ISG.

The study coordinator and subject will review the study medication diary information
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Study Week 36 (Visit 10) for DSG

Only subjects assigned to the DSG will return for Study Week 36 (Visit 10).

All procedures for Study Week 36 (Visit 10) listed on the Study Flow Chart (Section 6.1) 
should be performed. 

Subjects will be required to fast for at least 8 hours prior to the study visit. Blood will be 
collected for safety laboratory evaluations, HIV-1 RNA quantification, CD4 cell count 
and HIV viral resistance at the time points specified on the Study Flow Chart.  These 
samples will be sent to the appropriate central laboratory(ies) following the procedure(s) 
set forth in the manual(s).

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at all study visits.  If the urine pregnancy test result is positive, the subject 
must be discontinued. 

Subjects will be instructed to complete the CNS toxicity questionnaire, the CBB and the 
other PRO questionnaires, as listed on the Study Flow Chart (Section 6.0).  Subjects are 
to complete the questionnaires on their own at the sit

All bottles of study drug will be returned to the study coordinator at the visit.  The 
number of tablets remaining in the bottle will be counted and recorded in the source 
documentation.  The primary source of adherence data, however, will be the subject’s 
study medication diary.

Site staff will access the IVRS/IWRS for registration of the visit. Subjects who are 
considered eligible and elect to enter the study extension will receive a 16-week supply of 
study drug at Study Week 36 (Visit 10).  For subjects in the DSG who do not enter the 
study extension, no study drug will be dispensed as Study Week 36 (Visit 10) will be the 
last treatment visit. 
Study Week 40 Through Week 120 for ISG 

All procedures for Study Week 40, Week 56, Week 72, Week 88, Week 104, and Week 
120 listed on the flow chart for the study extension (Section 6.2) should be performed.

Blood will be collected for safety laboratory evaluations and HIV-1 RNA quantification
at the time points specified in the Study Flow Chart. Samples for CD4 counts will also
be collected at the Study Week 72 and 120 visits. Subjects will be required to fast for at
least 8 hours prior to the Study Week 72 and 120 visits. Samples for HIV viral resistance
will be collected at the Virologic Failure Confirmation visit or at the discontinuation visit
(if not already obtained at Virologic Failure Confirmation visit). These samples will be
sent to the appropriate central laboratory(ies) following the procedure(s) set forth in the
manual(s).  For a female subject who is of childbearing potential, a urine pregnancy test 
will be performed at all study visits.  If the urine pregnancy test result is positive, the 
subject must be discontinued. 

Subjects will be instructed to complete the CNS toxicity questionnaire as listed on the 
Study Flow Chart (Section 6.0).  Subjects are to complete the questionnaires on their own 
at the site.
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
All bottles of study drug will be returned to the study coordinator at the visit.  The 
number of tablets remaining in the bottle will be counted and recorded in the source 
documentation.  The primary source of adherence data, however, will be the subject’s 
study medication diary.

Site staff will access the IVRS/IWRS for registration of visits.  Subjects will receive a 
16-week supply of study drug at each study visit through Week 104.  Study drug for 
study extension 2 will be dispensed at Week 120 for subjects continuing into study 
extension 2.

At each study visit the study coordinator and subject will review the study medication 
diary information.
Study Week 52 Through Week 132 for DSG

All procedures for Study Week 52, Week 68, Week 84, Week 100, Week 116, and Week 
132 listed on the flow chart for the study extension (Section 6.3) should be performed for 
the DSG.

Blood will be collected for safety laboratory evaluations and HIV-1 RNA quantification 
at the time points specified in the Study Flow Chart.

Samples for CD4 counts will be collected at the Study Week 84 and 132 visits.  Subjects 
will be required to fast for at least 8 hours prior to the Study Week 84 and 132 visits. 
Samples for HIV viral resistance will be collected at the virologic failure confirmation 
visit or at the discontinuation visit (if not already obtained at Virologic Failure 
Confirmation visit). These samples will be sent to the appropriate central laboratory(ies) 
following the procedure(s) set forth in the manual(s).

For a female subject who is of childbearing potential, a urine pregnancy test will be
performed at all study visits. If the urine pregnancy test result is positive, the subject must 
be discontinued.

Subjects will be instructed to complete the CNS toxicity questionnaire, as listed on the 
Study Flow Chart (Section 6.0).  Subjects are to complete the questionnaires on their own 
at the site.

All bottles of study drug will be returned to the study coordinator at each visit, at which
time the drug supplies for the following time period will be dispensed. The number of
tablets remaining in the bottle will be counted and recorded in the source documentation.  
The primary source of adherence data, however, will be the subject’s study medication
diary.

Site staff will access the IVRS/IWRS for registration of visits. Subjects will receive a
16-week supply of study drug at each study visit through Week 116. Study drug for 
extension 2 will be dispensed at Week 132 for subjects continuing into extension 2.

At each study visit the study coordinator and subject will review the study medication 
diary information.
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Week 136 Through Week 216 for ISG

All procedures for Study Week 136, Week 152, Week 168, Week 184, Week 200, and 
Week 216 listed on the Study Flow Chart (Section 6.4) should be performed. 

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at all study visits.  If the urine pregnancy test result is positive, the subject 
must be discontinued. 

All bottles of study drug will be returned to the study coordinator at each visit, at which 
time the drug supplies for the following time period will be dispensed.  The number of 
tablets remaining in the bottle will be counted and recorded in the source documentation.  
Only first dose, last dose, overdose (if applicable) and study drug interruption (if 
applicable) due to any toxicity, ECI or (S)AE will be collected in the database.

Site staff will access the IVRS/IWRS for registration of visits.  Subjects will receive a 
16-week supply of study drug at each study visit through Week 200. Study drug for study 
extension 3 will be dispensed at Week 216 for subjects continuing into study extension 3.
Week 148 Through Week 228 for DSG

All procedures for Study Week 148, Week 164, Week 180, Week 196, Week 212, and 
Week 228 listed on the Study Flow Chart (Section 6.5) should be performed. 

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at all study visits.  If the urine pregnancy test result is positive, the subject 
must be discontinued. 

All bottles of study drug will be returned to the study coordinator at each visit, at which 
time the drug supplies for the following time period will be dispensed.  The number of 
tablets remaining in the bottle will be counted and recorded in the source documentation.  
Only first dose, last dose, overdose (if applicable) and study drug interruption (if 
applicable) due to any toxicity, ECI or (S)AE will be collected in the database.

Site staff will access the IVRS/IWRS for registration of visits.  Subjects will receive a 
16-week supply of study drug at each study visit through Week 212. Study drug for study 
extension 3 will be dispensed at Week 228 for subjects continuing into study extension 3.
Week 232 Through Week 312 for ISG

All procedures for Study Week 232, Week 248, Week 264, Week 280, Week 296, and 
Week 312 listed on the Study Flow Chart (Section 6.6) should be performed. 

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at all study visits.  If the urine pregnancy test result is positive, the subject 
must be discontinued. 

All bottles of study drug will be returned to the study coordinator at each visit, at which 
time the drug supplies for the following time period will be dispensed.  The number of 
tablets remaining in the bottle will be counted and recorded in the source documentation.  
Only first dose, last dose, overdose (if applicable) and study drug interruption (if 
applicable) due to any toxicity, ECI or (S)AE will be collected in the database.
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
Site staff will access the IVRS/IWRS for registration of visits.  Subjects will receive a 
16-week supply of study drug at each study visit through Week 296.
Week 244 Through Week 324 for DSG

All procedures for Study Week 244, Week 260, Week 276, Week 292, Week 308, and 
Week 324 listed on the Study Flow Chart (Section 6.7) should be performed. 

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at all study visits.  If the urine pregnancy test result is positive, the subject 
must be discontinued. 

All bottles of study drug will be returned to the study coordinator at each visit, at which 
time the drug supplies for the following time period will be dispensed.  The number of 
tablets remaining in the bottle will be counted and recorded in the source documentation.  
Only first dose, last dose, overdose (if applicable) and study drug interruption (if 
applicable) due to any toxicity, ECI or (S)AE will be collected in the database.

Site staff will access the IVRS/IWRS for registration of visits.  Subjects will receive a 
16-week supply of study drug at each study visit through Week 308.
Virologic Failure Confirmation Visit (Base Study and Study Extension 1)

When a subject has a virologic failure confirmation visit performed, all procedures for the 
virologic failure confirmation visit listed on the Study Flow Charts should be performed.
Note: Protocol-defined virologic failure (PDVF) is defined as subjects who have 2
consecutive measurements of HIV-1 RNA ≥200 copies/mL at least one week apart.

The virologic failure confirmation visit should be done between 1 and 4 weeks (>1 to ≤ 
4) after the first measurement of HIV-1 RNA ≥200 copies/ml.
Subjects should be discontinued if they meet the protocol-defined virologic failure criteria.  
The choice of subsequent antiretroviral therapy will be at the discretion of the study 
investigator or subject’s physician.
Early Discontinuation Visit (Base Study, Study Extensions 1, 2, and 3)

When a subject discontinues/withdraws from participation in the trial, all procedures for 
the Early Discontinuation visit listed on the Study Flow Charts should be performed.
At a minimum, the following information should be collected when a subject 
discontinues:  
o
The reason the subject discontinued
o
The date of the last dose of study medications from the trial
o
The date of the last assessment and/or contact
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o
All adverse events (including serious adverse events) in the base study and study 
extension 1
o
Only serious adverse events in study extension 2 and study extension 3

Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing 
and Recording Adverse Events.

Subjects who discontinue early from the base study will be instructed to complete the 
CNS toxicity questionnaire, the CBB and the other PRO questionnaires, as listed on the 
Study Flow Chart (Section 6.1); subjects who discontinue early from study extension 1
will be instructed to complete the CNS toxicity questionnaire.  Subjects are to complete 
the questionnaires on their own at the site.

Subjects who discontinue early from the study are expected to return for a 14-day post-
therapy follow-up visit. 
7.1.5.4
Post-Trial

Following the completion of study therapy (in the base study or study extensions) or in 
the event of early discontinuation, subjects will be required to return to the clinic 
approximately 14 days after the last dose of study drug for the post-study visit as outlined 
in the Study Flow Charts (Section 6.0).  

If the post-study visit occurs less than 14 days after the last dose of study drug, a 
subsequent follow-up phone call should be made at 14 days post the last dose of study 
drug to determine if any adverse events have occurred since the post-study clinic visit.
7.1.5.5
Trial Unblinding
For emergency unblinding please refer to Section 7.1.4.2.
For planned unblinding at study week 16, please refer to Section 5.2.3.
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
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Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator during the base 
study and study extension 1 as specified in Section 2. During study extension 2 and study 
extension 3, serious adverse events must be reported by the investigator as specified in 
Section 2; and if an investigator chooses to report a non-serious adverse event (NSAE), it 
should be submitted using the same process used to submit NSAEs in the base study and 
study extension 1. Such events will be recorded at each examination on the Adverse Event 
case report forms/worksheets.  The reporting timeframe for adverse events meeting any 
serious criteria is described in section 7.2.3.1. The investigator will make every attempt to 
follow all subjects with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than twice the recommended daily dose in a 
calendar day.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
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All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: 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 in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
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Refer to Table 8 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
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2. 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).
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 8.  The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 8 for instructions in evaluating adverse events.
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Table 8
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 an MSD product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
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 drug 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 subject 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 underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
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 subject 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 SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND IF REQUIRED, BY THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.  IF
ADVANCED APPROVAL OF RECHALLENGE IS NOT REQUIRED BY LOCAL REGULATIONS, THE IRB/IEC WILL RECEIVE 
NOTIFICATION FOR INFORMATION ONLY.
Consistency 
with Trial 
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.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject 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 subject with overdose without 
an associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
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.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Separate analysis plans (ie, separate documents from the sSAP) may be 
developed to detail other planned analyses (e.g. analysis of PK data, subject - reported 
outcomes other than endpoints related to the CNS toxicity questionnaire, and future 
biomedical research). 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 8.2 to 8.12.  Analysis of data from the study extensions does not 
require changes to the SAP. All data from study extension 1 will be summarized 
descriptively only. These data will be summarized separately from data generated from the 
base study; only data from the base study will be used to address the primary objectives and 
hypotheses. Serious adverse event data from study extension 2 and study extension  3 will be 
summarized separately from data for the base and study extension 1 portions of the study.
Study Design Overview
Phase IIb, Double-Blinded, Multicenter, Randomized Study to Assess 
the Effect on Central Nervous System (CNS) Toxicity of Switching 
from ATRIPLA™ (Efavirenz, Tenofovir, Emtricitabine) to MK-1439A 
(Doravirine, Tenofovir, Lamivudine) in Virologically-Suppressed 
Subjects
Treatment Assignment
Subjects will be randomized to either the Immediate Switch Group or 
Deferred Switch Group in a 1:1 ratio.  A total of 84 subjects (42/group) 
are planned to be randomized.  There will be no stratification in this 
study.  Centralized randomization will be used and implemented via an 
interactive voice recognition system (IVRS).
Analysis Populations
Efficacy and CNS toxicity assessment: Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
The proportion of subjects with at least one CNS toxicity of at least 
Grade 2 intensity at Week 12.
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Key Secondary Endpoints
1.
Proportion of subjects with at least one CNS toxicity of at least 
Grade 2 intensity at Week 4
2.
Change from baseline in the proportion of subjects with at least one 
CNS toxicity of at least Grade 2 intensity at 24 weeks post-switch
3.
Change from baseline in CNS toxicity score at Weeks 4 and 12
4.
Change from baseline in CNS toxicity score at 24 weeks post-
switch
5.
The proportion of subjects with HIV-1 RNA < 50 copies/mL (and 
<40 copies/mL) at 24 weeks post-switch
6.
Change from baseline in fasting lipids at Week 12
7.
Change from baseline in fasting lipids at 24 weeks post-switch
8.
Change from baseline in CD4 cell count at 24 weeks post-switch
9.
Overall safety and tolerability through Week 12
10. Overall safety and tolerability through 24 weeks post-switch
Statistical Methods for 
Primary Objective/Hypothesis
The treatment difference and the associated 95% confidence interval 
will be calculated for the proportion of subjects with at least 1 CNS 
toxicity of at least Grade 2 intensity at Week 12 using Miettinen and 
Nurminen’s method (1985) [17], an unconditional, asymptotic method, 
and p-values based on this method will be provided.  The immediate 
switch group will be considered to have a statistically significantly 
smaller proportion of subjects with at least one CNS toxicity of at least 
Grade 2 intensity at Week 12 if the upper bound of the 95% confidence 
interval for the treatment difference (immediate – deferred) is less than 
0.
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Proportion of Subjects Maintaining HIV-1 RNA <50 copies/mL and 
<40 copies/mL
The proportion of subjects achieving HIV-1 RNA < 50 copies/mL (and 
separately for < 40 copies/mL) will be summarized separately by 
treatment group at 4 and 12 weeks post-switch and for the combined 
treatment groups at 24 weeks post-switch (with primary interest in the 
combined analysis). At each time point of interest, the 95% confidence 
interval for the proportion will be calculated using the exact binomial 
method proposed by Clopper and Pearson (1934) [18]. Subjects who 
discontinue prior to the switch in the deferred switch group will be 
excluded from the combined analysis.
Change from Baseline in CD4 cell count
Change from baseline in CD4 cell counts will be summarized
separately by treatment group at 4 and 12 weeks post-switch and for the 
combined treatment groups at 24 weeks post-switch (with primary 
interest in the combined analysis). The observed failure approach will 
be used for the calculations of change from baseline in CD4 cell count. 
Subjects who discontinue prior to the switch in the deferred switch 
group will be excluded from the combined analysis.
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Statistical Methods for Key 
Safety Analyses
Overall safety and tolerability will be assessed by clinical review of all 
relevant parameters including adverse experiences (AEs), laboratory
tests and vital signs.  Descriptive statistics will be provided for these 
safety parameters for both the base study and for the entire treatment 
period, ie, base study plus the 96-week study extension, in which all 
subjects receive open-label MK-1439A.  
The proportions of subjects with clinical or laboratory adverse 
experiences of the following types will be tabulated: (1) at least one
adverse experience; (2) a drug-related adverse experience; (3) a
serious adverse experience; (4) a serious and drug-related adverse 
experience; (5) an adverse experience leading to discontinuation.  The
percentage of subjects with specific adverse experiences by system
organ
class
and the
number
and
percentage
of
subjects
with
laboratory test results that exceed Pre-Defined Limit of Change will
also be summarized in the same fashion.
Safety data through Week 12 by treatment group and post switch 
combining treatment groups will be summarized.  In the post switch 
summary, all accumulated safety data through the end of treatment + 
14 days of follow-up post treatment will be included in the analyses of 
safety.  
Interim Analyses
No interim analyses are planned.
Multiplicity
No multiplicity adjustment is planned as there is a single comparison of 
2 treatments using 1 endpoint in the primary hypothesis. Other efficacy 
and safety analyses will be considered supportive and/or explanatory.
Sample Size and Power 
All subjects will have at least one Grade 2 or worse CNS toxicity at 
baseline.  It is anticipated that by Week 12, only 67.0% of the subjects 
in the Immediate Switch Group will have such a toxicity, while 91.5% 
of the subjects in the Deferred Switch Group will have at least one such 
event.  The assumed proportions are based on a study of similar design 
[3].  With these assumed incidence rates and randomization of 42 
subjects per group, there is 80% power to demonstrate a statistically 
significantly lower proportion of subjects with a Grade 2 or worse CNS 
toxicity in the Immediate Switch Group than in the Deferred Switch 
Group using a one-sided alpha level of 0.025.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The official, final adverse event data for a subject for the double-blind period will not be 
unblinded until review has been performed and data are clean and final. Results of the open-
label period will be presented along with those of the double-blind period in the CSR.
The Clinical Biostatistics department will generate the randomized allocation schedule for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
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Analysis Endpoints
Efficacy, safety, subject-reported outcomes (including responses to the primary CNS toxicity 
questionnaire) and neurocognitive endpoints for the base study and study extension 1 that 
will be evaluated for within- and/or between-treatment differences are listed below followed 
by descriptions of the derivations of selected endpoints.
Due to the fact that the Immediate Switch Group will still be in the double-blind treatment 
phase at 4 and 12 weeks post-switch and the Deferred Switch Group will be in the open-label 
treatment phase at 4 weeks post-switch (Week 16) and 12 weeks post-switch (Week 24), the 
treatment groups will not be combined for the assessments at 4 and 12 weeks post-switch.  
The treatment groups will be combined for the evaluation of endpoints at 24 weeks post-
switch (when both treatment groups are in the open-label treatment phase).  No treatment 
group comparisons will be made at post-switch time points.
For analyses that compare the 2 treatment groups at Study Week 4 and Study Week 12, 
“baseline” for the change from baseline analyses will refer the measurements taken at Study 
Day 1.  For analyses that combine the 2 treatment groups at 24 weeks post switch, “baseline” 
for the change from baseline analyses will refer to the measurements taken on the day of
switch to MK-1439A (Study Day 1 for the Immediate Switch Group and Study Week 12 for 
the Deferred Switch Group).
CNS Toxicity Questionnaire
Section 4.2.3.1 provides an initial description of these measures.
A separate analysis plan will be developed for the subject-reported outcomes measuring sleep 
quality, anxiety and depression, neurocognitive function, and health-related quality of life.  
Therefore, these endpoints are described here with only limited detail.
Proportion of subjects with ≥1 CNS Toxicity of at least Grade 2 Intensity
CNS toxicity is measured using the CNS toxicity questionnaire (as described in Section 
4.2.3.1).  On the CNS toxicity questionnaire, the following 10 CNS toxicities are assessed by 
subjects with respect to whether or not they are present and the level of intensity of the 
toxicity using a scale of Grade 0 = none, Grade 1 = mild, Grade 2 = moderate, and Grade 3 =
severe: 
1. Dizziness 
2. Depression/low mood 
3. Insomnia/sleeplessness 
4. Anxiety/nervousness 
5. Confusion
6. Impaired concentration/attention 
7. Headache 
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8. Somnolence/daytime sleepiness 
9. Aggressive mood/behavior
10. Abnormal dreams
The questionnaire will be used to assess CNS toxicity at baseline and each subsequent visit.  
All enrolled subjects are required will have at least one Grade 2 or worse CNS toxicity at 
baseline.  The primary efficacy endpoint is the proportion of subjects with at least one Grade 
2 or worse CNS toxicity at Week 12. The proportion of subjects with at least one Grade 2 or 
worse CNS toxicity at Study Week 4 (comparing treatment groups) as well as at 4 weeks 
post-switch (by treatment group), 12 weeks post-switch (by treatment group), and 24 weeks 
post-switch (combining both treatment groups) will also be summarized.  
Change from baseline in CNS Toxicity Score 
A CNS toxicity score will be calculated for each subject at baseline and each post-baseline 
visit.  Each of the 10 CNS toxicities will be assigned a number determined by the intensity 
reported (None=0, Mild=1, Moderate=2, Severe=3).  Each subject will have a CNS toxicity 
score calculated as the sum across all 10 CNS toxicities expressed as a percentage of the 
maximum sum possible (10 x 3 = 30).  Lower scores represent better CNS toxicity profiles.  
The change from baseline will be defined as the CNS toxicity score at the post-baseline time 
point of interest minus the CNS toxicity score at baseline.  Negative numbers with a large 
magnitude indicate a substantial improvement in CNS toxicity relative to baseline. The 
median change from baseline will be summarized for the immediate versus deferred switch 
groups at Study Weeks 4 and 12 (primary time points of interest). The change from baseline 
to 4 weeks post-switch (by treatment group), 12 weeks post-switch (by treatment group), and 
24 weeks post-switch (combining both treatment groups) will also be summarized.
Efficacy Endpoints
Section 4.2.3.2 provides an initial description of efficacy measures.
Proportions of Subjects Maintaining HIV-1 RNA < 50 (and <40) copies/mL (by the Abbott 
RealTime HIV-1 Assay)
The proportions of subjects maintaining HIV-1 RNA <50 (and <40) copies/mL will be 
estimated separately by treatment group at 4 and 12 weeks post-switch and for the combined 
treatment groups at 24 weeks post-switch (with primary interest in the combined analysis).  
The Abbott RealTime HIV-1 Assay, which has a lower limit of reliable quantification (LoQ) 
of 40 copies/mL, will be used to measure the HIV-1 RNA level in blood samples obtained at 
each visit. 
Change from Baseline in CD4 Cell Count
Change from baseline in CD4 cell count will be estimated separately by treatment group at 4 
and 12 weeks post-switch and for the combined treatment groups at 24 weeks post-switch
(with primary interest in the combined analysis).
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For the calculations of change from baseline, baseline measurements are defined as the 
values collected predose on the day of the switch to MK-1439A for each subject. In the rare 
event when data for this visit are missing, the value obtained at the most recent screening 
visit (Immediate Switch Group) or Week 4 (Deferred Switch Group) will be used as baseline.  
This rule will also be applied to define the baseline measurements for other laboratory tests.
Protocol-Defined Virologic Failure (PDVF)
Subjects with protocol-defined virologic failure (PDVF) as defined in Section 4.2.3.2 will be 
identified and summarized for each treatment group.
Safety Endpoints
Section 4.2.3.3 provides an initial description of safety measures.
All accumulated safety data through 14 days following the end of treatment will be included 
in the analysis of safety with the exception of the summary of safety data limited to the 
double-blind period of the study through the Week 12 visit.  Because some safety data will 
be collected in an open-label manner post-switch these data should be interpreted with 
caution.  
Adverse Experiences
The following clinical and laboratory adverse experiences will be summarized: 1) subjects 
with at least one adverse experience; 2) subjects with at least one drug-related adverse 
experience; 3) subjects with at least one serious adverse experience; 4) subjects with at least 
one serious and drug related adverse experience; and 5) subjects who discontinued study 
therapy due to an adverse experience. The percentage of subjects with specific adverse
experiences by system organ class will also be summarized.
Laboratory Parameters
The mean (SD) for the change from baseline in laboratory tests including the change from 
baseline in fasting lipids (LDL-C, non-HDL-C, total cholesterol, HDL-C, and triglycerides) 
will be summarized.
Pre-defined Limits of Change in Laboratory Parameters
Subjects must have both a baseline and post-randomization on-treatment measurement to be 
included in the summaries of laboratory tests. Subjects’ laboratory values (based on their 
most abnormal laboratory test values, in the direction of interest, while on study therapy) will 
be classified as to whether or not they fall outside of the Pre-Defined Limit of Change 
(PDLC) and are worse in grade (ie, more abnormal in the direction of interest) than at 
baseline.  The PDLC grading criteria are adapted from DIVISION OF AIDS TABLE FOR 
GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS, 
PUBLISH DATE: AUGUST 2009 Version 1 (Section 12.6). A listing of the subjects who 
meet the PDLC grading criteria will be provided.
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Analysis Populations
Efficacy and CNS Toxicity Questionnaire Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy and the CNS toxicity questionnaire data in this study.  The FAS population 
consists of all randomized subjects who:

receive at least one dose of study treatment,

have baseline data for those analyses that require baseline data.
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy and CNS toxicity data using the FAS population.  Details on the 
approach to handling missing data are provided in Section 8.6 Statistical Methods.
Additionally, for the primary CNS endpoint a per-protocol population will be used which 
excludes subjects who discontinue prior to Week 12.  
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received.  Otherwise, 
subjects will be included in their randomized treatment groups.
At least one laboratory or vital sign measurement obtained subsequent to at least one 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 
8.6 Statistical Methods.
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 8.6.3.
Unless otherwise stated, all statistical tests will be conducted at the α=0.025 (1-sided) level.
Time Window
Table 9 and Table 10 list the time windows and the target days for the scheduled visits in the 
study that will be used for all analyses. The measurement closest to the target date within a 
window will be used for analyses at a specific time point.
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Table 9
Definition of Study Time Point – Immediate Switch Group
Treatment Phase
Treatment 
Period
Protocol
Time Point
Day-Range Rules
Target Day Post 
Switch
CSR Time Post 
Switch
Pre-treatment
Baseline
Day 1 (Baseline)
1
1
Day 1
Treatment
Double-Blind
Week 4
>1 and  56
29
Week 4
Week 12
57 and last day 
of double-blind 
treatment period
85
Week 12
Open-Label
Week 16
first day of open 
label treatment and 
140
113
Week 16
Week 24
141 and 
reported Week 24 
visit date for 
subject completed 
Week 24 visit or 
last day of 
treatment period 
for subject 
discontinued 
before having 
Week 24 visit
169
Week 24
Treatment
Extension 1
Week 40
≥first day after 
reported Week 24 
visit date and ≤337
281
Week 40
Week 56
≥338 and ≤448
393
Week 56
Week 72
≥449 and ≤561
505
Week 72
Week 88
≥562 and ≤672
617
Week 88
Week 104
≥673 and ≤789
729
Week 104
Week 120
≥790 and ≤last day 
of Extension 1 
treatment period
841
Week 120
Relative days are counted from the first day of study medication at randomization.  
The clinical study report (CSR) time post-switch is the time label to be used in the post-switch analysis tables.  Relative 
days are counted from the day of switch.
Note, PK only visits are not included (ie, Weeks 1, 2, and 3).
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Table 10
Definition of Study Time Point – Deferred Switch Group
Treatment 
Phase
Treatment 
Period
Protocol
Time Point
Day-Range 
Rules
Target 
Day
Day-Range Rules 
Post Switch
Target 
Day 
Post 
Switch
CSR Time 
Post Switch
Pre-
treatment
Baseline
Day 1 
(Baseline)
1
1
Treatment
Double-
Blind
Week 4
>1 and  56
29
Week 12
57 and last 
day of double-
blind treatment
period
85
1
1
Day 1
Open-
Label
Week 16
>1 and  56
29
Week 4
Week 24
>57 and  126
85
Week 12
Week 36
>127 and  
reported Week 36
visit date for 
subject completed 
Week 36 visit or 
last day of 
treatment period for 
subject 
discontinued before 
having Week 36
visit
169
Week 24
Treatment
Extension 
1
Week 52
≥first day after 
reported Week 36
visit date and ≤337
281
Week 40
Week 68
≥338 and ≤448
393
Week 56
Week 84
≥449 and ≤561
505
Week 72
Week 100
≥562 and ≤672
617
Week 88
Week 116
≥673 and ≤789
729
Week 104
Week 132
≥790 and ≤last day 
of study extension 1 
treatment period
841
Week 120
Relative days are counted from the first day of study medication at randomization.  
The clinical study report (CSR) time post-switch is the time label to be used in the post-switch analysis tables.  Relative 
days are counted from the day of switch.
Note, PK only visits are not included (ie, Weeks 1, 2, and 3).
Statistical Methods for Subject-Reported Outcomes for CNS Toxicity
CNS Toxicity Questionnaire
Missing Data
All missing post-baseline data will be assigned the intensity score for the same item from the 
closest prior visit with non-missing data.  For example, for a given questionnaire item, the 
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Week 4 data would be used at Week 12 if a subject’s information at Week 12 was incomplete 
or completely missing.
All subjects who discontinue will be asked to complete the CNS toxicity questionnaire at the 
discontinuation visit.  These data, which are potentially informative, would also be used to 
impute missing data.
An analysis of the per-protocol population will be performed as a sensitivity analysis which 
excludes subjects who discontinue prior to Week 12.  No data will be carried forward for this 
analysis, and only those subjects who have completed the Week 12 CNS toxicity 
questionnaire will be included.
Methods of Analysis
Proportion of subjects with ≥1 CNS Toxicity of at least Grade 2 Intensity at Study Week 4 
and Study Week 12 (Primary Endpoint)
The treatment difference and the associated 95% confidence interval will be calculated for 
the proportion of subjects with at least 1 CNS toxicity of at least Grade 2 intensity at Study 
Week 12 using the Miettinen and Nurminen’s method (1985) [17], an unconditional, 
asymptotic method, and p-values based on this method will be provided.  The immediate 
switch group will be considered to have a statistically significantly smaller proportion of 
subjects with at least one CNS toxicity of at least Grade 2 intensity at Week 12 if the upper 
bound of the 95% confidence interval for the treatment difference (immediate – deferred) is 
less than 0.  Data from Study Week 4 will be summarized in a similar manner with no 
inferential test of hypothesis.
Change from baseline in CNS Toxicity Score
The mean and standard deviation (SD) for the change from baseline in CNS toxicity score 
will be summarized by treatment group at Study Weeks 4 and 12 (primary interest).  The 
difference in mean scores between treatment groups and the associated 95% CI based on a t-
distribution will be summarized at Study Weeks 4 and 12.  The median change from baseline 
and interquartile range will also be provided.  
Table 11 summarizes the key CNS toxicity questionnaire analyses.
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Table 11
Analysis Strategy for CNS Toxicity Questionnaire Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Objective
The proportion of subjects with at 
least one CNS toxicity of at least 
Grade 2 intensity at Week 12.
Primary
Miettinen and Nurminen’s
method: 95% CI and 
associated p-value
FAS
Last observation 
carried forward
The proportion of subjects with at 
least one CNS toxicity of at least 
Grade 2 intensity at Week 12.
Supportive
Miettinen and Nurminen’s
method: 95% CI
Per-protocol
Data as observed
Secondary Objectives
Proportion of subjects with at least 
one CNS toxicity of at least Grade 2 
intensity at Week 4
Primary
Miettinen and Nurminen’s
method: 95% CI
FAS
Last observation 
carried forward
Change from baseline in the 
proportion of subjects with at least 
one CNS toxicity of at least Grade 2 
intensity at 24 weeks post-switch
Primary
Descriptive Statistics
FAS
Last observation 
carried forward
Change from baseline in CNS 
toxicity score at Weeks 4 and 12
Primary
Descriptive Statistics
95% CI based on a t-
distribution
FAS
Last observation 
carried forward
Change from baseline in CNS 
toxicity score at 24 weeks post-
switch
Primary
Descriptive Statistics
95% CI based on a t-
distribution
FAS
Last observation 
carried forward
Statistical Methods for Efficacy Analyses
Missing Data
Missing HIV-1 RNA Data
The Non-Completer=Failure (NC=F) approach as defined by the FDA “snapshot” approach
will be used to handle missing HIV-1 RNA data. Under this approach, only subjects meeting 
the following can be classified as virologic success at a given time point: 1) subject is on 
study-assigned treatment, 2) subject has HIV-1 RNA measurement(s) within the time 
window specified in Table 9 and Table 10, and 3) subject has the measurement closest to the 
target date of the time point <50 copies/mL. Subjects with an HIV-1 RNA measurement 
≥50 copies/mL or no virologic data within the time window due to intermittent missing data 
or premature discontinuation (regardless of the reason) will be considered failures in the 
analyses of the proportion of subjects maintaining HIV-1 RNA <50 copies/mL at that time
point.  The proportion of subjects maintaining HIV-1 RNA <40 copies/mL will be 
summarized in a similar fashion.
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Missing CD4 Cell Count Data
The observed failure (OF) approach will be used for the analysis of the change from baseline 
in CD4 cell count. Under this approach, baseline values will be carried forward for subjects 
who discontinue due to lack of efficacy.  Otherwise, subjects with missing data are excluded.
Methods of Analysis
Proportion of Subjects Maintaining HIV-1 RNA <50 copies/mL and <40 copies/mL
The proportion of subjects maintaining HIV-1 RNA < 50 copies/mL and <40 copies/mL will 
be summarized at each time point post-switch, with a primary interest at 24 weeks post-
switch. At each time point, the 95% confidence interval for the proportion will be calculated
using the exact binomial method proposed by Clopper and Pearson (1934) [18].  Subjects 
who discontinue prior to switching to MK-1439A in the deferred switch group will be 
excluded from this analysis.
The NC=F approach as defined by FDA “snapshot” approach will be used as the primary 
approach to analysis with respect to the proportion of subjects with virologic response (HIV-
1 RNA <50 copies/mL). All subjects with missing data at the time point of interest will be 
treated as failures regardless of the reason for the missing data.
To provide a full picture of the virologic outcome at a given time point, subjects who are not 
classified as a virologic success will be further categorized as a virologic failure (HIV-1 
RNA ≥50 copies/mL or ≥40 copies/mL depending on the endpoint) or as having no virologic 
data in the time window for reasons of 1) discontinuation from the study due to an AE, 
2) discontinuation from the study for other reasons (includes withdrawal of consent, loss to 
follow-up, relocation, etc.), or 3) on study but missing data in the window. The full 
categorization of virologic outcome at 24 weeks post-switch will be summarized.
Change from Baseline in CD4 cell count
The change from baseline in CD4 cell counts will be summarized in the combined treatment 
groups at each time point post-switch at which the CD4 cell count is collected with a key 
interest at 24 weeks post-switch. The OF approach will be used for the analyses of the 
change from baseline in CD4 cell count. Subjects who discontinue prior to switching to MK-
1439A in the deferred switch group will be excluded from this analysis.
Protocol-Defined Virologic Failure (PDVF)
The number of subjects with protocol-defined virologic failure will be summarized.
Table 12 summarizes the key efficacy analyses.
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Table 12
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Secondary Objectives
Proportion of Subjects Achieving 
HIV-1 RNA <50 copies/mL at 24 
weeks post switch
Proportion of Subjects Achieving 
HIV-1 RNA <40 copies/mL at 24 
weeks post switch
Descriptive statistics
FAS
NC=F
Change from Baseline in CD4 
cell count at 24 weeks post switch
Descriptive statistics
FAS
OF
The strategy to address multiplicity issues with regard to multiple treatment comparisons, 
multiple endpoints, multiple timepoints, and/or interim analyses is described in Section 8.7, 
Interim Analyses and in Section 8.8, Multiplicity.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters 
including adverse experiences (AEs), laboratory tests and vital signs. Note that the data 
collected from the CNS toxicity questionnaire is not included as part of the safety analyses.  
Safety data through Week 12 and through 24 weeks post-switch will be summarized 
separately.  The treatment groups will be combined for the analysis of safety post-switch 
as both groups will receive the same treatment.  All accumulated safety data through 14 
days following the end of treatment will be included in the analyses of post-switch safety 
data.  Key timepoints of interest are Week 12 (comparing treatment groups) and 24 weeks 
post-switch (combining treatment groups).
The analysis of safety results will follow a tiered approach as summarized in Table 13.  The 
tiers differ with respect to the analyses that will be performed.  Safety parameters or adverse 
experiences of special interest that are identified a priori constitute “Tier 1” safety endpoints 
that will be subject to inferential testing for statistical significance with p-values and 95% 
confidence intervals provided for between-group comparisons.  Other safety parameters will 
be considered Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates with 
95% confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and pre-defined
limits of change in laboratory parameters that are not pre-specified as Tier-1 endpoints 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 subjects in any treatment group exhibit the 
event; all other adverse experiences and pre-defined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
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groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and pre-defined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs parameters 
that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters.  
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.  
For this protocol, there are no Tier 1 events.  
The change from baseline in fasting lipids will be analyzed using ANCOVA models adjusted 
by baseline lipid level and treatment group (pre-switch period only). The treatment 
differences and 95% confidence intervals will be provided for all lipid parameters. The 
missing lipid data will be handled by the following principle: For subjects who have missing 
lipid data, the last lipid observation after randomization will be carried forward. For subjects 
who modify (start, stop, increase or decrease dosage) lipid-lowering therapy use during the 
study, the last lipid observation before modifying the lipid-lowering therapy use will be 
carried forward for later time points.
The percentages of subjects who modify lipid-lowering therapy during the study will be 
summarized by treatment group in the pre-switch period and overall in the post-switch 
period. In the pre-switch period, the difference in percentages between treatment groups and 
the associated 95% confidence interval will be calculated using Miettinen and Nurminen’s 
method.
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, with a drug-related AE, with a serious AE, with an AE which is both 
drug-related and serious, and who discontinued due to an AE will be considered Tier 2 
endpoints.  The 95% confidence intervals will be provided for between-treatment differences 
in the percentage of subjects with events; these analyses will be performed using the 
Miettinen and Nurminen’s method and restricted to the comparative Week 12 safety 
analyses.
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Table 13
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison‡‡
Descriptive 
Statistics
Tier 1
None
Tier 2
Change from baseline in fasting lipids
Starting lipid-lowering therapy
X
X
Any AE
Any Serious AE
Any Drug-Related AE
Any Serious and Drug-Related AE
Discontinuation due to AE
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 of 
subjects in one of the treatment groups‡‡) 
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of 
subjects in all of the treatment groups‡‡)
X
Change from Baseline Results (Labs, Vital 
Signs)
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
‡
Includes only those endpoints not pre-specified as Tier 1 and not already pre-specified as Tier-2 endpoints.
‡‡    Only for the Week 12 safety analysis.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
Statistical Methods for Exploratory Endpoints
Other Subject-Report Outcomes and Neurocognitive Assessment
The analyses of the change from baseline (the day of the switch to MK-1439A) in sleep 
quality, neurocognitive function, anxiety and depression and health-related quality of life will 
be described in a separate statistical analysis plan.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.5.1
Demographic and Baseline Characteristics
Baseline characteristics for all allocated and treated subjects will be summarized by treatment 
group and overall. No statistical hypothesis tests will be performed on these characteristics. 
The number and percentage of subjects screened and allocated along with the primary 
reasons for screen failure and the primary reasons for discontinuation will be displayed. 
Demographic variables (e.g., age, gender and race), primary and secondary diagnoses, and 
prior and concomitant therapies will be summarized either by descriptive statistics or 
categorical tables. Summary statistics for baseline efficacy and CNS toxicity questionnaire
measures will also be provided.
8.6.5.2
PK Analyses
Plasma concentrations of MK-1439 and efavirenz will be summarized.  
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Interim Analyses
There are no interim analyses planned for this study.
Multiplicity
No multiplicity adjustment is planned as there is a single comparison of 2 treatments using 1 
endpoint in the primary hypothesis. Other analyses will be considered supportive and/or 
explanatory.
Sample Size and Power Calculations
Sample Size and Power for Primary Analysis to address the Primary Hypothesis
This study will randomize 42 subjects into the Immediate Switch Group and 42 into the 
Deferred Switch Group and has 80% power to demonstrate the superiority of an immediate 
switch to MK-1439A over continuation of ATRIPLATM with respect to the proportion of 
subjects with a Grade 2 or worse CNS toxicity at Week 12 at an overall one-sided, 2.5% 
alpha-level, if the underlying treatment difference in the proportion of subjects with at least 
one Grade 2 or worse CNS toxicity at Week 12 is -24.5% (immediate switch – deferred
switch) and the assumed proportion of subjects with at least one CNS toxicity of at least 
Grade 2 intensity at Week 12 is 67% in the Immediate Switch Group.  These assumptions are
based on a similarly designed study of a switch from ATRIPLATM to an etravirine-based 
regimen that had the same primary endpoint [3]. The power calculation is based on an 
asymptotic method proposed by Farrington and Manning (1990) [19] and is carried out using 
SAS v9.3.  The immediate switch group will be considered to have a statistically 
significantly smaller proportion of subjects with at least one CNS toxicity of at least Grade 2 
intensity at Week 12 if the upper bound of the 95% confidence interval for the treatment 
difference (immediate – deferred) is less than 0.  Given the assumed 67% event rate in the 
immediate switch group, this may occur when the observed difference between treatment 
groups is approximately -16.5% or smaller.  Table 14 summarizes the power for the primary 
comparison under various assumptions for the deferred switch group proportion and 
underlying difference in proportions. 
Table 14
Power (%) Under Various Assumptions (With 42 Subjects Randomized in Each 
Treatment Group)
Percentage of subjects with a CNS 
toxicity (Grade 2 to higher) at Week 12
in the Deferred Switch Group
Underlying Difference in Percentage of Subjects with a CNS 
toxicity (Grade 2 or higher) at Week 12
(Immediate Switch – Deferred Switch)
-24.5
-20
-16.5
85%
91.5%
95%
72
56
43
80
66
53
86
74
61
Note:  The power calculation assumes 42 subjects will be included in the analysis for each treatment group.
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Sample Size and Power for Safety Analyses
The probability of observing at least one of a particular type of adverse experience in this 
study depends on the number of subjects treated and the underlying percentage of subjects 
with that adverse experience in the study population. If the underlying incidence of a 
particular adverse experience is 1% (1 of every 100 subjects receiving the drug), there is a 
57% chance of observing at least one adverse experience among the 84 subjects in this study 
(both treatment groups combined). If no adverse experience of that type is observed among 
the 84 subjects, this study will provide 95% confidence that the underlying percentage of 
subjects with that particular adverse experience is 4.3%.   
The estimate of, and the upper bound of the 95% confidence interval for, the underlying 
percentage of subjects with an AE given various hypothetical observed numbers of subjects 
with the AE are provided in Table 15 . These calculations are based on the exact binomial 
method proposed by Clopper and Pearson (1934) [18].
Table 15
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Subjects With AEs Among 84 Subjects Randomized
Hypothetical Number of
Subjects With An Adverse
Event
Estimate of Incidence
95% Upper Confidence 
Bound†
0
0%
4.3%
1
1.2%
6.5%
2
2.4%
8.3%
3
3.6%
10.1%
4
4.8%
11.8%
5
6.0%
13.4%
6
7.1%
14.9%
7
8.3%
16.4%
8
9.5%
17.9%
9
10.7%
19.4%
10
11.9%
20.8%
Subgroup Analyses and Effect of Baseline Factors
To characterize the CNS toxicity profile across various subgroups, the primary
endpoint will be summarized by treatment group and plotted within each category of the 
following classification variables:
   Age category (≤median vs. >median)
   Gender (female, male)
   Race (White, Black, Asian, Other)
   Baseline CD4 categories (<50, 50-200, and >200 cells/mm3)
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Compliance (Medication Adherence)
Study Medication Diary Cards will be used to document drug compliance in the base study 
and study extension 1.
Subjects are to take one tablet from Bottle A and one tablet from Bottle B once daily during 
the double-blind portion of the trial and one tablet from Bottle C once daily in the open-label 
phase. For the main analysis of compliance in this study, a day within the study will be 
considered an “On-Therapy” day if the subject takes one tablet from both Bottle A and 
Bottle B during the double-blind phase and a single MK-1439A tablet during the open-label 
phase of the trial.
For a subject who is followed for the entire study 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 administration for that subject. For a subject who discontinued from the study
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 subject, percent compliance will then be calculated using the following 
formula: 
Therapy
on 
be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 

× 100.
Summary statistics will be provided for the percent compliance in the FAS population.  
Compliance will be summarized for the double-blind phase through Week 12 by treatment 
group.  In addition, compliance will be summarized using all data post-switch, pooling the 2
treatment groups.  
Data from the study medication diary, rather than the returned pill count will serve as
the primary data for compliance.
Compliance data will not be collected and analyzed for study extension 2 or study extension 3. 
Extent of Exposure
The extent of exposure to study therapy for all treated subjects will be summarized.
The number of subjects 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 
subjects were exposed to various doses.
Extent of exposure will be summarized for the double-blind phase through Study Week 12 
by treatment group.  In addition, extent of exposure will be summarized using all data post 
switch, pooling the 2 treatment groups.  
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9.0 LABELING,
PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 16.
Table 16
Product Descriptions
Product Name & Potency
Dosage Form
MK-1439A (MK-1439 100mg / Lamivudine
300mg / Tenofovir Disoproxil Fumarate 300mg) or placebo to 
match MK-1439A (MK-1439 100mg / Lamivudine 300mg /
Tenofovir Disoproxil Fumarate 300mg) (Bottle A)
Tablets
Efavirenz 600mg / Emtricitabine 200mg / Tenofovir Disoproxil 
Fumarate 300mg (Tenofovir Disoproxil Fumarate, which is 
equivalent to 245 mg of Tenofovir Disoproxil) (ATRIPLA™) or 
placebo to match Efavirenz 600mg / Emtricitabine 200mg / 
Tenofovir Disoproxil Fumarate 300mg (Tenofovir Disoproxil 
Fumarate, which is equivalent to 245 mg of Tenofovir Disoproxil)
(ATRIPLA™) (Bottle B)
Tablets
MK-1439A (MK-1439 100mg / Lamivudine 300mg / Tenofovir 
Disoproxil Fumarate 300mg) (Bottle C)
Tablets
All placebos were created by the Sponsor to match the active product.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive both blinded (Bottle A and B) and open label (Bottle C) bottles in 
accordance with the dispensing schedule. No kitting is required.
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity. The emergency unblinding call 
center should only be used in cases of emergency (see Section 7.1.4.2). 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 
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to unblind subjects and to unmask treatment/vaccine identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
After Week 12 / Visit 7 the trial is open-label; therefore, the subject, the trial site personnel, 
the Sponsor and/or designee are not blinded to the new treatment type from this point 
forward. Treatment (name, strength or potency) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
Treatment identification information prior to study Week 16 is to be unmasked ONLY if 
necessary for the welfare of the subject.  Every effort should be made not to unblind the 
subject unless necessary. 
In the event that unblinding prior to study Week 16 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 
subject.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 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.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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At the close of the trial after unblinding, a letter is to be sent by the investigator to those 
subjects who received placebos in the image of the competitor’s product to provide the 
following advice: 
“You have participated in a trial conducted by the Sponsor. This is to advise you that you 
were among those who received a look-alike tablet created by the Sponsor to resemble the 
drug ATRIPLATM (Efavirenz 600mg / Emtricitabine 200mg / Tenofovir Disoproxil Fumarate 
300mg) as much as possible. You did not receive the active  drug ATRIPLATM (Efavirenz 
600mg / Emtricitabine 200mg / Tenofovir Disoproxil Fumarate 300mg) as manufactured by 
Gilead Sciences.”
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
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/ERC) 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 Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, 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 subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
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2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member 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.
Compliance with Financial Disclosure Requirements
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 or through a secure password-protected electronic portal 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.
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 (e.g., International Conference on Harmonization of Technical 
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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 MSD, is provided in Section 12.1 -
Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
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need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
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.  MSD, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
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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.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, 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.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. MSD will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
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the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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11.0 LIST OF REFERENCES
1. Gatell JM, Morales-Ramirez JO, Hagins DP, Thompson M, Arastéh K, Hoffmann C, 
Rugina S, Osiyemi O, Erscoiu S, Dretler R, Harvey C, Xu X, Teppler H.  48 week 
Efficacy and Safety and Early CNS tolerability of Doravirine, a novel NNRTI, with 
TDF/FTC in ART-Naïve HIV Infected patients.  Presented at the Conference on HIV 
Drug Therapy, Glasgow; November 2 – 6, 2014.
2. Leutscher PDC, Stecher, C, Storgaard, M, Larsen, CS. Discontinuation of efavirenz 
therapy in HIV patients due to neuropsychiatric adverse effects. Scandinavian Journal of 
Infectious Diseases 2013: Early Online 1-7
3. Waters L, Fisher M, Winston A, Higgs C, Hadley W, Garvey L, Mandalia, S, Perry N, 
Mackie, N, Nelson, M. A phase IV, double-blind, multicentre, randomized, placebo-
controlled, pilot study to assess the feasibility of switching individuals receiving 
efavirenz with continuing central nervous system adverse events to etravirine. AIDS 
2011; 25: 65-71
4. Nguyen, A, Calmy A, Delhumeau, C, Mercier, I, Cavassini, M, Mello, AF, Elzi, L, 
Rauch, A, Bernasconi, E, Schmid, P, Hirschel, B. A randomized cross-over study to 
compare raltegrevir and efavirenz (SWITCH-ER study). AIDS 2011; 25: 1481-148
5. Gatell, J, Raffi, F, Plettenberg, A, Smith, D, Portilla, J, Hoffman, C, Arasteh, K, 
Thompson, M, Hagins, D, Morales-ramirez, J, Xu, X, Teppler, H. Efficacy and safety of 
Doravirine 100mg QD vs Efavirenz 600 mg QD with TDF/FTC in ART-Naïve HIV 
infected patients: week 24 results. Presented at the IAS Conference on HIV 
pathogenesis, Vancouver; July, 2015.
6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and 
Human 
Services. 
October 
1, 
2015;
Available 
at 
https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultAndAdolescentGL.pdf
7. British HIV Association Guidelines for the treatment of HIV-1-positive adults with 
antiretroviral 
therapy 
2015, 
Available 
at 
http://www.bhiva.org/documents/Guidelines/Treatment/2015/2015-treatment-
guidelines.pdf
8. Yee KL, Sanchez R, Auger P, Liu R, Triantafyllou I, Tomek C, Iwamoto M, Khalilieh 
S. An evaluation of doravirine pharmacokinetics when switching from efavirenz to 
doravirine treatment. Presented at the International Workshop on Clinical Pharmacology 
of HIV & Hepatitis Therapy - 16th Annual. 2015;abs54.
9. Nelson M, Stellbrink H, Podzamczer D, et al. A comparison of neuropsychiatric adverse 
events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive,
HIV-1-infected population. AIDS 2011; 25:335–340
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10. Maruff P, Thomas E, Cysique LA, et al. Validity of the CogState brief battery: 
relationship to standardized tests and sensitivity to cognitive impairment in mild 
traumatic brain injury, schizophrenia, and AIDS dementia complex. Arch Clin 
Neuropsychol. 2009; 24:165–178.
11. Cysique LAJ, Maruff P, Darby D, et al. The assessment of cognitive function in 
advanced HIV-1 infection and AIDS dementia complex using a new computerised 
cognitive test battery. Arch Clin Neuropsychol. 2006; 21:185–194.
12. Buysse DJ1, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep 
Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 
1989 May; 28(2):193-213.
13. Snaith RP. The Hospital Anxiety And Depression Scale. Health Qual Life Outcomes 
2003; 1(1):29.
14. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and 
Depression Scale: An updated literature review. Journal of Psychosomatic Research 
2002; 52(2):69-77.
15. The EuroQol Group. EuroQol - a new facility for the measurement of health-related
quality of life. Health Policy 1990; 16:199-208.
16. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X.  
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-
5L). Qual Life Res 2011 Dec; 20(10): 1727-36.
17. Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4:213-226.
18. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of binomial. Biometrika 1934; 26: 404-13.
19. 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. 
Statistics in Medicine 1990; 9: 1447-54.
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12.0 APPENDICES
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
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B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the extent 
scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to patients, 
physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named authors 
must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance with 
local and/or national regulations. Changes to the protocol that are required urgently to eliminate an immediate hazard 
and to protect participant safety may be enacted in anticipation of ethics committee approval. MSD will inform 
regulatory authorities of such new measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is obtained. 
Participants may withdraw from an MSD trial at any time, without any influence on their access to, or receipt of, 
medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an ethics 
committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
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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 collected in this trial as outlined in Section 7.1.3.9 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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.
Subjects for Enrollment
All subjects 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 subjects 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 subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject 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 Collections
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 subject is having blood drawn for other trial purposes.
4. Confidential Subject 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 subject' 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 subject 
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 for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first 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 MSD Biorepository 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 (e.g., 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 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects 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 
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mailbox (clinical.specimen.management@MSD.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 (e.g., 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 subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not 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 (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects 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 subjects 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 subject have been minimized.  Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
The Sponsor has developed strict security, policies and procedures to address subject 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@MSD.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
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types
Table A: Approximate Blood Volumes Drawn in Base Study: Screening Through Week 24 (ISG) or Week 36 (DSG) Plus 14 days 
Follow Up
Visit number/Title
1
2
Randomi-
zation
3
4
5
6
7
8
9
10
U
U
99
Total 
Volume
TRIAL PROCEDURES
Screen-
ing
Day 1 a
WK 1
WK 2
WK 3
WK 4
WK 
12a
WK 16
WK 24a
WK 36
(DSG 
ONLY) a
Virologic 
Failure 
Confirm-
ation 
Early
Discont-
inuation 
14-Day 
Follow-
Up 
Immediate Switch Group 
(ISG)
Weeks Post Switch
Day 1
WK 1
WK 2
WK 3
WK 4
WK 12
WK16
WK 24
Deferred Switch Group 
(DSG)
Weeks Post Switch
(-12 WKs)
(-11 
WKs)
(-10 WKs)
(-9 WKs)
(-8 
WKs)
Day 1
WK 4
WK 12
WK 24
Laboratory
Procedures/Assessments
Hematology 
2
2
2
2
2
2
2
2
2
2
20
Chemistry
29
7
7
7
7
7
7
7
7
7
92
Serum Pregnancy Test b
HIV/Hepatitis Screen c
Hemostatic Function Test d
4.5
4.5
HIV Viral RNA (Plasma)
10
10
10
10
10
10
10
10
10
10
100
CD4 Cell Count
2
2
2
2
8
Viral Resistance Test 
(Plasma)
14
14
14
14
14
14
14
14 g
14
112
Blood for Genetic
Analysis
8.5
8.5
Plasma for Future 
Biomedical Research
10
10
MK1439 and EFV PK e
8
8
8
8
8
40
Expected Total (mL)
45.5
61.5
8
8
8
41
35
33
35
35
33
33
9
385
Total (tablespoons) f
~3.0
~4.1
~0.5
~0.5
~0.5
~2.7
~2.3
~2.2
~2.3
~2.3
~2.2
~2.2
~0.6
~25.7
a.
Fasting required at these visits for lipid measurements.
b.
For women of childbearing potential.
c.
Includes Enzyme Immunoassay HIV Antibody Screen, Serum Hepatitis B Surface Antigen, Serum Hepatitis B Surface Antibody, Serum Hepatitis B e-Antigen and Serum Hepatitis C Antibody. 
A plasma Hepatitis C virus PCR quantitative test (an additional ~6 ml= 0.4 tablespoon of blood) will be performed if the Hepatitis C antibody test is positive.
d.
Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) and International Normalized Ratio (INR).
e.
Sample must be collected predose. 
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Visit number/Title
1
2
Randomi-
zation
3
4
5
6
7
8
9
10
U
U
99
Total 
Volume
TRIAL PROCEDURES
Screen-
ing
Day 1 a
WK 1
WK 2
WK 3
WK 4
WK 
12a
WK 16
WK 24a
WK 36
(DSG 
ONLY) a
Virologic 
Failure 
Confirm-
ation 
Early
Discont-
inuation 
14-Day 
Follow-
Up 
Immediate Switch Group 
(ISG)
Weeks Post Switch
Day 1
WK 1
WK 2
WK 3
WK 4
WK 12
WK16
WK 24
Deferred Switch Group 
(DSG)
Weeks Post Switch
(-12 WKs)
(-11 
WKs)
(-10 WKs)
(-9 WKs)
(-8 
WKs)
Day 1
WK 4
WK 12
WK 24
f.
One Tablespoon = 15 mL.
g.
If viral failure or relapse is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for resistance does not need to be 
collected again at the discontinuation visit
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Table B: Approximate Blood Volumes Drawn in Study Extension 1: Week 40 (ISG) or 52 (DCG) Through Week 120 (ISG) or 132 
(DSG) Plus 14 Days Follow Up
U
U
99
Total 
Volume
TRIAL PROCEDURES
Virologic 
Failure 
Confirm-
ation 
Early
Discont-
inuation 
14-Day 
Follow-
Up 
Immediate Switch Group (ISG): Study Week
WK 40
WK 56
WK 72
WK 88
WK 104
WK 120
Deferred Switch Group (DSG): Study Week
WK 52
WK 68
WK 84
WK 100
WK 116
WK 132
Laboratory Procedures/Assessments
Hematology 
2
2
2
2
2
2
2
2
2
18
Chemistry
7
7
7 a
7
7
7 a
7
7
7
63
HIV Viral RNA (Plasma)
10
10
10
10
10
10
10
10
10
90
CD4 Cell Count
2
2
4
Viral Resistance Test (Plasma)
14
14b
28
Expected Total (mL)
19
19
21
19
19
21
33
33
19
203
Total (tablespoons)c
1.3
1.3
1.4
1.3
1.3
1.4
2.2
2.2
1.3
~13.5
a. Fasting is required at these visits for lipids measurement.
b. If viral failure or relapse is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for resistance
need not be collected again at the discontinuation visit. 
c. One tablespoon = 15 mL.
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CCI
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DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS, 
PUBLISH DATE: AUGUST 2009 Version 1 
LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY 
LIFE-THREATENING
HEMATOLOGY Standard International Units are listed in italics 
Absolute CD4+ count – Adult and Pediatric > 
13 years (HIV NEGATIVE ONLY) 
300 – 400/mm3 300 –
400/μL 
200 – 299/mm3 200 –
299/μL 
100 – 199/mm3 100 –
199/μL 
< 100/mm3 < 100/μL 
Absolute lymphocyte count – Adult and 
Pediatric > 13 years (HIV NEGATIVE 
ONLY) 
600 – 650/mm3 0.600 x 109 
– 0.650 x 109/L 
500 – 599/mm3 0.500 x 
109 – 0.599 x 109/L 
350 – 499/mm3 0.350 x 
109 – 0.499 x 109/L 
< 350/mm3 < 0.350 x 109/L 
Comment: Values in children ≤ 13 years are not given for the two parameters above because the absolute counts are variable. 
Absolute neutrophil count (ANC) 
Adult and Pediatric, > 7 days 
1,000 – 1,300/mm3 1.000 x 
109 – 1.300 x 109/L 
750 – 999/mm3 0.750 x 109 
– 0.999 x 109/L 
500 – 749/mm3 0.500 x 109 
– 0.749 x 109/L 
< 500/mm3 < 0.500 x 109/L 
Fibrinogen, decreased 
100 – 200 mg/dL 1.00 –
2.00 g/L OR 0.75 – 0.99 x 
LLN 
75 – 99 mg/dL 0.75 – 0.99 
g/L OR 0.50 – 0.74 x LLN 
50 – 74 mg/dL 0.50 – 0.74 
g/L OR 0.25 – 0.49 x LLN 
< 50 mg/dL < 0.50 g/L OR < 0.25 
x LLN OR Associated with gross 
bleeding 
† Use age and sex appropriate values (e.g., bilirubin).
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LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY 
LIFE-THREATENING
Hemoglobin (Hgb) 
Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been changed from 0.155 to 0.6206 (the most commonly
used conversion factor). For grading Hgb results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the 
appropriate conversion factor for that lab. 
Adult and Pediatric ≥ 57 days (HIV 
POSITIVE ONLY) 
8.5 – 10.0 g/dL 5.24 – 6.23 
mmol/L 
7.5 – 8.4 g/dL 4.62–5.23 
mmol/L 
6.50 – 7.4 g/dL 4.03–4.61 
mmol/L 
< 6.5 g/dL < 4.03 mmol/L 
Adult and Pediatric ≥ 57 days (HIV 
NEGATIVE ONLY) 
10.0 – 10.9 g/dL 6.18 – 6.79 
mmol/L OR Any decrease 2.5 
– 3.4 g/dL 1.58 – 2.13 mmol/L 
9.0 – 9.9 g/dL 5.55 - 6.17 
mmol/L OR Any decrease 3.5 
– 4.4 g/dL 2.14 – 2.78 mmol/L 
7.0 – 8.9 g/dL 4.34 - 5.54 
mmol/L OR Any decrease ≥ 
4.5 g/dL > 2.79 mmol/L 
< 7.0 g/dL < 4.34 mmol/L 
Comment: The decrease is a decrease from baseline 
International Normalized Ratio of 
prothrombin time (INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 124,999/mm3 
100.000 x 109 – 124.999 x 
109/L 
50,000 – 99,999/mm3 50.000 
x 109 – 99.999 x 109/L 
25,000 – 49,999/mm3 25.000 
x 109 – 49.999 x 109/L 
< 25,000/mm3 < 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3 2.000 x 
109 – 2.500 x 109/L 
1,500 – 1,999/mm3 1.500 x 
109 – 1.999 x 109/L 
1,000 – 1,499/mm3 1.000 x 
109 – 1.499 x 109/L 
< 1,000/mm3 < 1.000 x 109/L 
* Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin).
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LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY LIFE-
THREATENING
CHEMISTRIES Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but ≥ 7.3 
pH < 7.3 without life-threatening 
consequences 
pH < 7.3 with life-threatening 
consequences 
Albumin, serum, low 
3.0 g/dL – < LLN 30 g/L – < 
LLN 
2.0 – 2.9 g/dL 20 – 29 g/L 
< 2.0 g/dL < 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but ≤ 7.5 
pH > 7.5 without life-threatening 
consequences 
pH > 7.5 with life-threatening 
consequences 
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 16.0 
mmol/L – < LLN 
11.0 – 15.9 mEq/L 11.0 –
15.9 mmol/L 
8.0 – 10.9 mEq/L 8.0 – 10.9 
mmol/L 
< 8.0 mEq/L < 8.0 mmol/L 
Comment: Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide (CO2). These are the same tests; values should be graded 
according to the ranges for Bicarbonate as listed above. 
Bilirubin (Total) 
Adult and Pediatric > 14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Calcium, serum, high 
Adult and Pediatric ≥ 7 days 
10.6 – 11.5 mg/dL 2.65 – 2.88 
mmol/L 
11.6 – 12.5 mg/dL 2.89 – 3.13 
mmol/L 
12.6 – 13.5 mg/dL 3.14 – 3.38 
mmol/L 
> 13.5 mg/dL > 3.38 mmol/L 
Calcium, serum, low 
Adult and Pediatric ≥ 7 days 
7.8 – 8.4 mg/dL 1.95 – 2.10 
mmol/L 
7.0 – 7.7 mg/dL 1.75 – 1.94 
mmol/L 
6.1 – 6.9 mg/dL 1.53 – 1.74 mmol/L < 6.1 mg/dL < 1.53 mmol/L 
Comment: Do not adjust Calcium, serum, low or Calcium, serum, high for albumin 
† Use age and sex appropriate values (e.g., bilirubin).
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LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY LIFE-
THREATENING
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with myocardial 
infarction or unstable angina as 
defined by the manufacturer 
Cardiac troponin T (cTnT) 
NA 
NA 
NA 
≥ 0.20 ng/mL OR Levels consistent 
with 
myocardial 
infarction 
or 
unstable angina as defined by the 
manufacturer 
Cholesterol (fasting)
Adult ≥ 18 years 
200 – 239 mg/dL 5.18 – 6.19 
mmol/L 
240 – 300 mg/dL 6.20 – 7.77 
mmol/L 
> 300 mg/dL > 7.77 mmol/L 
NA 
Pediatric < 18 years 
170 – 199 mg/dL 4.40 – 5.15 
mmol/L 
200 – 300 mg/dL 5.16 – 7.77 
mmol/L 
> 300 mg/dL > 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
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LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY 
LIFE-THREATENING
Glucose, serum, high
Nonfasting 
116 – 160 mg/dL 6.44 –
8.88 mmol/L 
161 – 250 mg/dL 8.89 –
13.88 mmol/L 
251 – 500 mg/dL 13.89 –
27.75 mmol/L 
> 500 mg/dL > 27.75 mmol/L 
Fasting 
110 – 125 mg/dL 6.11 –
6.94 mmol/L 
126 – 250 mg/dL 6.95 –
13.88 mmol/L 
251 – 500 mg/dL 13.89 –
27.75 mmol/L 
> 500 mg/dL > 27.75 mmol/L 
Glucose, serum, low
Adult and Pediatric ≥ 1 month 
55 – 64 mg/dL 3.05 – 3.55 
mmol/L 
40 – 54 mg/dL 2.22 – 3.06 
mmol/L 
30 – 39 mg/dL 1.67 – 2.23 
mmol/L 
< 30 mg/dL < 1.67 mmol/L 
Infant*†, < 1 month 
50 – 54 mg/dL 2.78 – 3.00 
mmol/L 
40 – 49 mg/dL 2.22 – 2.77 
mmol/L 
30 – 39 mg/dL 1.67 – 2.21 
mmol/L 
< 30 mg/dL < 1.67 mmol/L 
Lactate 
ULN - < 2.0 x ULN without 
acidosis 
≥ 
2.0 
x 
ULN 
without 
acidosis 
Increased lactate with pH < 
7.3 without life-threatening 
consequences 
Increased lactate with pH < 7.3 
with life-threatening consequences 
Comment: Added ULN to Grade 1 parameter
LDL cholesterol (fasting)
Adult ≥ 18 years 
130 – 159 mg/dL 3.37 –
4.12 mmol/L 
160 – 190 mg/dL 4.13 – 4.90 
mmol/L 
≥ 190 mg/dL ≥ 4.91 mmol/L 
NA 
Pediatric > 2 - < 18 years 
110 – 129 mg/dL 2.85 –
3.34 mmol/L 
130 – 189 mg/dL 3.35 – 4.90 
mmol/L 
≥ 190 mg/dL ≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 
1.2 – 1.4 mEq/L 0.60 – 0.70 
mmol/L 
0.9 – 1.1 mEq/L 0.45 – 0.59 
mmol/L 
0.6 – 0.8 mEq/L 0.30 – 0.44 
mmol/L 
< 0.60 mEq/L < 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
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LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY 
LIFE-THREATENING
Phosphate, serum, low
Adult and Pediatric > 14 years 
2.5 mg/dL – < LLN 0.81 
mmol/L – < LLN 
2.0 – 2.4 mg/dL 0.65 – 0.80 
mmol/L 
1.0 – 1.9 mg/dL 0.32 – 0.64 
mmol/L 
< 1.00 mg/dL < 0.32 mmol/L 
Pediatric 1 year – 14 years 
3.0 – 3.5 mg/dL 0.97 – 1.13 
mmol/L 
2.5 – 2.9 mg/dL 0.81 – 0.96 
mmol/L 
1.5 – 2.4 mg/dL 0.48 – 0.80 
mmol/L 
< 1.50 mg/dL < 0.48 mmol/L 
Pediatric < 1 year 
3.5 – 4.5 mg/dL 1.13 – 1.45 
mmol/L 
2.5 – 3.4 mg/dL 0.81 – 1.12 
mmol/L 
1.5 – 2.4 mg/dL 0.48 – 0.80 
mmol/L 
< 1.50 mg/dL < 0.48 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 5.6 – 6.0 
mmol/L 
6.1 – 6.5 mEq/L 6.1 – 6.5 
mmol/L 
6.6 – 7.0 mEq/L 6.6 – 7.0 
mmol/L 
> 7.0 mEq/L > 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 3.0 – 3.4 
mmol/L 
2.5 – 2.9 mEq/L 2.5 – 2.9 
mmol/L 
2.0 – 2.4 mEq/L 2.0 – 2.4 
mmol/L 
< 2.0 mEq/L < 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 146 – 150 
mmol/L 
151 – 154 mEq/L 151 – 154 
mmol/L 
155 – 159 mEq/L 155 – 159 
mmol/L 
≥ 160 mEq/L ≥ 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 130 – 135 
mmol/L 
125 – 129 mEq/L 125 – 129 
mmol/L 
121 – 124 mEq/L 121 – 124 
mmol/L 
≤ 120 mEq/L ≤ 120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 5.65 – 8.48 
mmol/L 
751 – 1,200 mg/dL 8.49 –
13.56 mmol/L 
> 1,200 mg/dL > 13.56 mmol/L 
† Use age and sex appropriate values (e.g., bilirubin).
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LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY LIFE-
THREATENING
Uric acid 
7.5 – 10.0 mg/dL 0.45 –
0.59 mmol/L 
10.1 – 12.0 mg/dL 0.60 –
0.71 mmol/L 
12.1 – 15.0 mg/dL 0.72 – 0.89 
mmol/L 
> 15.0 mg/dL > 0.89 mmol/L 
URINALYSIS Standard International Units are listed in italics
Hematuria (microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without clots 
OR with RBC casts 
Transfusion indicated 
Proteinuria, random collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection
Adult and Pediatric ≥ 10 years 
200 – 999 mg/24 h 0.200 –
0.999 g/d 
1,000 –
1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h 2.000 –
3.500 g/d 
> 3,500 mg/24 h > 3.500 g/d 
Pediatric > 3 mo - < 10 years 
201 –
499 mg/m2/24 h 
0.201 – 0.499 g/d 
500 –
799 mg/m2/24 h 
0.500 – 0.799 g/d 
800 –
1,000 mg/m2/24 h 
0.800 – 1.000 g/d 
> 1,000 mg/ m2/24 h > 1.000 g/d 
† Use age and sex appropriate values (e.g., bilirubin).
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List of Abbreviations and Acronyms
3TC
Lamivudine
AE
Adverse Event
AIDS
Acquired Immunodeficiency Syndrome
ALT
Serum Alanine Aminotransferase
ANCOVA
Analysis of covariance
APTT
Activated Partial Thromboplastin Time
ART
Antiretroviral Therapy
ASaT
All Subjects as Treated
AST
Serum Aspartate Aminotransferase
BLoQ
Below the Limit of Quantification 
cART
Combination Antiretroviral Therapy
CBB
Cogstate Brief Battery
CCR5
Chemokine Receptor Type 5
CI
Confidence Interval; or (as in Section 10.3 only) Coordinating Investigator
Clcr
Creatinine Clearance
CNS
Central Nervous System
CSR
Clinical Study Report
CTCAE
Common Terminology for Adverse Events
CYP
Cytochrome
DAIDS
Division of Acquired Immunodeficiency Syndrome
DILI
Drug-induced Liver Injury
DNA
Deoxyribonucleic Acid
DSG
Deferred Switch Group
ECG
Electrocardiogram
ECI
Event of Clinical Interest
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture System
EFV
Efavirenz
EOC
Executive Oversight Committee
EQ-5D-5L
EuroQol Five Dimensional Descriptive System, Five Level Version
ERC
Ethical Review Committee
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDC
Fixed-Dose Combination
FDR
Fixed-dose Regimen
FTC
Emtricitabine
GCP
Good Clinical Practice
HAART
Highly Active Antiretroviral Therapy
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HADS
Hospital Anxiety and Depression Scale Questionnaire
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL-C
High-Density Lipoprotein Cholesterol
HIV-1
Human Immunodeficiency Virus Type 1
HIV-SI
Human Immunodeficiency Virus - Symptom Index
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio 
InSTI
Integrase Strand Inhibitors
IRB
Institutional Review Board
ISG
Immediate Switch Group
IUD
Intrauterine Device
IVRS/IWRS
Interactive Voice Response System/Integrated Web Response System
LDL-C
Low-Density Lipoprotein Cholesterol
LOQ
Lower Limit of Reliable Quantification
MedDRA
Medical Dictionary for Regulatory Activities
N(t)RTI
Nucleotide Reverse Transcriptase Inhibitor
NC=F
Non-Completer = Failure
NHS
Normal Human Serum
NNRTI
Non-Nucleoside Reverse Transcriptase Inhibitor
NRTI
Nucleoside Reverse Transcriptase Inhibitor
OF
Observed Failure
OTC
Over the counter
PCR
Polymerase Chain Reaction
PDLC
Pre-Defined Limit of Change
PDVF
Protocol-Defined Virologic Failure
PGt
Pharmacogenetic 
PI
Protease Inhibitors
PK
Pharmacokinetics
PK/PD
Pharmacokinetic/Pharmacodynamic
PO
Per os
PSQ1
Pittsburgh Sleep Quality Index Questionnaire
PT
Prothrombin Time 
q.d.
Once Daily
RAL
Raltegravir
RBC
Red blood cell
(v)RNA
(viral) Ribonucleic Acid
SAE
Serious Adverse Event
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SOC
System Organ Class
(s)SAP
(supplemental) Statistical Analysis Plan
TDF
Tenofovir Disoproxil Fumarate
TDF/FTC
Tenofovir Disoproxil Fumarate/ Emtricitabine (TRUVADA™)
TLOVR
Time to Loss of Virologic Response
ULN
Upper Limit of Normal
US
United States
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
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 (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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