Clinical trial NCT02275780
Conditions: HIV-1
Sponsor: Merck Sharp & Dohme LLC
Start date: 2014-12-01; Completion date: 2023-03-06
Enrollment: 769 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To establish a new treatment option for treatment-naïve participants with HIV-1, the efficacy and safety of doravirine will be determined relative to a protease inhibitor (PI). Participants will receive double-blind treatment during the 96-week Base Study. Eligible participants in either of the Base Study groups will continue to receive the doravirine-containing regimen open label for an additional 96 weeks in the Study Extension 1. Eligible participants who are deriving benefit will continue in Study Extension 2 to receive the doravirine-containing regimen open label until doravirine becomes locally available or for an additional 96 weeks, whichever comes first. The primary hypothesis is that doravirine 100 mg once a day (q.d.) is non-inferior to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as assessed by the proportion of participants with HIV-1 ribonucleic acid (RNA) \<50 copies/mL at Week 48. If non-inferiority is established, then the superiority of doravirine 100 mg q.d. compared to darunavir/ ritonavir (800 mg/100 mg) q.d. will be assessed.

Detailed description:
Participants in Australia, Russia, and South Africa who are deriving benefit from MK-1439A are also eligible to continue receiving study drug during Study Extension 3, which will last for 2 years or until drug is available locally, whichever comes first.

Arms: arm 1: Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants may continue in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o., q.d. for an additional 96 weeks. Eligible participants may continue to receive the Doravirine regimen in Study Extension 2 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. Eligible participants may continue to receive the Doravirine regimen in Study Extension 3 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. arm 2: Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks. Eligible participants may continue in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants may continue to receive the Doravirine regimen in Study Extension 2 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. Eligible participants may continue to receive the Doravirine regimen in Study Extension 3 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first.
Interventions: intervention 1: Doravirine intervention 2: Darunavir intervention 3: Ritonavir intervention 4: TRUVADA™ or EPZICOM™/KIVEXA™
Intervention descriptions: intervention 1: Doravirine 100 mg tablet administered p.o. q.d. intervention 2: Darunavir 800 mg tablet administered p.o. q.d. intervention 3: Ritonavir 100 mg tablet administered p.o. q.d. intervention 4: The investigator selects either TRUVADA™, a tablet containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate p.o. q.d. or EPZICOM™/KIVEXA™, a tablet containing 600 mg abacavir sulfate and 300 mg lamivudine, p.o. q.d.

Protocol documents:
Prot_SAP_000.pdf: 
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NCT02275780
'RFXPHQW'DWH 23-Aug-2022
A Phase 3 Multicenter, Double-Blind, Randomized, Active 
Comparator-Controlled Clinical Trial to Evaluate the Safety and 
Efficacy of Doravirine (MK-1439) 100 mg Once Daily Versus 
Darunavir 800 mg Once Daily plus Ritonavir 100 mg Once Daily, 
Each in Combination with TRUVADA™ or EPZICOM™/KIVEXA™, 
in Treatment-Naïve HIV-1 Infected Subjects


Product:  MK-1439 
1
Protocol/Amendment No.: 018-12
MK-1439-018-12 Final Protocol
23-Aug-2022
Confidential
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 Australia, Russia and 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:
A Phase 3 Multicenter, Double-Blind, Randomized, Active Comparator-Controlled Clinical 
Trial to Evaluate the Safety and Efficacy of Doravirine (MK-1439) 100 mg Once Daily 
Versus Darunavir 800 mg Once Daily plus Ritonavir 100 mg Once Daily, Each in 
Combination with TRUVADA™ or EPZICOM™/KIVEXA™, in Treatment-Naïve HIV-1 
Infected Subjects
IND NUMBER:  112,796
EudraCT NUMBER:  [2014-001127-69]
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 14
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
Trial Diagram........................................................................................................ 19
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es).............................................................. 20
Secondary Objective(s) & Hypothesis(es)........................................................... 21
Exploratory Objectives......................................................................................... 22
Base Study .......................................................................................................... 22
Study Extension 1 ............................................................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
Pharmaceutical and Therapeutic Background .................................................... 22
Rationale................................................................................................................ 24
Rationale for the Trial and Selected Subject Population .................................... 24
Rationale for Dose Selection/Regimen............................................................... 25
Rationale for Endpoints ...................................................................................... 26
4.2.3.1
Efficacy Endpoints....................................................................................... 26
4.2.3.2
Safety Endpoints.......................................................................................... 28
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 28
4.2.3.4
Future Biomedical Research........................................................................ 29
Rationale for Study Extensions........................................................................... 29
5.0
METHODOLOGY ................................................................................................... 29
Entry Criteria........................................................................................................ 29
Diagnosis/Condition for Entry into the Trial...................................................... 29
Subject Inclusion Criteria.................................................................................... 30
Subject Exclusion Criteria .................................................................................. 33
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Trial Treatment(s) ................................................................................................ 34
Dose Selection .................................................................................................... 35
5.2.1.1
Dose Selection (Preparation) ....................................................................... 35
5.2.1.2
Dose Modification\Interruption\Discontinuation......................................... 36
Timing of Dose Administration.......................................................................... 36
5.2.2.1
Base Study ................................................................................................... 36
5.2.2.2
Study Extensions.......................................................................................... 37
Trial Blinding/Masking....................................................................................... 38
Randomization or Treatment Allocation (Base Study)..................................... 38
Stratification.......................................................................................................... 38
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 39
Rescue Medications & Supportive Care............................................................. 44
Diet/Activity/Other Considerations..................................................................... 44
Subject Withdrawal/Discontinuation Criteria................................................... 44
Subject Replacement Strategy............................................................................. 46
Beginning and End of the Trial ........................................................................... 46
Clinical Criteria for Early Trial Termination ................................................... 47
6.0
TRIAL FLOW CHART ........................................................................................... 48
7.0
TRIAL PROCEDURES ........................................................................................... 55
Trial Procedures ................................................................................................... 55
Administrative Procedures.................................................................................. 55
7.1.1.1
Informed Consent......................................................................................... 55
7.1.1.1.1
General Informed Consent.................................................................... 55
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 56
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 56
7.1.1.3
Subject Identification Card .......................................................................... 56
7.1.1.4
Medical History ........................................................................................... 56
7.1.1.5
Prior and Concomitant Medications Review............................................... 57
7.1.1.5.1
Prior Medications.................................................................................. 57
7.1.1.5.2
Concomitant Medications..................................................................... 57
7.1.1.6
Assignment of Screening Number............................................................... 57
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7.1.1.7
Assignment of Randomization Number....................................................... 57
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 57
Clinical Procedures/Assessments........................................................................ 58
7.1.2.1
Physical Examination................................................................................... 58
7.1.2.2
Weight and Height Assessment ................................................................... 58
7.1.2.3
Vital Signs.................................................................................................... 59
7.1.2.4
12-Lead ECG (performed locally)............................................................... 59
7.1.2.5
Adverse Events ............................................................................................ 59
7.1.2.6
Toxicity Management .................................................................................. 60
7.1.2.7
Birth Control Confirmation.......................................................................... 60
Laboratory Procedures/Assessments .................................................................. 61
7.1.3.1
Serum /Urine Pregnancy Test...................................................................... 61
7.1.3.2
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 61
7.1.3.3
HIV/ Hepatitis Screening............................................................................. 62
7.1.3.4
Human Leukocyte Antigen.......................................................................... 62
7.1.3.5
Virology Test ............................................................................................... 62
7.1.3.6
Viral Resistance Testing .............................................................................. 62
7.1.3.7
CD4 Cell Counts.......................................................................................... 63
7.1.3.8
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 63
7.1.3.9
Future Biomedical Research........................................................................ 63
Other Procedures................................................................................................. 64
7.1.4.1
Withdrawal/Discontinuation........................................................................ 64
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 64
7.1.4.2
Blinding/Unblinding .................................................................................... 65
7.1.4.3
Calibration of Equipment............................................................................. 65
Visit Requirements.............................................................................................. 66
7.1.5.1
Screening...................................................................................................... 66
7.1.5.2
Treatment Visits in Base Study (Visit 2 to Visit 13) ................................... 66
7.1.5.3
Treatment Visits in Study Extension 1 (Visit 14 to Visit 20)...................... 69
7.1.5.4
Treatment Visits in Study Extension 2 (Visit 21 to Visit 26)...................... 70
7.1.5.5
Treatment Visits in Study Extension 3 (Visit 27 to Visit 32)...................... 70
7.1.5.6
Virologic Failure Confirmation Visit (Base Study and Extension 1).......... 71
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7.1.5.7
Early Discontinuation Visit (Base Study, Study Extension 1, Study 
Extension 2, and Study Extension 3)........................................................... 71
7.1.5.8
Post-Trial...................................................................................................... 72
Assessing and Recording Adverse Events .......................................................... 72
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 73
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 73
Immediate Reporting of Adverse Events to the Sponsor.................................... 74
7.2.3.1
Serious Adverse Events ............................................................................... 74
7.2.3.2
Events of Clinical Interest............................................................................ 75
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 76
Evaluating Adverse Events................................................................................. 76
Sponsor Responsibility for Reporting Adverse Events ...................................... 79
TRIAL GOVERNANCE AND OVERSIGHT................................................... 79
Scientific Advisory Committee........................................................................... 79
Executive Oversight Committee......................................................................... 79
Data Monitoring Committee............................................................................... 79
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 80
Statistical Analysis Plan Summary ..................................................................... 80
Efficacy Analyses ............................................................................................... 80
Safety Analyses................................................................................................... 82
Power and Sample Size....................................................................................... 83
Interim Analysis.................................................................................................. 84
Statistical Analysis Plan ....................................................................................... 85
Responsibility for Analyses/In-House Blinding ................................................. 85
Hypotheses/Estimation ....................................................................................... 86
Analysis Endpoints ............................................................................................. 86
8.2.3.1
Efficacy/Pharmacokinetics Endpoints ......................................................... 86
8.2.3.1.1
Efficacy Endpoints................................................................................ 86
8.2.3.1.2
Pharmacokinetic Endpoints .................................................................. 88
8.2.3.2
Safety Endpoints.......................................................................................... 88
Analysis Populations........................................................................................... 89
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8.2.4.1
Efficacy Analysis Populations..................................................................... 89
8.2.4.2
Safety Analysis Populations ........................................................................ 89
Statistical Methods.............................................................................................. 89
8.2.5.1
Statistical Methods for Efficacy Analyses................................................... 90
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 94
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 96
8.2.5.3.1
Demographic and Baseline Characteristics .......................................... 96
8.2.5.3.2
Population PK and PK/PD Analyses .................................................... 96
Multiplicity ......................................................................................................... 96
Sample Size and Power Calculations.................................................................. 97
8.2.7.1
Sample Size and Power for Efficacy Analyses............................................ 97
8.2.7.2
Sample Size and Power for Safety Analyses ............................................... 97
Subgroup Analyses and Effect of Baseline Factors (Base Study) .................... 100
Interim Analyses ............................................................................................... 100
8.2.9.1
Efficacy Interim Analyses.......................................................................... 100
8.2.9.2
Safety Interim Analyses............................................................................. 101
Compliance (Medication Adherence)............................................................... 102
Extent of Exposure............................................................................................ 102
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 103
Investigational Product ...................................................................................... 103
Packaging and Labeling Information ............................................................... 103
Clinical Supplies Disclosure............................................................................... 103
Storage and Handling Requirements................................................................ 104
Discard/Destruction/Returns and Reconciliation ............................................ 104
Standard Policies................................................................................................. 104
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 105
Confidentiality..................................................................................................... 105
Confidentiality of Data ..................................................................................... 105
Confidentiality of Subject Records................................................................... 105
Confidentiality of Investigator Information...................................................... 105
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Confidentiality of IRB/IEC Information........................................................... 106
Compliance with Financial Disclosure Requirements..................................... 106
Compliance with Law, Audit and Debarment ................................................. 107
Compliance with Trial Registration and Results Posting Requirements...... 108
Quality Management System............................................................................. 109
Data Management............................................................................................... 109
Publications ......................................................................................................... 109
11.0
LIST OF REFERENCES....................................................................................... 111
12.0
APPENDICES......................................................................................................... 112
Code of Conduct for Clinical Trials.................................................................. 112
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 115
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff. ................................................................................... 120
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
by Sample Types ................................................................................................. 131
Screening through Week 48 (Base Study)........................................................ 131
Week 60 Through Post 14 Day Follow- up (Base Study) ................................ 132
Week 100 Through Post-Study 14-Day Follow-up (Study Extension 1) ......... 133
Guidelines for Grading Severity of Laboratory Adverse Experiences for 
Toxicity Management......................................................................................... 134
Plasma Assay—Sample Collection, Handling, Labeling, Storage, and 
Shipment.............................................................................................................. 141
List of Abbreviations and Acronyms ................................................................ 142
13.0
SIGNATURES......................................................................................................... 144
Sponsor's Representative ................................................................................... 144
Investigator.......................................................................................................... 144
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LIST OF TABLES
Table 1
Treatment Regimens During Base Study............................................................ 35
Table 2
Treatment Regimen During Study Extensions.................................................... 35
Table 3
Stratification........................................................................................................ 38
Table 4
Laboratory Tests ................................................................................................. 61
Table 5
Pharmacokinetic Sampling Timepoints .............................................................. 63
Table 6
Study Drug Bottle/Container (A, B, C, and either D or E) Components............ 67
Table 7
Evaluating Adverse Events................................................................................. 77
Table 8
Summary of Analysis Strategy for Efficacy Endpoints...................................... 82
Table 9
Summary of Interim Analysis Strategy............................................................... 85
Table 10
Definition of Study Timepoint............................................................................ 90
Table 11
Summary of the Two Approaches to Handle Missing Values............................ 92
Table 12
Analysis Strategy for Safety Parameters............................................................. 95
Table 13
Power (%) Under Various Assumptions (With 340 Subjects Randomized in 
Each Treatment Group)...................................................................................... 97
Table 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Subjects with AEs Among 340 Subjects 
Randomized in Each Treatment Group.............................................................. 99
Table 15
Differences in Incidences of AEs (MK-1439 100 mg q.d. minus 
Darunavir/ritonavir [800 mg/100mg] q.d.) That Can Be Ruled Out With 
340 Subjects in Each Treatment Group ............................................................. 99
Table 16
Product Descriptions: Base Study and Study Extensions................................. 103
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LIST OF FIGURES
          
Figure 1
Trial Design for Protocol 018 Base Study .......................................................... 19
Figure 2
Trial Design for Protocol 018 Study Extensions 1, 2, and 3............................... 20
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
12
23-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.
11
(country-specific to 
Australia, Russia and South 
Africa)
06-Apr-2022

Study extension 3 was added to (1) provide continued access to MK-1439 for 
participants who are deriving benefit from MK-1439 until the drug is available 
locally in countries 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-1439 in this study extension.
10
(country-specific to US)
05-Nov-2018

Added an additional 32 weeks past the Week 192 visit so that a subject may 
continue to receive MK-1439 during this time or until commercial MK-1439 is 
locally available (whichever occurs first). 

Added 2 treatment visits in the study extension and updated blood volumes.
09
(country-specific to Italy)
20-Apr-2018

Added open-label study extension 2 to provide continued access to MK-1439 
until the drug is available locally in countries participating in the trial or for an 
additional 2 years (whichever comes first).
08
(country-specific to Austria, 
Denmark, France, Germany, 
Romania, Russia, South 
Africa, Spain, UK)
19-Apr-2018

Added open-label study extension 2 to provide continued access to MK-1439 
until the drug is available locally in countries participating in the trial or for an 
additional 2 years (whichever comes first).
07
(country-specific to 
Argentina, Australia, 
Canada, Chile, US)
23-Apr-2018

Added open-label study extension 2 to provide continued access to MK-1439 
until the drug is available locally in countries participating in the trial or for an 
additional 2 years (whichever comes first).
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Document
Date of Issue
Overall Rationale
06
(country-specific to Italy)
20-Sep-2016

Added open-label study extension 1 for 2 years to collect long-term efficacy 
and safety data.

Requirements for use of oral contraceptives were modified to allow for use of 
hormonal contraceptives during the study extension.
05
(country-specific to Austria, 
Denmark, France, Germany, 
Romania, Russia, South 
Africa, Spain, UK)
20 Sep 2016

Added open-label study extension 1 for 2 years to collect long-term efficacy 
and safety data.

Requirements for use of oral contraceptives were modified to allow for use of 
hormonal contraceptives during the study extension.
04
(country-specific to 
Argentina, Australia, 
Canada, Chile, US)
10-Aug-2016

Added open-label study extension 1 for 2 years to collect long-term efficacy 
and safety data.

Requirements for use of oral contraceptives were modified to allow for use of 
hormonal contraceptives during the study extension.
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Document
Date of Issue
Overall Rationale
03
(country-specific to Italy)
08-Apr-2015

The HIV RNA cut-off used to define viral efficacy was changed from <40 
copies/mL to <50 copies/mL.

Acceptable birth control methods (Inclusion Criterion 8) were modified to
exclude oral contraceptives and the contraceptive rod; and to add a provision 
for more restrictive contraceptive methods to be used if locally required.

Clarified that (Child-Pugh Class C) hepatic impairment, as well as other 
significant conditions contraindicated in product labeling for the comparator 
products, are excluded (Exclusion Criterion 1).

Specified that all chronic hepatitis B-infected subjects for whom tenofovir was 
discontinued, be discontinued from the study to allow for appropriate hepatitis 
B treatment with medications not permitted by the protocol and to avoid 
hepatitis B treatment with lamivudine monotherapy.

Text was added to indicate that Kivexa may be packaged in either a bottle or 
blister pack. 

Quetiapine, ergometrine, dronedarone, ranolazine, systemic lidocaine, 
sertindole, and ticagrelor were added as prohibited for darunavir; and 
clorazepate, diazepam, estazolam, flurazepam, pethidine, piroxicam 
propoxyphene, and alfuzosin were added as prohibited for ritonavir.
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Document
Date of Issue
Overall Rationale
02
(country-specific to EU, 
Russia, South Africa)
10-Feb-2015

The HIV RNA cut-off used to define viral efficacy was changed from <40 
copies/mL to <50 copies/mL.

Acceptable birth control methods (Inclusion Criterion 8) were modified to 
exclude oral contraceptives and the contraceptive rod; and to add a provision 
for more restrictive contraceptive methods to be used if locally required.

Specified that all chronic hepatitis B-infected subjects for whom tenofovir was 
discontinued, be discontinued from the study to allow for appropriate hepatitis 
B treatment with medications not permitted by the protocol and to avoid 
hepatitis B treatment with lamivudine monotherapy.

Text was added to indicate that Kivexa may be packaged in either a bottle or
blister pack. 
01
(non-country specific)
04 Feb 2015

The HIV RNA cut-off used to define viral efficacy was changed from <40 
copies/mL to <50 copies/mL.

Acceptable birth control methods (Inclusion Criterion 8) were modified to 
exclude hormonal contraceptives containing ethinyl estradiol; and to add a 
provision for more restrictive contraceptive methods to be used if locally 
required.

Specified that all chronic hepatitis B-infected subjects for whom tenofovir was 
discontinued, be discontinued from the study to allow for appropriate hepatitis 
B treatment with medications not permitted by the protocol and to avoid 
hepatitis B treatment with lamivudine monotherapy.

Text was added to indicate that Kivexa may be packaged in either a bottle or 
blister pack. 
Original protocol
01-Aug-2014

Not applicable.
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Sponsor underwent an entity name change and update to the address.
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Title Page
Section 12.1
Throughout
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.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-1439 versus ritonavir-boosted darunavir, in combination with 
TRUVADA™ or EPZICOM™/KIVEXA™, in treatment-naïve HIV-1 
infected subjects
Trial Phase
Phase 3
Clinical Indication
Treatment of HIV-1 infection
Trial Type
Interventional
Type of control
Active control
Route of administration
Oral    
Trial Blinding
Double-blind for the base study then open-label for the study extensions.
Treatment Groups
Base Study (double-blind)
Group 
1: 
MK-1439 
100 
mg
q.d. 
plus 
TRUVADA™
or 
EPZICOM™/KIVEXA™
Group 2: Ritonavir-boosted Darunavir (100 mg RTV with 800 mg 
Darunavir) plus TRUVADA™or EPZICOM™/KIVEXA™
Study Extensions (open-label)
(All subjects): MK-1439 100 mg q.d. plus either tenofovir (as tenofovir 
disoproxil fumarate [TDF] or tenofovir alafenamide fumarate [TAF]) or 
abacavir (ABC), each administered with either emtricitabine (FTC) or 
lamivudine (3TC). 
Number of trial subjects
Approximately 680 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 9 years
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
The study consists of a screening phase of up to 45 days (~6.5 weeks) 
followed by a 96-week double-blind base study, 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-1439 becomes commercially available once approved in the 
local country (whichever comes first).
The  approximate cumulative durations of participation in the trial (from 
informed consent through follow-up) are 104 weeks for subjects who 
complete the base study; 200 weeks for subjects who complete the base 
study and study extension 1; up to 296 weeks for subjects who complete 
the base study and study extensions 1 and 2; and up to 392 weeks for 
subjects who complete the base study and study extensions 1, 2, and 3.
Randomization Ratio
1:1
with 
~340 
on 
MK-1439 
+
either
TRUVADA™ 
or 
EPZICOM™/KIVEXA™and ~340 on  Ritonavir-boosted Darunavir + 
either TRUVADA™or EPZICOM™/KIVEXA™
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2.0 TRIAL DESIGN
Trial Design
This is a multicenter, double-blind (with in-house blinding), randomized, active-controlled, 
trial of MK-1439 100 mg once daily (q.d.) compared with ritonavir-boosted darunavir q.d. 
(given as separate tablets of 800 mg darunavir and 100 mg ritonavir, hereafter referred to as 
darunavir/ritonavir [800 mg/100 mg]), when each is given in combination with investigator-
selected TRUVADA™ or EPZICOM™/KIVEXA™ q.d., in the treatment of antiretroviral 
treatment-naïve subjects with HIV-1 infection.
The study consists of a screening period of approximately 6.5 weeks, a 96-week blinded base 
study (MK-1439 100 mg q.d. compared with ritonavir-boosted darunavir q.d., each given in 
combination with investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ q.d.) 
followed by 3 consecutive open-label study extensions (MK-1439 100 mg q.d. in 
combination with investigator-selected NRTI backbone therapy), 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-1439 becomes locally available (whichever comes first).
The study is to be conducted in conformance with Good Clinical Practice.  
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 six hundred and eighty (680) subjects will be stratified by: 1) screening HIV-
1 RNA (≤ or >100,000 copies/mL) and 2) NRTI backbone therapy (TRUVADA™ or 
EPZICOM™/KIVEXA™, as selected by the investigator) and randomized within strata in a 
1:1 ratio to receive either MK-1439 100 mg q.d. or darunavir/ritonavir (800 mg/100 mg q.d.), 
each in combination with the selected backbone therapy.  The duration of treatment for a 
given subject in the base study is 96 weeks (approximately 2 years). The primary endpoint is 
the proportion of subjects achieving HIV-1 RNA <50 copies/mL at Week 48.  
The safety of this trial will be monitored during the base study by an external Data 
Monitoring Committee (eDMC), which will provide ongoing review of the safety data with 
suggested periodic reviews to occur every ~4-6 months.  The eDMC will recommend any 
steps to ensure the safety of study participants and the integrity of the trial. The eDMC will 
also review interim efficacy data and make a recommendation on study conduct based on a 
pre-defined futility rule. To guarantee the unrestricted performance of its task, the eDMC 
will receive individual study data from a designated unblinded statistician.  Details regarding 
the eDMC will be described in a charter document.
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Subjects who meet the virologic failure criteria (see Section 4.2.3.1) in the base study or 
study extension 1 will return to the site between 1 and 4 weeks (≥1 and ≤4 weeks) later for 
repeat viral RNA testing (at a virologic failure confirmation visit).  If virologic failure is 
confirmed and the viral load meets the criterion for resistance testing (greater than 
400 copies/mL), in the base study or study extension 1, viral resistance testing will then be 
performed.  In addition, viral resistance testing will be performed for subjects who 
discontinue for any reason from the study (if viral load is greater than 400 copies/mL).
Blood samples to support the evaluation of population pharmacokinetics (PK) will be 
collected from all subjects at randomization and Weeks 4, 8, 24 and 48.
All subjects entering the study extensions will receive open-label treatment with MK-1439
(100 mg q.d.) in combination with investigator-selected NRTI backbone therapy.
Treatment group assigned during the base study will not be unblinded when a subject enters 
study extension 1; unblinding will occur after all subjects have completed the base study and 
database lock has been achieved for the base study.    
Study Extension 1
At Study Week 96, eligibility for enrollment into study extension 1 will be determined, thus 
continuing study treatment for approximately 2 years beyond the base study. The total 
duration of treatment for subjects who continue into study extension 1 is 192 weeks 
(approximately 4 years).
For all subjects who enter study extension 1, the backbone NRTI therapy will remain the 
same as that in the base study whenever possible.  In order to address issues of either drug 
access or tolerability, single-drug or fixed-dose combinations of the 4 permitted NRTIs may 
be used, and both TAF and TDF formulations of tenofovir may be used.  Decisions on 
potential changes in NRTI backbone therapy, between the base study and study extension 1, 
will be made on a case-by-case basis, as needed, by mutual agreement of the investigator and 
the Sponsor; in cases where lack of immediate access to allowed NRTIs presents a barrier to 
participation in study extension 1, provision of NRTI therapy between Week 96 and Week 
100 for a given subject may be considered by the Sponsor. The same backbone therapy is to 
be maintained throughout study extension 1 for a given subject.
Subjects who meet virologic failure criteria during study extension 1 will follow the same 
procedures as those who do so during the base study. Subjects who discontinue from study
extension 1 will have a serum sample collected for viral resistance testing, as in the base 
study.
Long-term safety and efficacy data will be collected during study extension 1 and 
summarized descriptively. Subjects will continue to be monitored for safety during study 
extension 1, including fasting lipids: long-term safety data will be collected and summarized.
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Study Extension 2
At Study Week 192, eligibility for enrollment 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-1439 until it becomes locally available or for approximately 2 
years beyond study extension 1 (whichever comes first). The maximum total duration of 
treatment with MK-1439 will be up to 288 weeks (i.e., up to approximately 2 years beyond 
study extension 1, depending on when MK-1439 is commercially available once approved in
the local country) for subjects who continue into study extension 2.   
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 288, eligibility for enrollment 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-1439 until it becomes locally available or for approximately 2 
years beyond study extension 2 (whichever comes first). The maximum total duration of 
treatment with MK-1439 will be up to 384 weeks (i.e., up to approximately 2 years beyond 
study extension 2, depending on when MK-1439 is commercially available once approved in 
the local country) for subjects who continue into study extension 3.  
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.
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 for the base study and Figure 2 for study extensions 1, 
2, and 3.  (Note that subjects who continue into study extension 1 will have a single follow-
up visit at the end of the extension only, not in the base study.)
Figure 1
Trial Design for Protocol 018 Base Study
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Figure 2
Trial Design for Protocol 018 Study Extensions 1, 2, and 3
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In HIV-1 positive, treatment-naïve subjects with pretreatment HIV RNA ≥ 1,000 copies/mL:
Base Study:
(1) Objective:  To evaluate the antiretroviral activity of MK-1439 100 mg q.d., compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, as measured by the proportion of subjects achieving HIV-1 
RNA <50 copies/mL at Week 48.
Hypothesis:  MK-1439 100 mg q.d. is non-inferior to darunavir/ritonavir (800 mg/100 
mg) q.d., each in combination with TRUVADA™or EPZICOM™/KIVEXA™, as 
assessed by the proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48. 
Superiority of MK-1439 100 mg q.d. to darunavir/ritonavir (800 mg/100 mg) q.d. will be 
assessed if non-inferiority is established.
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Secondary Objective(s) & Hypothesis(es)
In HIV-1 positive, treatment-naïve subjects with pretreatment HIV RNA ≥ 1,000 copies/mL:
Base Study:
(1) Objective: To evaluate the safety and tolerability of MK-1439 100 mg q.d., compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, as assessed by review of the accumulated safety data at Week 
48 and Week 96.
(2) Objective: To evaluate the effect on fasting serum lipids of MK-1439 100 mg q.d.
compared to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with 
TRUVADA™ or EPZICOM™/KIVEXA™, as measured by mean change from baseline 
in fasting serum lipids at Week 48.
Hypothesis:  MK-1439 100 mg q.d. is superior to darunavir/ritonavir (800 mg/100 mg) 
q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as assessed 
by the mean change from baseline in fasting LDL-C at Week 48. If superiority is 
established with respect to LDL-C, the following subsequent hypothesis will be tested: 
MK-1439 100 mg q.d. is superior to darunavir/ritonavir (800 mg/100 mg) q.d., each in 
combination with TRUVADA™ or EPZICOM™/KIVEXA™, as assessed by the mean 
change from baseline in fasting non-HDL-C at Week 48.  
(3) Objective: To evaluate the safety and tolerability of MK-1439 100 mg q.d. compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, as measured by the time to discontinuation from study due to 
an adverse experience.
(4) Objective:  To evaluate the immunologic effect of MK-1439 100 mg q.d., compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, as measured by the change from baseline in CD4 cell count at 
Week 48 and Week 96.
(5) Objective:  To evaluate the antiretroviral activity of MK-1439 100 mg q.d. compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, as measured by the proportion of subjects achieving HIV-1 
RNA <50 copies/mL at Week 96.
Hypothesis:  MK-1439 100 mg q.d. is non-inferior to darunavir/ritonavir (800 mg/100 
mg) q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as 
assessed by the proportion of subjects with HIV-1 RNA <50 copies/mL at Week 96.
Superiority of MK-1439 100 mg q.d. to darunavir/ritonavir (800 mg/100 mg) q.d. will be 
assessed if non-inferiority is established. 
(6) Objective: To evaluate the antiretroviral activity of MK-1439 100 mg q.d., compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or 
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EPZICOM™/KIVEXA™, as measured by the proportion of subjects achieving HIV-1 
RNA <40 copies/mL at Week 48 and 96.
Exploratory Objectives
Base Study
In HIV-1 positive, treatment-naïve subjects with pretreatment HIV RNA ≥1,000 copies/mL:
(1) Objective: To evaluate the antiretroviral activity of MK-1439 100 mg q.d., compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or 
EPZICOM™/KIVEXA™, as measured by the proportion of subjects achieving HIV-1 
RNA <200 copies/mL at Week 48 and 96.
(2) Objective: To evaluate the antiretroviral activity of MK-1439 100 mg q.d., compared to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, as measured by the Time to Loss of Virologic Response 
(TLOVR).
(3) Objective: 
To evaluate the pharmacokinetics of MK-1439 100 mg q.d. and
pharmacokinetic-pharmacodynamic associations, if supported by the data.
(4) Objective: To assess the development of resistance to MK-1439 100 mg q.d. in subjects 
who are virologic failures.
Study Extension 1
(1)
Objective: To assess data on long-term efficacy and safety of MK-1439 100 mg q.d. 
administered for up to 192 weeks (approximately 4 years) total in subjects enrolled in 
study extension 1.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-1439.
Pharmaceutical and Therapeutic Background
HIV-infected patients have been successfully treated with combination antiretroviral therapy 
(cART) or 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]), 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 
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immune function is preserved or restored.  Yet, while cART can favorably influence disease 
progression 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 
medication non-compliance. In these circumstances, selection for resistant virus can and does 
occur. As a result, virus with reduced susceptibility to the licensed agents will remain a 
constant threat.  Additionally, there is significant concern regarding long-term toxicities of 
some widely-used antiretroviral agents, including central nervous system toxicities associated 
with efavirenz (an NNRTI), gastrointestinal toxicities such as diarrhea associated with 
multiple protease inhibitors (PIs), and serum lipid abnormalities associated with multiple 
mechanistic classes.
Currently available NNRTIs constitute an important option for use as anchor agents, along 
with 2 NRTIs, for initiation of combination antiretroviral therapy for HIV infection. 
Efavirenz remains the preferred NNRTI for treatment initiation according to multiple 
guidelines, and rilpivirine, more recently approved, has been recommended by these 
guidelines as an alternative NNRTI agent for treatment initiation. However, each of the 
currently available NNRTI agents has disadvantages. For example, while efavirenz has 
shown excellent efficacy over many years of use, it is associated with substantial CNS 
intolerance and skin rash, as well as lipid abnormalities. In addition it can be a perpetrator of 
drug-drug interactions as a mixed inducer or inhibitor of CYP3A and CYP2B6 enzymes. 
Rilpivirine has shown suboptimal efficacy in patients with high viral load or CD4 cells below 
200/µL at baseline, and thus is not indicated in patients with baseline viral load above 
100,000 copies/mL. In addition, rilpivirine requires dosing with food, and while it is not a 
metabolic inducer or inhibitor, it is subject to metabolic induction/inhibition of CYP3A 
isoenzymes and should not be co-administered with proton pump inhibitors and several 
anticonvulsants.  Importantly, high-level resistance may occur in response to a single 
mutation for all currently available NNRTIs except etravirine. Therefore, new agents of the 
NNRTI class that offer high potency, a distinct resistance profile, dosing convenience and a 
favorable safety and tolerability profile are needed.
MK-1439 is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) being studied 
for treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-
naïve HIV-infected subjects.  MK-1439 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.  MK-1439 displays excellent potency
against wild type virus with 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 an IC50 of 21, 31, and 55 nM against mutants containing the most
frequently transmitted NNRTI mutations K103N, Y181C and G190A respectively, under the
same conditions. Its preclinical toxicity profile is favorable in rats following dosing for up to 
6 months at 3, 30, and 450 mg/kg/day, and in dogs following dosing for up to 9 months 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 of significant drug-drug interactions.
Furthermore, the available 
long-term (beyond Week 48) data from a Phase 2 study in treatment-naïve individuals
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demonstrate that MK-1439, in combination with tenofovir/emtricitabine, is highly
efficacious, even in patients with high baseline viral load, and is well tolerated.
Rationale
Rationale for the Trial and Selected Subject Population
Factors that impact HIV treatment success include efficacy, safety and tolerability, barrier to 
resistance, simplicity/convenience of administration and drug-drug interactions.  There is a 
clear medical need for new regimens and strategies that are highly effective, have a high 
barrier to resistance development, are very well tolerated, are simple to administer, and thus 
will promote increased adherence and decrease treatment fatigue.  Therapies and regimens 
with these characteristics are particularly important for treatment-naïve patients where initial 
success is predictive of long-term outcomes.  This need is further driven by the necessity for 
lifelong treatment of HIV infection in patients who are increasingly older and have co-
morbid diseases/conditions.
Currently available therapies for HIV infection include PIs, a diverse class of potent agents 
with a high genetic barrier to resistance, but which generally require boosting by ritonavir to 
achieve appropriate levels.  As a class, PIs are highly efficacious, and several are 
recommended as preferred agents for first-line therapy of treatment-naïve HIV-infected 
subjects; however, they are also associated with a variety of toxicities including 
gastrointestinal issues (especially diarrhea), serum lipid abnormalities, and lipodystrophy, 
among others, which are of particular concern in view of the need for lifelong HIV therapy.  
Based on preclinical and clinical data to date, MK-1439 is not expected to have similar safety 
concerns.  Therefore, establishing the efficacy and safety of MK-1439 relative to a PI will 
help establish it as a valuable new treatment option for treatment-naïve patients.  
Darunavir/ritonavir has been extensively studied and was selected as the comparator agent in 
this study for a number of reasons including efficacy, tolerability, and ease of maintaining the 
study blind during the base study.  As compared with the other recommended agents for 
treatment initiation in the Protease Inhibitor (PI) class such as atazanavir/ritonavir and 
lopinavir/ritonavir, it offers potent efficacy and generally good tolerability. With regard to 
safety, darunavir/ritonavir showed lower rates of diarrhea and discontinuation of treatment 
due to adverse events compared with lopinavir/ritonavir. Use of darunavir/ritonavir will also 
better maintain the blinding to randomized treatment assignment at a practical level, due to 
the high likelihood of obvious hyperbilirubinemia/icterus with atazanavir/ritonavir use, 
which would cue the patient and investigator to the actual treatment assignment. The choice 
of darunavir as the comparator anchor (or 3rd) agent is further supported by its recommended 
use in treatment-naïve patients according to multiple recent international guidelines (e.g., 
from EACS, BHIVA, and US-DHHS, IAS-USA). 
Similarly, both tenofovir/emtricitabine and abacavir/lamivudine are also recommended 
backbones in these guidelines. Tenofovir and abacavir have relatively similar efficacy 
profiles but somewhat different safety profiles.
Allowing investigator choice and 
optimization of NRTIs will provide data on the use of MK-1439 with both of the most 
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commonly used NRTI fixed-dose combinations. The potent efficacy for MK-1439 
demonstrated in Phase 1 and 2 studies predict that MK-1439 in combination with either 
NRTI backbone should provide the expected efficacy.
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.
Rationale for Dose Selection/Regimen
MK-1439 is a potent NNRTI.  In a Phase 1b study (Protocol 005), once daily oral 
administration of 25 mg and 200 mg MK-1439 as monotherapy for 7 days to treatment-naïve 
HIV-infected patients reduced plasma viral RNA burden as compared to placebo treated 
controls.  The mean change from baseline in log10 HIV RNA copies/mL on Day 7 (24 hours 
postdose) 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 vs. 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 once daily versus efavirenz (600 mg once daily) both in combination with the 
fixed-dose combination of TDF/FTC 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) and < 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).  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 in 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.  In general, the incidence of CNS adverse 
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events was lower in the MK-1439 groups relative to the efavirenz group. Based upon the 
24-week results of PN007, 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 
CNS 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).  
Three of the 4 dose groups of MK-1439 had numerically lower proportion of patients with 
CNS adverse events by Week 8 and by Week 24 than efavirenz. The 50 mg group of MK-
1439 had a similar proportion of patients with CNS adverse events compared to efavirenz.  
The dose of MK-1439 that was selected for study in Phase 3 is 100 mg q.d.  The MK-1439 
100 mg daily dose was selected based on Week 24 safety and efficacy data from Protocol 
007, as well as considerations for potential drug-drug interactions, forgiveness of the 
occasional missed dose, and coverage of a variety of NNRTI mutations against which MK-
1439 is expected to be active with minimal (less than 3-fold) shift in the in vitro, 95% 
inhibitory concentration (IC95).    
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 has taken into consideration a 
number of additional factors.  Firstly, MK-1439 is a substrate of CYP3A metabolism and is 
subject to induction and inhibition of CYP3A by other concomitant medications.  
Consequently, selection of a higher dose, such as 100 mg, may provide assurance of adequate 
MK-1439 exposures (similar to those achieved at 25 mg daily) even in the setting of 
moderate metabolic inducers.  Secondly, the 100-mg dose may provide forgiveness in the 
setting of the occasional missed dose.  Thirdly, the 100-mg dose is expected 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 G190A mutations, as well as the dual K103N/Y181C mutation.  Further 
details can be found in the Investigators’ Brochure.  
The doses of the active comparators (darunavir 800 mg and ritonavir 100 mg, each given as 
separate tablets q.d.) are the standard approved doses for these agents.  In addition, the doses 
of the NRTI backbones, TRUVADA™ (tenofovir disoproxil fumarate 300 mg /emtricitabine 
200 mg) and EPZICOM™/KIVEXA™(abacavir sulfate 600 mg /lamivudine 300 mg) are 
the standard approved doses for these agents.
Rationale for Endpoints
The primary efficacy endpoint in the study is viral load as measured by HIV-1 RNA, which 
is consistent with other clinical trials in HIV-infected patients and the current regulatory 
guidance.  Suppressing HIV RNA to low levels (<50 copies/mL) has been demonstrated in 
many clinical trials to preserve the immune system and prevent the development of 
opportunistic infections and progression of the disease.  The HIV RNA assay that will be 
used in the study (Abbott RealTime HIV-1 Assay) has a lower limit of quantification of 
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40 copies/mL. The primary efficacy endpoint, however, is the proportion of subjects 
achieving HIV-1 RNA <50 c/mL to reflect the clinically relevant standard used across 
antiretroviral medications. Week 48 was chosen as the primary efficacy time point and Week 
96 was chosen as the secondary efficacy time point, as recommended by regulatory agencies 
for HIV treatment-naïve studies.
Secondary and exploratory measurements for efficacy include HIV-1 RNA <40 copies/mL, 
HIV-1 RNA <200 copies/mL, change from baseline CD4 cell counts, time to loss of 
virologic response (TLOVR), and viral resistance for subjects who meet protocol-defined 
virologic failure criteria and whose virus can be amplified. 
Protocol-defined virologic failure for this study is defined as one of the following:
1) Confirmed (2 consecutive measures at least one week apart) HIV-1 RNA ≥200 
copies/mL at week 24 or week 36, or confirmed (2 consecutive measures at least one 
week apart) HIV-1 RNA ≥50 copies/mL at week 48; 
OR 
2) Confirmed (2 consecutive measures at least one week apart) HIV-1 RNA ≥50 copies/mL 
after initial response of HIV-1 RNA <50 copies/mL at any time during the study.
Subjects should be discontinued, regardless of compliance to study therapy, if they meet the 
PDVF criteria. 
The protocol allows a subject to switch from one of the study backbone NRTI regimens to 
the 
other 
(either 
from 
TRUVADA™ 
to 
EPZICOM™/KIVEXA™
or 
from 
EPZICOM™/KIVEXA™to TRUVADA™) in the base study for management of toxic 
effects.  If the switch occurs prior to the Week 2 visit, the subject will not be counted as a 
failure in the primary efficacy analysis; however if the switch occurs after Week 2 and the 
subject has HIV RNA ≥50 copies/mL at the time of the switch, the subject will be regarded 
as a failure for the primary efficacy analysis as specified by FDA’s snapshot approach in the 
base study.
During the open-label extension, in order to address issues of drug access, tolerability, or 
subject convenience, single-drug or fixed-dose combinations of the 4 permitted NRTIs may 
be used, and both TAF and TDF formulations of tenofovir may be used.  (Permitted 
combinations are tenofovir [as TDF or TAF] or ABC, each administered with either FTC or 
3TC).  A switch to another NRTI backbone regimen during study extension 1 for drug 
access, tolerability, or subject convenience reasons will not be counted as a failure in the 
efficacy analysis in the open-label study extension, regardless of viral load at the time of the 
switch.
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Primary and secondary safety endpoints include change from baseline in fasting serum lipids, 
summary of clinical and laboratory adverse experiences, the time to discontinuation from 
study due to an adverse experience, and predefined limits of change in laboratory parameters.  
Safety evaluations in the base study will include physical examinations (including vital signs) 
and laboratory tests (blood) performed at the screening visit, Randomization (Day 1), Weeks 
2, 4, 8, 16, 24, 36, 48, 60, 72, 84, and 96, a virologic failure confirmation visit, if applicable
(no physical exam or vital signs), and, for subjects who do not enter study extension 1, an 
early discontinuation visit (for subjects who discontinue the study early) and the 14-day 
follow-up visit.  
For subjects who enter study extension 1, safety evaluations will be performed at Weeks 100, 
116, 132, 148, 164, 180, and 192, a virologic failure confirmation visit if applicable (no 
physical exam or vital signs), an early discontinuation visit (for subjects who discontinue the 
study early) and a 14-day follow-up visit.  Adverse experiences will be evaluated at each visit 
and graded according to the guidelines which are provided in Section 7.2.  Subjects may be 
asked to return for unscheduled visits in order to perform additional safety monitoring.
Note that the first visit in study extension 1 is at Week 100, such that there is a 4-week 
interval following the last study treatment visit in the base study (Week 96).  This interval 
was made shorter than the 12- to 16-week intervals beginning with Week 24 in the base study 
(and between subsequent visits in study extension 1) in order to more closely monitor all 
subjects, including those who were switched from ritonavir-boosted darunavir to MK-1439, 
since treatment in the base study remains blinded at the beginning of study extension 1.
Treatment group assigned during the base study will not be unblinded when a subject enters 
study extension 1; unblinding will occur after all subjects have completed the base study and 
database lock has been achieved for the base study.
During study extension 2 and study extension 3, SAEs and pregnancy test results will be 
collected at each study visit (study extension 2: Week 208, Week 224, Week 240, Week 256, 
Week 272, and Week 288; study extension 3: Week 304, Week 320, Week 336, Week 352, 
Week 368, and Week 384) as applicable, depending on when MK-1439 is available locally, 
and, if applicable, at the early discontinuation and follow-up visits).
Cmin (defined as the minimum concentration for an individual subject collected predose) is 
the primary pharmacokinetic endpoint of this study. Individual patient data will also be 
assessed in regards to AUC, Cmax and C24hr for MK-1439. Population pharmacokinetic (PK) 
samples will be collected at the Day 1 Randomization visit as a pre-drug sample.  Population 
PK samples will also be taken at Weeks 4, 8, 24 and 48.  At Week 4 the sample must be 
collected predose.  At weeks 24 and 48, the samples must be collected predose and within 0.5 
to 2 hours postdose; at Week 8, the samples may be collected irrespective of time of dose 
(time of last dose and time of PK sample collection must be documented).
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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 Study Extensions
Because HIV infection is chronic, with treatment generally lifelong, collection of long-term 
safety and efficacy data will provide useful information on MK-1439.  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-1439 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.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects 18 years of age or older who are HIV-1 positive and naïve to 
antiretroviral therapy (ART) will be enrolled in this trial.
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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)
for the trial.  The subject or their legal representative may also provide consent for 
Future Biomedical research.  However, the subject may participate in the main trial 
without participating in Future Biomedical research.
3. be HIV-1 positive as determined by a positive result on an enzyme-immuno assay, 
have screening plasma HIV-1 RNA (determined by the central laboratory) ≥1000 
copies/mL within 45 days prior to the treatment phase of this study, and have HIV 
treatment indicated based on physician assessment.  Local treatment guidelines 
should be considered in the decision to initiate therapy.
4. be naïve to antiretroviral therapy (ART) including investigational antiretroviral 
agents.
Note: Naïve is defined as having received no (0 days of) ART therapy for the 
treatment of HIV infection.
5. have the following laboratory values at screening within 45 days prior to the 
treatment phase of this study:

Alkaline phosphatase ≤3.0 x upper limit of normal

AST (SGOT) and ALT (SGPT) ≤5.0 x upper limit of normal
Note:  A single repeat of a laboratory screening test will be allowed for test results 
that are unexpected based on documented prior laboratory results.
6. have a calculated creatinine clearance at time of screening ≥50 mL/min, based on the 
Cockcroft-Gault equation which is as follows : 
Clcr (mL/min) =
(140-age) x weight (in kg)
for males and
72 x serum creatinine (mg/dL)
Clcr (mL/min) =
(140-age) x weight (in kg)
x  0.85 for females
72 x serum creatinine (mg/dL)
7. 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 (i.e., clinical status 
and all chronic medications should be unchanged for at least 2 weeks prior to the start 
of treatment in this study).
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8. be highly unlikely to become pregnant or to impregnate a partner since the subject 
meets 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 
and for 14 days after the last dose of study drug 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.  
Contraceptives containing ethinyl estradiol cannot be used as a method of birth 
control in the base study due to an interaction with ritonavir which may reduce 
their effectiveness. Therefore, it is recommended that a condom or other non-
hormonal method of contraception should be used instead.  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)
•
cervical cap with spermicide (nulliparous women only)
•
contraceptive sponge (nulliparous women only)
•
male condom or female condom (cannot be used together) ↑
During the study extensions, subjects may use hormonal contraceptive: oral 
contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin 
patch, vaginal contraceptive ring, or subcutaneous contraceptive injection
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† 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.  In addition, more restrictive 
contraceptive methods must be used if required by local ethics or regulatory 
authorities.
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 at the Week 96 visit, the subject 
must:
9. have completed the Week 96 visit.
10. be considered, in the opinion of the investigator, to have derived benefit from study 
participation through Week 96.
11. be considered, in the opinion of the investigator, a clinically appropriate candidate for 
96 weeks (approximately 2 years) of treatment, following the end of the base study,
with MK-1439 100 mg q.d. in combination with either tenofovir (as TDF or TAF) or 
ABC, each administered with either FTC or 3TC, as single entities or as a fixed-dose 
combination.
12. understand the procedures in study extension 1 and provide written informed consent 
to enter study extension 1, thus continuing for approximately 2 years beyond the base 
study.   
In order to be eligible to continue receiving MK-1439 in study extension 2 at the Week 192 
visit the subject must: 
13. have completed the Week 192 visit.
14. be considered, in the opinion of the investigator, to have derived benefit from MK-
1439 by Week 192 of the study.
15. be considered, in the opinion of the investigator, a clinically appropriate candidate for 
an additional 2 years (additional 96 weeks) of treatment with MK-1439.
16. understand the procedures in study extension 2 and have provided written informed 
consent to enter study extension 2, thus continuing until MK-1439 is locally available 
or for up to approximately 2 years (whichever comes first) beyond study extension 1.
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In order to be eligible to continue receiving MK-1439 in study extension 3 at the Week 288
visit the subject must: 
17. have completed the Week 288 visit.
18. be considered, in the opinion of the investigator, to have derived benefit from MK-
1439 by Week 288 of the study.
19. be considered, in the opinion of the investigator, a clinically appropriate candidate for 
an additional 2 years (additional 96 weeks) of treatment with MK-1439.
20. understand the procedures in study extension 3 and have provided written informed 
consent to enter study extension 3, thus continuing until MK-1439 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 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, tenofovir, 
entecavir, emtricitabine, or lamivudine.  
Note: Subjects may be enrolled if treatment occurred prior to the diagnosis of HIV.
4. has documented or known resistance to study drugs including MK-1439, darunavir, 
ritonavir, emtricitabine, tenofovir, abacavir and/or lamivudine, as defined below:  
a.
Resistance to MK-1439, for the purpose of this study, includes mutants 
containing the following 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 darunavir/ritonavir includes any of the following PI mutations: 
V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, or L89V. 
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c.
Resistance to emtricitabine, tenofovir, abacavir and lamivudine includes the 
following mutations: M184V/I, K65R, M41L, D67N, K70R/E, T69S, L210W, 
T215Y/F, K219Q/E, L74V, and Y115F.
5. 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.
6. 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. 
7. requires or is anticipated to require any of the prohibited medications noted in the 
protocol (Refer to Section 5.5).
8. has significant hypersensitivity or other contraindication to any of the components of 
the study drugs.
9. 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).  
10. is pregnant, breastfeeding, or expecting to conceive at any time during the study.  
11. 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.
12. is or has an immediate family member (spouse or children) who is investigational site 
or sponsor staff directly involved with this trial.
Trial Treatment(s)
Following completion of the Day 1 procedures and confirmation of eligibility, the site will 
contact the IVRS for assignment of the drug (MK-1439 or darunavir/ritonavir) to be 
administered. Trial treatment should begin on Day 1.  Sites should not call IVRS 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. The 2 treatment regimens/groups to be used in this 
trial are outlined below in Table 1 and Table 2.
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Table 1
Treatment Regimens During Base Study
Group 1
n = ~ 340
MK-1439 100 mg q.d. + TRUVADA™ or EPZICOM™/KIVEXA™, q.d.†, ‡
Group 2
n = ~ 340
Darunavir 800 mg / Ritonavir 100 mg PO q.d. + TRUVADA™or 
EPZICOM™/KIVEXA™q.d. †, ‡
† TRUVADA™i s  a fixed-dose combination (FDC) tablet containing 200 mg of emtricitabine and 300 mg
of tenofovir disoproxil fumarate.  EPZICOM™/KIVEXA™is an FDC tablet containing 600 mg of abacavir 
sulfate and 300 mg of lamivudine.
‡ A dosing interval adjustment of TRUVADA™to 1 tablet every 48 hours is recommended in all subjects with
creatinine clearance of 30-49 mL/min (see TRUVADATM package insert for further details).
Table 2
Treatment Regimen During Study Extensions
Group 1
MK-1439 100 mg q.d. + investigator-selected NRTI backbone therapy
†
, consisting of 
either tenofovir (as TDF or TAF) or ABC, each administered with either FTC or 3TC, q.d.
Group 2
† The NRTI backbone therapy may be administered as single entities or as a fixed-dose combination.
ABC = abacavir; FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TDF = tenofovir disoproxil 
fumarate; 3TC = lamivudine.
Subjects will receive study medication at the Day 1 visit and should take the first dose of 
medication the same day.
MK-1439 (or placebo) will be taken without regard to food.  In the base study, darunavir and 
ritonavir (or their respective placebos) will be taken with food.  If TRUVADA™ is selected 
as background therapy it will be taken with food.  If EPZICOM™/KIVEXA™is selected as 
background therapy, it can be taken without regard to food.
MK-1439 for the base study and for the study extensions (provided that development of 
MK-1439 is continuing) will be provided centrally by the Sponsor, as will TRUVADA™and 
EPZICOM™/KIVEXA™ during the base study only.  In the study extensions, NRTIs will be 
provided by the trial site as part of standard of care; these medications will be administered 
according to the labeling in use in each country.
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
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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Dose Modification:
No dose modification of MK-1439, darunavir, ritonavir or EPZICOM™/KIVEXA™is 
allowed during the base study or the study extensions.  
A dosing interval adjustment of TRUVADA™to 1 tablet every 48 hours is recommended in
all subjects with creatinine clearance of 30-49 mL/min (see TRUVADATM package insert for 
further details).
Dose Interruption:
Consideration should be given to interrupting study therapy for toxicity management (see 
7.1.2.6).  If study therapy is interrupted, all ARTs should be interrupted to minimize risk of 
resistance, and, if appropriate, should be restarted concurrently at full dose.  
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.
Dose Discontinuation
A discontinuation of TRUVADA™ is recommended in all subjects with a creatinine 
clearance of < 30 mL/min (see TRUVADA™ package circular for further details).   
Subjects who require discontinuation of any component of study therapy (MK-1439, 
darunavir, 
ritonavir, 
TRUVADA™, 
or 
EPZICOM™/KIVEXA™) 
must
be 
discontinued from the trial with the following exception: if an Investigator determines 
that a subject needs to discontinue from one of the open label therapies (TRUVADA™
or EPZICOM™/KIVEXA™), the Subject will be allowed to stay in the protocol as long 
as they transition to the other open label therapy that is available as part of the 
protocol.
Timing of Dose Administration
EPZICOM™/KIVEXA™is packaged as either blister packs or bottles. Therefore packaging 
for this product is referred to hereafter as ‘container.’
All subjects will take one tablet daily from each of 4 bottles/containers as follows:
Bottle A (MK-1439 or placebo):  
Subjects will be instructed to take one tablet from Bottle A once a day (q.d.) orally, with or 
without food at approximately the same time each day. 
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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 (darunavir or placebo) and Bottle C (ritonavir or placebo):  
Subjects will be instructed to take one tablet from Bottle B and one tablet from Bottle C, 
once a day (q.d.) orally, together, with food at approximately the same time each day. 
If a subject misses a dose of drug from Bottle B or 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.
All subjects will take one tablet once daily from EITHER Bottle D or Container E as follows:
Bottle D (TRUVADA™)
Subjects will be instructed to take one tablet from Bottle D once a day (q.d.) orally, with food 
at approximately the same time each day. 
OR 
Container E (EPZICOM™/KIVEXA™)
Subjects will be instructed to take one tablet from Container E once a day (q.d.) orally, with 
or without food at approximately the same time each day. 
If a subject misses a dose of drug from Bottle D or Container E, then the subject should take 
it as soon as he/she remembers within a 24 hour day. The subject should not take more than 1 
dose of Bottle D or Container E in a day. The subject should not double the next dose in 
order to compensate for what has been missed.
Subjects will be instructed to take 1 tablet of MK-1439 once a day (q.d.) orally along with 
2 NRTIs, as either 2 single-drug entities or as an FDC, as determined appropriate by each 
investigator.  The NRTIs will be supplied by each site, and instructions on dose regimen will 
be based on the recommendations according to the labeling in use in each country.
MK-1439 will be supplied open-label in a bottle labeled ‘F’ (oral compressed tablets) or, if 
subsequently available, ‘G’ (film-coated tablets).  The instructions are the same as those in 
the base study for Bottle A (MK-1439 or placebo).
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Trial Blinding/Masking
A double-blind/masking technique will be used in the base study.  MK-1439, darunavir, 
ritonavir, and 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.
TRUVADA™ and EPZICOM™/KIVEXA™will be supplied open-label during the base 
study. During the study extensions, MK-1439 will be provided open-label, and the NRTI 
backbone medications of choice will be provided open-label by each site.
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 or Treatment Allocation (Base Study)
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 MK-1439 100 mg q.d., or darunavir/ritonavir (800 mg/100 mg) 
q.d.
Stratification
Randomization will be stratified according to the following factors:
1. Screening HIV-1 RNA (≤100,000 or >100,000 copies/mL), based on central laboratory 
result 
2. NRTI backbone therapy, TRUVADA™ or EPZICOM™/KIVEXA™
Thus, IVRS will randomize subjects within 4 strata, as outlined in in Table 3.
Table 3
Stratification
Stratum
Screening 
HIV-1 RNA levels
(copies/mL)
NRTI backbone therapy
I
≤100,000
TRUVADA™
II
≤100,000
EPZICOM™/KIVEXA™
III
>100,000
TRUVADA™
IV
>100,000
EPZICOM™/KIVEXA™
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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.
No medications are to be taken within 30 days of the start of the 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 Medications/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 darunavir, ritonavir, 
TRUVADA™ (tenofovir, or emtricitabine), and EPZICOM™/KIVEXA™(lamivudine and 
abacavir).
1. Short courses of corticosteroids (e.g., as for asthma exacerbation) are allowed.
2. During the study extensions only, use of oral or other hormonal birth control is permitted.
3. 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 the whether there is a potential drug-drug interaction with a 
specific treatment that the Investigator is planning to give the subject.
Prohibited Medications 
With the exception of short courses of corticosteroids (e.g., as for asthma exacerbation), 
concomitant use of immune therapy agents or other immunosuppressive therapy is not 
allowed during the course of the study.  Several important exceptions should be noted with 
regard to immune therapy or other immunosuppressive therapy:

Intralesional or localized electron beam therapy for cutaneous Kaposi’s sarcoma is 
permitted. 
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
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 potential benefits outweigh the 
risks.  Depending on the type of chemotherapy, study medication may need to be 
interrupted until completion of the chemotherapy.

If a subject requires interferon-based treatment for hepatitis C after randomization, 
the subject may receive treatment and remain in the study if, in the opinion of the 
investigator, the potential benefits outweigh the risks.  If it is possible, interferon-
based therapy should be deferred until the completion of the study.
Other antiretroviral therapies beyond those described in the study (MK-1439, darunavir, 
ritonavir, TRUVADA™, EPZICOM™/KIVEXA™) are also not permitted during the course 
of the study.
Investigational agents must be discontinued for 30 days prior to treatment in this study and
are not permitted during the course of the study.
Prohibited Medications Acting as moderate or strong Inducers of CYP3A4 Drug Metabolism 
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 broad inducers of CYP3A4 and their coadministration with MK-1439 
could possibly result in reduced drug levels of MK-1439, or they have the potential for 
additional drug-drug interactions.  
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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.
Prohibited Medication/Therapy 
Due to MK-1439 Interaction During Base Study and 
Study Extension
Carbamazepine
Oxcarbazepine
Rifapentine
Phenobarbital
Phenytoin
Rifabutin
Rifampin
St. John’s Wort
Modafinil
Bosentan
Nafcillin
Mitotane
Enzalutamide
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Prohibited Concomitant Therapy Due to Potential Interaction with Darunavir or Ritonavir
The following medications are prohibited during the base study because competition for 
CYP3A4 by darunavir (or ritonavir) could result in inhibition of metabolism of these drugs 
and create the potential for serious and/or life-threatening adverse events.  Several of these 
medications are also prohibited during the study extensions because of interaction with 
MK-1439; see footnotes in table below.  For complete information, refer to the most recent 
darunavir (or ritonavir) package circulars.
Prohibited Medication/Therapy During Base Study
Due to Darunavir Interaction
Alfuzosin
Dihydroergotamine
Ergonovine
Ergotamine
Methylergonovine 
Cisapride
Pimozide
Oral midazolam
Triazolam
St. John’s Wort†
Lovastatin
Simvastatin
Sildenafil (for treatment of pulmonary arterial 
hypertension)
Rifampin†
Amiodarone
Dronedarone
Lidocaine, systemic 
Quinidine
Astemizole
Terfenadine
Bepridil
Colchicine when used in patients with renal and/or 
hepatic impairment
Quetiapine
Sertindole 
Ranolazine
Ticagrelor
† Several of these medications are also prohibited during the 
study extensions because of interaction with MK-1439:
specifically, rifampin, and St. John’s Wort are prohibited 
throughout the base study and the extensions.
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Prohibited Medication/Therapy During Base Study
Due to Ritonavir Interaction
Alfuzosin HCL
Amiodarone
Bepridil
Flecainide
Propafenone
Quinidine
Voriconazole
Astemizole
Terfenadine
Dihydroergotamine
Ergonovine
Ergotamine
Methylergonovine
Midazolam
Triazolam
Pimozide
Cisapride
Eletriptan
Avanafil
Vardenafil
Clorazepate
Flurazepam
Diazepam
Estazolam
Clozapine
Quetiapine
Encainide
Fusidic acid
Rifabutin†
Pethidine
Piroxicam
Propoxyphene
† Rifabutin is also prohibited during the study extensions
because of interaction with MK-1439.  
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director or Designee.  
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Concomitant Therapy to be used With Caution
For complete information, please refer to the darunavir, ritonavir, TRUVADA™, 
EPZICOM™/KIVEXA™, TDF/TAF, ABC, FTC and 3TC package circulars, as appropriate, 
for drugs that are permitted in the protocol but that should be used with caution, since they 
have established drug interactions with these agents.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
Diet
MK-1439 (or placebo) can be taken without regard to food.  
Darunavir, and ritonavir (or their respective placebos) will be taken with food.  
TRUVADA™, if selected as the backbone NRTI regimen, will be taken with food.
EPZICOM™/KIVEXA™, if selected as the backbone NRTI regimen, can be taken without 
regard to food.
These drugs should generally be taken at approximately the same time each day.
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.
NRTI backbone therapy and recommended treatment guidelines.
The Investigator should consider local treatment guidelines when determining the backbone 
therapy for subjects in this protocol.

Subjects with hepatitis B co-infection should be treated with TRUVADA™.
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 
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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.

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.

All chronic hepatitis B-infected subjects who require discontinuation of tenofovir 
should be discontinued from the study to allow for appropriate hepatitis B treatment 
with medications not permitted per protocol and to avoid lamivudine monotherapy.

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.

The subject has an adverse experience or tolerability issue related to study medication 
which requires discontinuation of the medication.

A physician investigator feels it is in the best interest of the subject to discontinue.

The subject experiences a severe skin or hypersensitivity reaction.

The subject has a creatinine clearance of <30 mL/min based on the following 
Cockcroft-Gault equation: 
Male:
Clcr (mL/min) =
(140-age) x weight (in kg)
72 x serum creatinine (mg/dL)
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Female:
Clcr (mL/min) =
(140-age) x weight (in kg)
X    0.85
72 x serum creatinine (mg/dL)

Subjects should be discontinued regardless of compliance with study therapy if they
meet the PDVF criteria in Section 4.2.3.1.

Subjects who participate in study extension 2 or study extension 3 should be 
discontinued at the next scheduled visit after MK-1439 becomes locally available.
Subjects who discontinue study therapy prior to the last scheduled treatment visit must be 
discontinued from the trial and should have an Early Discontinuation visit conducted. All 
applicable procedures will be done at this time. Subjects will be required to return to the 
clinic approximately 14 days after the last dose of study drug for a post-study visit as 
outlined in the Study Flow Chart (Sec 6.0).
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. 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).
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Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The External Data Monitoring Committee (eDMC) recommends that the trial be 
terminated and the Executive Oversight Committee agrees.
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
Flow Chart A applies to all subjects in the base study from screening through follow-up after the Week 96 visit. Flow Chart B applies 
to those subjects continuing into study extension 1 from Week 96 through follow-up after the Week 192 visit.  Flow Chart C applies to 
those subjects continuing into study extension 2 from Week 208 through follow-up after the Week 288 visit. Flow Chart D applies to 
those subjects continuing into study extension 3 from Week 304 through follow-up after the Week 384 visit. 
Flow Chart A (Base Study): Screening Through Week 96 Plus 14 Days Follow-up 
Visit Number/Title:
1
2
3
4
5
6
7
8
9
10
11
12
13
U
(Virologic 
Failure 
Confirmation)
U
(Early 
Discon)
99
Trial Period
Screening
Treatment
TRIAL PROCEDURES
Screen
Fasting 
(Day1) a
WK
2
WK
4
WK
8
WK
16
Fasting 
WK    24
WK 
36
Fasting 
WK   
48
W
K6
0
WK
72
WK
84
Fasting 
WK    
96r
>1 week to < 4 
weeks after the 
time virologic 
failure is first
identified
At time of 
Discon
Post-
study
14 day 
follow-
up p
Administrative Procedures
Informed Consent
X
X q
Informed Consent for Future 
Biomedical Research (optional) b
X
Inclusion/Exclusion Criteria
X
X
X q
Provide Subject Identification 
Cards
X
Medical Historyo
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment 
Allocation/Randomization
X
Register Study Visit and/or 
Dispense Study Therapy via 
Interactive Voice Response System 
(IVRS)c
X d
X
X d,e
X
X
X
X
X
X
X
X
X
X c 
X d
Provide/Review Study Medication 
Diary 
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
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Visit Number/Title:
1
2
3
4
5
6
7
8
9
10
11
12
13
U
(Virologic 
Failure 
Confirmation)
U
(Early 
Discon)
99
Trial Period
Screening
Treatment
TRIAL PROCEDURES
Screen
Fasting 
(Day1) a
WK
2
WK
4
WK
8
WK
16
Fasting 
WK    24
WK 
36
Fasting 
WK   
48
W
K6
0
WK
72
WK
84
Fasting 
WK    
96r
>1 week to < 4 
weeks after the 
time virologic 
failure is first
identified
At time of 
Discon
Post-
study
14 day 
follow-
up p
Vital Signs (including pulse rate, 
blood pressure, respiratory rate, & 
body temperature)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG (local) m
X
Laboratory Procedures/Assessments n
Serum Pregnancy Test 
X f,
Urine Pregnancy test f
Xg
X
X
X
X
X
X
X
X
X
X
X
X
Collected Blood for Safety 
Laboratory Tests 
Hematology/Chemistry h
X
Xn
X
X
X
X
Xn
X
Xn
X
X
X
Xn
X
Xn
X
Hemostatic Function Test i
X
Human Leukocyte Antigen Test
X
HIV/Hepatitis Screening j   
X
Virology Test  Plasma HIV viral 
RNA quantification test  (Abbott 
RealTime 
HIV-1)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect Blood for CD4 Cell Count
X
X
X
X
X
X
X
Collect Blood for  PK k
X
X
X
X
X
Collect Plasma for Viral Resistance 
Test
X
X
X
Xl
Collect Blood (DNA) for Future 
Biomedical Research (optional)b
X
Collect Plasma for Future 
Biomedical Research (optional)b
X
X
X
a.
Prior to first dose on Day 1.
b.
The optional informed consent for future biomedical research samples must be obtained before the FBR samples for DNA and plasma are collected. The FBR sample for DNA analysis should 
be obtained pre-dose, on Day 1 (or with the next scheduled blood draw), as the last sample drawn, on randomized subjects only, or at a later date as soon as the informed consent is obtained.  
The plasma samples for FBR should be collected at Day 1, Weeks 48 and 96.
c.
Site personnel will access IVRS to register subjects at the screening visit. IVRS will be used to allocate drug and to manage distribution of clinical supplies; for Week 96, drug will be 
dispensed only to subjects who enter study extension 1, after providing informed consent.
d.
At these visits, IVRS will be called to register the subject visit but no drug will be dispensed.
e.
At the Week 2 (Visit 3) visit, the IVRS will be called to register the subject visit but no drug will be dispensed.  In addition, the study coordinator will visually examine the bottles/container 
dispensed at Day 1 (Visit 2) for compliance (pills will not be counted), and drug will be returned to the subject following evaluation.
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Visit Number/Title:
1
2
3
4
5
6
7
8
9
10
11
12
13
U
(Virologic 
Failure 
Confirmation)
U
(Early 
Discon)
99
Trial Period
Screening
Treatment
TRIAL PROCEDURES
Screen
Fasting 
(Day1) a
WK
2
WK
4
WK
8
WK
16
Fasting 
WK    24
WK 
36
Fasting 
WK   
48
W
K6
0
WK
72
WK
84
Fasting 
WK    
96r
>1 week to < 4 
weeks after the 
time virologic 
failure is first
identified
At time of 
Discon
Post-
study
14 day 
follow-
up p
f.
For women of childbearing potential.
g.
Results of test need to be available prior to randomization.
h.
Refer to Table 4 for listing of specific blood safety and chemistry tests.
i.
Hemostatic Function Test includes: Prothrombin time (PT), Activated Partial Thromboplastin Time (APTT), and International Normalized Ratio (INR).
j.
HIV/hepatitis Screening  test 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 will be performed if the Hepatitis C antibody test is positive.
k.
Sample(s) for population PK will be collected at Day 1 and Weeks 4, 8, 24, 48.   At Week 4, the sample must be collected predose.  At weeks 24 and 48, the samples must be collected predose 
and within 0.5 to 2 hours postdose; and at Week 8, the samples may be collected irrespective of time of dose.
l.
If virologic failure is confirmed (with a confirmatory HIV-1 RNA at least one week following the initial assessment), and the decision is made to discontinue the subject, plasma for resistance 
should still be collected at the discontinuation visit.  
m.
A local ECG should be performed prior to the subject’s first dose of study medication.  
n.
Subjects will fast for at least 8 hours prior to the study visits at Day 1, Week 24, Week 48 and Week 96 and, if applicable, at the Discontinuation Visit. Fasting is required at these visits for 
lipids measurements. 
o.
Include smoking history in Medical History.
p.
The follow-up visit 14 days after the Week 96 visit in the base study applies only to subjects who do not enter study extension 1.
q.
If the subject is eligible and elects to enter study extension 1, he/she will be considered to have completed the base study and will, after providing informed consent for study extension 1, 
immediately enter study extension 1.
r.
The visit window for Week 96 is approximately +/- 7 days and, for the post-study 14-day follow-up visit, the window is approximately –2 to 0 days.  The timing of each visit is relative to the 
randomization (Day 1) visit.  Every attempt must be made to keep subjects on schedule.
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Flow Chart B (Study Extension 1): Week 100 Through Week 192 Plus 14 Days Follow-up 
Visit Number/Title:
14 a
15
16
17
18
19
20
U
(Virologic Failure 
Confirmation)
U
(Early 
Discontinuation)
99
Trial Period
Treatment b
TRIAL PROCEDURES
WK 
100
WK 
116
WK    
132
Fasting 
WK 
148
WK
164
WK
180
Fasting 
WK
192
>1 to < 4 wks after 
the time virologic 
failure is first 
identified
At time of 
Discontinuation
Post-study 
14-day 
follow-up
Administrative Procedures
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
Register Study Visit via Interactive Voice 
Response System (IVRS) c
X
X
X
X
X
X
X
X
Dispense Study Therapy
X
X
X
X
X
X
Xd
Provide/Review Study Medication Diary
X
X
X
X
X
X
X
X
Assess Subject Eligibility for Study 
Extension 2e
X
Informed Consent for Study Extension 2e
X
Clinical Procedures/Assessments
Directed Physical Examination
X
X
X
X
X
X
X
X
X
Weight
X
X
Vital Signs (including pulse rate, blood 
pressure, respiratory rate, & body
temperature)
X
X
X
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments 
Urine Pregnancy test f
X
X
X
X
X
X
X
X
X
Collect Blood for Safety Laboratory 
Tests Hematology/Chemistry g
X
X
X
X g
X
X
X g
X
X
X
Virology Test Plasma HIV viral RNA 
quantification test (Abbott RealTime 
HIV-1)
X
X
X
X
X
X
X
X
X
X
Collect Blood for CD4 Cell Count
X
X
X
Collect Plasma for Viral Resistance Test
X
X i
a.
Subjects who enter study extension 1 are considered enrolled in the study extension upon providing written informed consent for the study extension at the Week 96 study 
visit of the base study.
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Visit Number/Title:
14 a
15
16
17
18
19
20
U
(Virologic Failure 
Confirmation)
U
(Early 
Discontinuation)
99
Trial Period
Treatment b
TRIAL PROCEDURES
WK 
100
WK 
116
WK    
132
Fasting 
WK 
148
WK
164
WK
180
Fasting 
WK
192
>1 to < 4 wks after 
the time virologic 
failure is first 
identified
At time of 
Discontinuation
Post-study 
14-day 
follow-up
b.
The visit window for Week 100 is approximately +/- 7 days, for all visits from Week 116 through Week 192 the windows are approximately +/- 14 days and, for the post-
study 14-day follow-up visit, the window is approximately –2 to 0 days. The timing of each visit is relative to the randomization (Day 1) visit.  Every attempt must be made 
to keep subjects on schedule.
c.
IVRS will be used to allocate drug and to manage distribution of clinical supplies.
d.
Study drug for extension 2 will be dispensed at Week 192, if subject is continuing into extension 2
e.
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-1439.
f.
For women of childbearing potential
g.
Subjects will fast for at least 8 hours prior to the study visits at Week 148 and Week 192 and, if applicable, at the Discontinuation Visit.  Fasting is required at these visits 
for lipids measurements. Refer to Table 4 for listing of specific blood safety and chemistry tests.
h.
If virologic failure is confirmed (with a confirmatory HIV-1 RNA at least one week following the initial assessment), and the decision is made to discontinue the subject, 
plasma for resistance testing should still be collected at the discontinuation visit..  
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Flow Chart C (Study Extension 2): Week 208 Through Week 288 Plus 14 Days Follow-up 
Visit Number/Title:
21 a
22
23
24
25
26
U
(Extension
Early
Discontinuation)
99
Trial Period:
Extension: Treatment b,c
Post-
Treatment d
TRIAL PROCEDURES
Wk 208
Wk 224
Wk 240
Wk 256
Wk 272
Wk 288
At time of
Discontinuation
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. Subjects who enter study extension 2 are considered enrolled in the extension upon providing written informed consent at the Week 192 study visit.
b. The total duration is dependent on when MK-1439 becomes locally available, with a maximum total duration of treatment of 288 weeks.  Subjects should discontinue at the 
next scheduled visit after MK-1439 becomes locally available in the market.
c. The visit windows are approximately +/- 14 days for all visits from Week 208 through Week 288.  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-1439.
f. Study drug for extension 3 will be dispensed at Week 288, 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-1439.
h. For women of childbearing potential.
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Flow Chart D (Study Extension 3): Week 304 Through Week 384 Plus 14 Days Follow-up 
Visit Number/Title:
27 a
28
29
30
31
32
U
(Extension
Early
Discontinuation)
99
Trial Period:
Extension: Treatment b, c
Post-
Treatment d
TRIAL PROCEDURES
Wk 304
Wk 320
Wk 336
Wk 352
Wk 368
Wk 384
At time of
Discontinuation
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
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.
Subjects who enter study extension 3 are considered enrolled in the extension upon providing written informed consent at the Week 288 study visit.
b.
The total duration is dependent on when MK-1439 becomes locally available, with a maximum total duration of treatment of 384 weeks.  Subjects should discontinue at the 
next scheduled visit after MK-1439 becomes locally available in the market.
c.
The visit windows are approximately +/- 14 days for all visits from Week 304 through Week 384.  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-1439.
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
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.
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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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.
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 Day 1 visit (prior to randomization).  For subjects who wish to 
continue into study extension 1, the additional inclusion criteria (9 to 12, Section 5.1.2) are to 
be reviewed at the Week 96 study visit of the base study.  For subjects who wish to continue 
into study extension 2, the additional inclusion criteria (13 to 16, Section 5.1.2) are to be 
reviewed at the Week 192 study visit. For subjects who wish to continue into study extension 
3, the additional inclusion criteria (17 to 20, Section 5.1.2) are to be reviewed at the 
Week 288 study visit.  
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.
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 Immune Deficiency Syndrome (if applicable) and the year diagnosed.
If a subject has previously been diagnosed with any Acquired Immune Deficiency Syndrome 
(AIDS) defining condition, or CD4 <200, the condition as well as a corresponding medical 
history of Acquired Immune Deficiency Syndrome must be reported.  In addition, the 
subject’s history of smoking should be obtained and recorded on the appropriate eCRF.
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The investigator or qualified designee will review prior medications use and record all  
medication taken by the subject within 30 days before starting the study.
Investigational agents must be discontinued for 30 days prior to receiving study therapy.
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
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 allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
The site must call the IVRS system to register each screening subject.
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a 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 randomization number.
Subject Diary Cards will be used to ensure and document drug compliance for the base study
and study extension 1.
On Day 1, the investigator/study coordinator will give the subject a diary card to be 
completed during the study period. The study coordinator will be responsible for entering the 
subject’s identification (allocation number), visit number, and visit dates before giving the 
diary card to the subject. The subject should follow the instructions on the diary card for 
recording all study drugs.  Aside from the initial information entered by the study 
coordinator, only the subject should enter information on the diary card.  The subject is to 
return the completed diary card at each scheduled visit.  The study coordinator will be 
responsible for reviewing the diary card for completeness and accuracy with the subject.  
Only the subject shall make any changes to the entries on the card.  The subject will initial 
the card to confirm that the information is accurate.  The study coordinator will be 
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responsible for transferring the appropriate information from the diary card onto the 
appropriate case report form.
Rigorous monitoring is especially important during the early part of the study, specifically 
between the Day 1 and Week 2 visits to ascertain problems with non-compliance as early as 
possible, taking study medication as directed and to ensure that subjects experiencing 
difficulties are re-educated, as appropriate. 
Subject Medication Diary will not be used during study extension 2 or study extension 3. 
Sites are responsible for source documentation of drug accountability.
Interruptions from the protocol specified plan for 7 days or greater due to non-compliance
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on subject management.
Clinical Procedures/Assessments
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 
subinvestigator (physician, physician assistant or nurse practitioner). 
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 Day 1 visits should be noted in 
the Medical History eCRF at Day 1.  Any significant changes in the physical examination 
after receiving study therapy at Day 1 must be reported as adverse events and entered on the 
adverse event eCRF. If the subject is discontinued for any reason during the treatment phase, 
every attempt should be made to perform a final physical examination.
The subject's height and weight 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.
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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.
After the Screening visit, the site should indicate whether or not the result is clinically 
significant and document the result in the subject’s chart. If any result is clinically 
significant, it should be captured as an adverse event on the eCRF.
A local 12-Lead ECG should also be performed prior to the subject’s first dose of study 
medication, as indicated in the study flow chart (Section 6.0), and any abnormalities 
documented.
Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to 
having ECG readings obtained. Clinically significant findings from the Day 1 ECG must be 
documented in the subject's chart and captured in the medical history eCRF.
If an ECG is performed for any medical reason while the subject is on the study treatment, or 
during the follow-up period, any clinically significant changes compared with the Day 1 
ECG must be captured as AEs on the eCRF and documented in the subject’s chart.
The principal investigator or subinvestigator (physician, physician assistant or nurse 
practitioner) must determine the severity and relationship to study medication(s) of all 
adverse events. A physician investigator must review, initial and date any assessment of 
severity or relationship to study medication when the initial assessment of an adverse event is 
made by a physician assistant or nurse practitioner. Designated medical practitioners must be 
licensed and the responsibilities transferred to them must be documented in the site file. 
Details on assessing and recording adverse events can be found in Section 7.2.
If a subject is diagnosed with an AIDS defining condition following randomization, the 
condition must be reported as an AE.  
When assessing the relationship of an AE to study medication during the base study, the 
investigator should indicate whether the relationship is to:

Blinded therapy (MK-1439 or darunavir/ritonavir) or
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
TRUVADA™ or 

EPZICOM™/KIVEXA™or

Combination 
ART
(Blinded 
therapy
combined 
with 
TRUVADA™ 
or 
EPZICOM™/KIVEXA™).
When assessing the relationship of an AE to study medication during the study extensions, 
the investigator should indicate whether the relationship is to: 

MK-1439 (open-label) alone or in combination with other background regimen.
Guidelines for grading the severity of adverse experiences are based on Division of Acquired 
Immunodeficiency Syndrome (DAIDS) criteria for grading severity of adverse events
(Appendix 12.5). 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 re-challenge must be approved in advance by 
the MSD Clinical Director or Designee and the Independent Ethics Committee/Institutional 
Review Board and a re-challenge consent is needed prior to re-initiation of study therapy.
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.
Care must be taken to avoid pregnancy in female subjects of childbearing potential and in the 
female partners of childbearing potential of male subjects.
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.
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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 Screening to the 14 days post-study visit), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per subject can be found in Section
12.4.
For women of childbearing potential, a pregnancy test must be performed at all study visits 
except Week 2.  A serum pregnancy is to be done at the Screening visit and a urine 
pregnancy test is to be done at all other visits of both the base study (except the Week 2 visit) 
and the study extensions, including the Day 1 visit prior to randomization, at the 
discontinuation visit and the 14-day post-study visit.  A subject found to be pregnant must be 
discontinued from the study. 
Laboratory tests (hematology, chemistry and other) which are to be performed during the 
base study and study extension 1 of the trial are specified in Table 4.
Table 4
Laboratory Tests
Hematology
Chemistry
Other
Hematocrit
Aspartate Aminotransferase  (AST, 
SGOT)
Prothrombin time (PT)2
Hemoglobin
Alanine Aminotransferase 
(ALT, SGPT)
Activated partial thromboplastin time (APTT)2
Platelet
Alkaline Phosphatase
International Normalized Ratio (INR) 2
Red blood cell count
Creatine Kinase 
Hepatitis B Virus surface Antigen 2
WBC Differential  
Leukocytes
Total Bilirubin  
Hepatitis B Virus surface antibody2
Erythrocyte Mean 
corpuscular volume
Direct Bilirubin 
Indirect Bilirubin 
Hepatitis B e-Antigen 2
CD4 % and Absolute 
CD4/Lymphocytes
Amylase
Hepatitis C Antibody 2
CD8 % and Absolute 
CD8/Lymphocytes
Lipase
Plasma hepatitis C virus PCR quantitative3
CD4/CD8 ratio
Glucose1 (fasting and non-fasting)
Enzyme immunoassay HIV antibody (with confirmation 
WB)2
Blood Urea Nitrogen
HIV viral RNA Quantification
Creatinine 6
Serum -human chorionic gonadotropin (hCG) test4
Calcium 
Urine -human chorionic gonadotropin (hCG) test5
Phosphorus
HIV Viral resistance
Magnesium
Human leukocyte antigen
Protein
Albumin
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Hematology
Chemistry
Other
Sodium
Potassium
Chloride
Bicarbonate
High-density lipoprotein cholesterol
(HDL-C) (fasting) 1
Low-density lipoprotein cholesterol 
(LDL-C) (fasting) 1
Triglycerides (fasting) 1
Total Cholesterol (fasting ) 1
1.
Perform lipid analyses at Randomization (Day 1), Week 24, Week 48, and Week 96 in the base study and, for 
subjects who continue into study extension 1, at Week 148 and Week 192, and, as applicable, at the Early 
Discontinuation visit if possible. Subjects should be fasting for 8 hours prior to the visit.  Perform non-fasting glucose 
at Screening and at Weeks 2, 4, 8, 16, 36, 60, 72 and 84 in the base study and, for subjects who continue into study 
extension 1, at Weeks 110, 116, 132, 164 and 180.
2.
Perform at screening visit only.
3.
If result of the hepatitis C Antibody testing is positive, then a plasma hepatitis C virus PCR quantitative test will also 
be performed.
4.
Serum hCG test at the Screening visit to be performed by central laboratory.
5.
Urine hCG test to be performed at the investigator site at Day 1 and every study visit thereafter (with the exception 
of Week 2).
6.
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.
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.
At the screening visit, a blood sample will be collected to screen for the HLA-B*5701 allele 
to potentially avoid a hypersensitivity reaction to EPZICOM™/KIVEXA™.
Plasma HIV-1 RNA quantification will be performed at all visits in both the base study and 
study extension 1, except for Week 2. The testing will be performed at the central laboratory 
using the Abbott RealTime HIV-1 assay. 
Blood samples will be collected for HIV viral resistance testing at the Screening visit to 
determine MK-1439, darunavir, ritonavir, emtricitabine, tenofovir, abacavir and lamivudine 
resistance. Blood samples will also be collected for HIV viral resistance testing at Week 24 
and, where applicable, at the Virologic Failure Confirmation visit and at the Early 
Discontinuation Visit.  All resistance testing in the base study and in study extension 1 will 
be performed by the central laboratory.
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CD4 cell count (absolute and percentage) will be determined at Screening, Day 1, and at 
Weeks 8, 24, 48, 72, and 96 in the base study and, for subjects who continue into study 
extension 1, at Weeks 100, 148 and 192.
The testing will be performed at the central 
laboratory using a commercially available assay. 
Population PK samples will be collected from all subjects as outlined in Table 5.  The exact 
time the dose of study medication (Bottle A) was taken prior to the sample collection will be 
recorded on the appropriate eCRF. The type of meal (full, medium, light or no meal) 
consumed with the last dose of study medication (Bottle A) prior to the collection of the PK 
sample will also be recorded on the appropriate eCRF.
Table 5
Pharmacokinetic Sampling Timepoints
Visit Number
Study 
Day/Week
Time Relative to Bottle A Dose 
(MK-1439 or placebo)
2
Day 1
Sample to be collected predose
4
Week 4
Sample to be collected predose
5
Week 8
Sample to be collected pre or postdose
7
Week 24
Sample to be collected predose and within 0.5 to 2 
hours postdose (Patient should remain fasting until 
postdose PK sample is collected).
9
Week 48
Sample to be collected predose and within 0.5 to 2 
hours postdose (Patient should remain fasting until 
postdose PK sample is collected).
Sample collection, storage and shipment instructions for the PK samples will be provided in 
the operations/laboratory manual. 
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Plasma for future biomedical research
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Other Procedures
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Early Discontinuation visit 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.
At a minimum, the following information should be collected when a subject discontinues:  
1. The reason the subject discontinued.  
2. The date of the last dose of study medications from the trial. 
3. The date of the last assessment and/or contact. 
4. All adverse events (including any serious adverse events) in the base study and study 
extension 1. 
5. Only serious adverse events in study extension 2 and study extension 3.
6. Final Assessments: Every effort should be made to ensure that all procedures and 
evaluations scheduled for the final study visit are performed.
In addition all investigative products must be retrieved from the subject.
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 
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subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Procedures for blinding and unblinding apply only to the base study; treatment during the 
study extensions is open-label.
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 subinvestigator 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 subinvestigator 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 subinvestigator must enter the intensity 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.
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.
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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.
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 as set forth in Section 5.1.  The investigator will 
discuss with each potential subject the study, its requirements, and its restrictions.  The study 
screening period is 45 days.

All procedures listed for the Screening visit (Visit 1) in the Study Flow Chart  (Section 
6.0) must be completed and the subject’s eligibility confirmed by the investigator prior to 
the subject’s randomization and drug administration on Day 1.

Blood will be collected at the Screening visit (Visit 1) as per the Trial Flow Chart 
(section 6.0).  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) 
collected at the screening visit.  Women who are found to be pregnant will be excluded 
from the study.

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.
Randomization Day 1 (Visit 2)

Procedures listed for Day 1 (Visit 2) on the Study Flow Chart (Section 6.0) should be 
performed prior to the subject’s randomization and drug administration on Day 1, unless 
otherwise specified.

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 criteria, the subject will be eligible for 
randomization and the remainder of the pretreatment (Day 1) testing/procedures will be 
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performed.  If the urine pregnancy test result is positive, the subject must not be 
randomized. 

Blood will be collected on Day 1 (Visit 2) as per the Trial Flow Chart (section 6.0). 
These samples will be sent to the appropriate central laboratories following the 
procedure(s) set forth in the manual(s).

The investigator should also have selected the optimal NRTI backbone (either 
TRUVADA™ or EPZICOM™/KIVEXA™) to be given in combination with the blinded 
study 
therapy. 
 
Pharmacogenetic 
testing 
for 
potential 
hypersensitivity 
to 
EPZICOM™/KIVEXA™will have been completed at the Screening Visit.

Following completion of the Day 1 pretreatment procedures and confirmation of 
eligibility, the site pharmacist or study coordinator will contact the IVRS for assignment 
of the drug to be administered. Sites should not call IVRS for drug administration until 
the subject has met all criteria for the study and are ready to receive the first dose of study 
medication on Day 1.

Randomized 
subjects 
will 
receive 
a
4-week 
supply
of 
study 
medication
(4 bottles/containers labeled A, B, C, and D or E) on Day 1 (Visit 2) (see Section 
7.1.5.2.1).  Subjects will be instructed to take their first dose of all study medication on 
the same day as the Day 1 study visit. 

The investigator/study coordinator will give the subject a study medication diary to be 
completed starting on Day 1 and continuing through the treatment period.  The site must 
ensure that the subject is properly trained and comfortable with completing the 
medication diary prior to leaving the clinic.
Drug Administration
Subjects will be dispensed study drug as outlined in Table 6 for the base study.  
Table 6
Study Drug Bottle/Container (A, B, C, and either D or E) Components  
     Bottle Label
Component
Bottle A
MK-1439 or placebo
Bottle B
Darunavir or placebo
Bottle C
Ritonavir or placebo
Bottle D
TRUVADA™†
Container E
EPZICOM™/KIVEXA™†
†Subject will take either bottle D (TRUVADA™) or container E (EPZICOM™/KIVEXA™) based on Investigator 
decision.
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Subjects will be instructed to take the study medication as follows:
All Subjects will take one tablet once daily from each of 4 bottles/containers as follows:
Note: In general study medication should be taken directly from the study bottle/container.  
Bottle A (MK-1439 or placebo):  
Subjects will be instructed to take one tablet from Bottle A once a day (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 
light and moisture sensitive.
Bottle B and Bottle C (darunavir/ ritonavir or placebo):  
Subjects will be instructed to take one tablet from Bottle B and one tablet from Bottle C, 
once a day (q.d.) orally, together, with food at approximately the same time each day.
All subjects will take one tablet once daily from EITHER Bottle D or Container E as follows:
Bottle D (TRUVADA™)
Subjects will be instructed to take one tablet from Bottle D once a day (q.d.) orally, with food 
at approximately the same time each day. 
OR
Container E (EPZICOM™/KIVEXA™)
Subjects will be instructed to take one tablet from Container E once a day (q.d.) orally, with 
or without food at approximately the same time each day. 
Week 2 (Visit 3) to Week 96 (Visit 13)

All procedures for treatment Week 2 (Visit 3) to Week 96 (Visit 13) listed on Study Flow 
Chart A (Section 6.0) should be performed. 

Blood will be collected for safety laboratory evaluations, HIV-1 RNA quantification, 
CD4 cell counts, HIV viral resistance and PK measurements 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 (except Week 2). If the urine pregnancy test result is positive
the subject must be discontinued. 
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
Subjects will be required to fast for at least 8 hours prior to study visits at Weeks 24, 48 
and 96. 

Except as noted below, all bottles/containers 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 recorded in the 
source documentation.  The primary source of adherence data, however, will be the 
subjects study medication diary.
Note: At Week 2 (Visit 3), the study coordinator will visually examine the 
bottles/containers dispensed at Day 1 (Visit 2) for compliance (bottles will not be opened, 
pills will not be counted).  Day 1 drug will be returned to the subject following 
evaluation.  If the study coordinator suspects the patient has been non-compliant based on 
visual inspection, a pill count can be done at their discretion to verify study drug 
compliance, but new unopened drug will then need to be dispensed to the patient.   

Subjects will receive a 4-week supply of study drug (4 bottles labeled Bottle A, Bottle B, 
Bottle C, and Bottle D or Container E) at Day 1 (Visit 2) and Week 4 (Visit 4); an 8-week 
supply (8 bottles/containers; 2 each of bottles labeled Bottle A, Bottle B, and Bottle C, 
and 2 bottles/containers of either Bottle D or Container E) at Week 8 (Visit 5) and Week 
16 (Visit 6); a 12-week supply (12 bottles/containers; 3 each of bottles labeled Bottle A,
Bottle B, Bottle C, and 3 bottles/containers of either Bottle D or container E) beginning 
from Week 24 (Visit 7) through Week 84 (Visit 12).

At Week 96 (Visit 13), subjects who continue into study extension 1 will receive a 
4-week supply of unblinded study drug: this will consist, for all subjects, of MK-1439, 
packaged in a single bottle labeled ‘Bottle F’ or ‘Bottle G’, plus investigator-selected 
backbone therapy consisting of the following NRTIs as single entities or as an FDC, and 
provided by individual sites in commercial packaging: either tenofovir (as tenofovir 
disoproxil fumarate [TDF] or tenofovir alafenamide fumarate [TAF]) or abacavir (ABC), 
each administered with either emtricitabine (FTC) or lamivudine (3TC).

At each treatment visit the study coordinator and subject will review the study medication 
diary information. 

All procedures listed in the Study Flow Chart B (Section 6.0) should be performed, as 
applicable to each study visit, including collection of blood and urine (urine only for 
female subjects of childbearing potential) for laboratory evaluations. 

Subjects will be required to fast for at least 8 hours prior to the Week 100, Week 148 and 
Week 192 visits.

Subjects will receive a 16-week supply of unblinded study drug, i.e., MK-1439 and either 
tenofovir (as TDF or TAF) or ABC, each administered with either FTC or 3TC, and 
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provided by individual sites in commercial packaging at each visit through Week 180.
Study drug for extension 2 will be dispensed at Week 192 for subjects continuing into 
extension 2.

All containers 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 (except for 
Week 192).  The number of tablets remaining in the container 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 visit, the study coordinator and subject will review the study medication diary 
information.

All procedures for Study Week 208 (Visit 21), Week 224 (Visit 22), Week 240 (Visit 23), 
Week 256 (Visit 24), Week 272 (Visit 25), and Week 288 (Visit 26) listed on the Study 
Flow Chart C (Section 6.0) 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 272. Subjects continuing 
into study extension 3, if applicable, will receive a 16-week supply of study drug for 
study extension 3 at Week 288 (Visit 26).

All procedures for Study Week 304 (Visit 27), Week 320 (Visit 28), Week 336 (Visit 29), 
Week 352 (Visit 30), Week 368 (Visit 31), and Week 384 (Visit 32) listed on the Study 
Flow Chart D (Section 6.0) 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.  
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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 368. 

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.
Protocol-defined virologic failure (PDVF) for this study is defined as one of the following:
1) Confirmed (2 consecutive measures at least one week apart) HIV-1 RNA ≥200 
copies/mL at week 24 or week 36, or confirmed (2 consecutive measures at least one 
week apart) HIV-1 RNA ≥50 copies/mL at week 48;
OR 
2) Confirmed (2 consecutive measures at least one week apart) HIV-1 RNA ≥50 copies/mL 
after initial response of HIV-1 RNA <50 copies/mL at any time during the study.
The protocol allows a subject to switch from one of the study backbone NRTI regimens to 
the 
other 
(either 
from 
TRUVADA™ 
to
EPZICOM™/KIVEXA™ 
or 
from 
EPZICOM™/KIVEXA™ to TRUVADA™) in the base study for management of toxic 
effects.  If the switch occurs prior to the Week 2 visit, the subject will not be counted as a 
failure in the primary efficacy analysis; however if the switch occurs after Week 2 and the 
subject has HIV-1 RNA ≥50 copies/mL at the time of the switch, the subject will be regarded 
as a failure for the primary efficacy analysis as specified by FDA’s snapshot approach in the 
base study.
During the open-label study extension 1, in order to address issues of drug access, 
tolerability, or subject convenience, single-drug or FDCs of the 4 permitted NRTIs may be 
used, and both TAF and TDF formulations of tenofovir may be used.  (Permitted 
combinations are tenofovir [as TDF or TAF] or ABC, each administered with either FTC or 
3TC).  A switch to another NRTI backbone regimen during study extension 1 for drug 
access, tolerability, or subject convenience reasons will not be counted as a failure in the 
efficacy analysis in open-label extension 1, regardless of viral load at the time of the switch.

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.
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
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.

Refer to Section 7.1.4.1 for the list of information which must be collected when a 
subject discontinues.

Subjects who discontinue early from the study are expected to return for a 14-day post-
therapy follow-up visit. 

Following the completion of study therapy in the base study (at 96 weeks) or in the study 
extensions (at 192, 288, or 384 weeks), or at the time 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.
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.
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.
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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 2 times the recommended daily dose in a 
calendar day for any of the study medications provided.
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.”
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 
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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
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.
Refer to Table 7 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 
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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.
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. 
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).
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Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 7. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Appendix 12.5 for instructions in evaluating adverse events.
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Table 7
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.
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.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
external Data Monitoring Committee regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. The DMC 
will include at least 3 clinicians experienced in infectious disease and 1 external statistician; 
this is in addition to the unblinded trial statistician who will be a non-voting member of the 
committee.  The DMC will monitor the trial at an appropriate frequency, with suggested 
periodic reviews to occur every ~4-6 months during the base study; there will be no 
involvement of the DMC in study extension 1. Details regarding the DMC will be described 
in a charter document.
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.2.9 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
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recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
A DMC recommendation will be communicated to the Sponsor as agreed to in the 
Collaboration agreement.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, along with an 
explanation as to when and why they occurred, will be listed in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.  No 
separate Statistical Analysis Plan (SAP) will be issued for this study.
The key objectives and hypotheses are to be addressed by the base study (double-blind with 
active comparator for 96 weeks).  Thus, between-treatment comparisons that address key 
efficacy and safety objectives will be limited to data from the base study.  Demography, 
efficacy and safety data from study extension 1, for those subjects who continue into 
extension 1, will be summarized separately using descriptive statistics only.  Serious adverse 
event data from study extension 2 and study extension 3 will be summarized separately.
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Efficacy Analyses
The efficacy endpoints, primary analysis population, and statistical methods that will be 
employed for the efficacy analyses are presented in Table 8 below. 
The primary hypothesis will be assessed based upon the proportion of subjects achieving 
HIV-1 RNA <50 copies/mL at Week 48 using the Full Analysis Set (FAS), which includes 
all randomized subjects who have taken at least one dose of study medication and have 
baseline data (for those analyses that require baseline data). The Non-Completer=Failure 
approach (NC=F) as defined by the 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, HIV-1 RNA <40 copies/mL, HIV-1 RNA < 200 copies/mL). All 
missing data will be treated as failures regardless of the reason. 
For the analysis at time points of interest, the difference in proportions between treatment 
groups and the associated 95% confidence interval will be calculated using the stratum-
adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of the 
sample size per arm for each stratum.
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A margin of 10 percentage points is used to define the non-inferiority of MK-1439 100 mg 
q.d. versus darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with 
TRUVADA™or EPZICOM™/KIVEXA™.  This non-inferiority margin is consistent with 
current regulatory agency guidelines for evaluation of drugs in treatment-naïve subjects with 
HIV-1 infection.   MK-1439 100 mg q.d. will be concluded non-inferior to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, if the lower bound of the two-sided 95% CI for the difference in 
the proportion of subjects with HIV-1 RNA<50 copies/mL at Week 48 (MK-1439 100 mg 
q.d. minus darunavir/ritonavir [800 mg/100 mg] q.d.) is greater than -10 percentage points. 
Provided non-inferiority is established, it can be further concluded that MK-1439 100 mg 
q.d. is superior to darunavir/ritonavir (800 mg/100 mg) q.d. if the lower bound of the two-
sided 95% CI for the difference in response rate (MK-1439 100 mg q.d. minus 
darunavir/ritonavir [800 mg/100 mg] q.d.) is greater than zero. The superiority will be tested 
only if the non-inferiority is demonstrated. Due to the principles of closed testing, no 
adjustment for multiplicity is required for the superiority test since non-inferiority can always 
be concluded whenever the data also support superiority. The non-inferiority and superiority 
of MK-1439 100 mg q.d. versus darunavir/ritonavir (800 mg/100 mg) q.d. at Week 96 will be 
assessed using the same approach as for Week 48.  
A sensitivity analysis will be performed using the Observed Failure (OF) approach under 
which non-intermittent missing data for subjects who prematurely discontinued their 
assigned treatment due to lack of efficacy are considered as failures thereafter.
The treatment difference in changes from baseline in CD4 cell count at time points of interest 
will be estimated between the 2 treatment groups. However, these estimates will not be 
subject to an absolute criterion for similarity.  The clinical interpretation of the treatment 
difference is dependent upon the absolute value at baseline and the magnitude and direction 
of the CD4 changes seen in each treatment arm. The OF approach will be used for the 
calculations of 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.
Time to loss of virologic response (TLOVR) will be estimated using Kaplan-Meier product-
limit estimates and graphically displayed. Log rank tests and Cox Proportional Hazards 
models may also be applied to this time-to-event data.
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Table 8
Summary of Analysis Strategy for Efficacy Endpoints
Endpoint/Variable
(Description, Timepoint)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis
Proportion of subjects achieving HIV-1 
RNA <50 copies/mL at Week 48
Stratum-adjusted 
Mantel-Haenszel†
Full Analysis set
NC=F approach
Supportive to the Primary Hypothesis
Proportion of subjects achieving HIV-1 
RNA <50 copies/mL at Week 48
Stratum-adjusted 
Mantel-Haenszel†
Full Analysis set
OF approach
Secondary Hypothesis
Proportion of subjects achieving HIV-1 
RNA <50 copies/mL at Week 96
Stratum-adjusted 
Mantel-Haenszel†
Full Analysis set
NC=F approach 
Supportive to the Secondary Hypothesis
Proportion of subjects achieving HIV-1 
RNA <50 copies/mL at Week 96
Stratum-adjusted 
Mantel-Haenszel†
Full Analysis set
OF approach 
Secondary Objective
Change from baseline in CD4 cell counts 
at Week 48 and Week 96
Two sample t-test
Full Analysis set
OF approach 
assuming 
baseline-
carried-forward
Proportion of subjects achieving HIV-1 
RNA <40 copies/mL at Week 48 and 96
Stratum-adjusted 
Mantel-Haenszel †
Full Analysis set
NC=F approach
Exploratory Objectives
Proportion of subjects achieving HIV-1 
RNA <200 copies/mL at Week 48 and 96
Stratum-adjusted 
Mantel-Haenszel †
Full Analysis set
NC=F approach
Time to Loss of Virological Response 
(TLOVR)
Kaplan-Meier 
product-limit 
estimates; Log-rank 
tests; Cox modeling
Full Analysis set
Not applicable
† Stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of the 
sample size per arm for each stratum.
Safety Analyses
The All Subjects as Treated population will be employed for safety analyses.  For this study, 
there are safety hypotheses (i.e., Tier 1 events) regarding the change from baseline in fasting 
LDL-C and non-HDL-C (non-HDL-C = total cholesterol – fasting HDL-C) at Week 48. The 
change from baseline in fasting lipids (LDL-C, non-HDL-C, total cholesterol, HDL-C and 
triglycerides) will be analyzed using ANCOVA models adjusted by baseline fasting lipids 
level and treatment group. The treatment differences and 95% confidence intervals will be 
provided for all lipids parameters and a p-value for the between treatment comparison will be 
provided for LDL-C and non-HDL-C. The significance of the treatment difference for LDL-
C will be tested first. Sequential testing for non-HDL-C will be done only if superiority is 
established for LDL-C.
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The treatment differences and the associated 95% confidence intervals will be provided for 
the percentage of subjects with the following events based on specific AE categories (i.e., 
Tier-2 events): (1) at least one adverse experience; (2) at least one drug-related adverse 
experience; (3) at least one serious adverse experience; (4) at least one serious and drug-
related adverse experience; (5) discontinuation from study therapy due to an adverse 
experience. Tier-2 events require a minimum of 4 subjects in at least one treatment group. 
These analyses will be performed using the Miettinen and Nurminen method, an 
unconditional, asymptotic method.
Time to discontinuation from study due to an adverse experience will be estimated using 
Kaplan-Meier product-limit estimates and graphically displayed. A log rank test may also be 
applied to analyze this time-to-event data.
Data Monitoring Committee
To supplement the routine safety monitoring outlined in this protocol, an external Data 
Monitoring Committee will monitor ongoing safety data and provide recommendations to 
ensure the safety of study participants and the integrity of the trial. The eDMC will also 
review the interim efficacy data and make a recommendation on study conduct based on the 
pre-defined futility rule. The voting members of the committee are external to the Sponsor.  
The members of the eDMC must not be involved with the trial in any other way (e.g., they 
cannot be trial investigators) and must have no competing interests that could affect their 
roles with respect to the trial. The voting members of the eDMC will include clinicians and 
an external statistician experienced in HIV-1 infection; in addition, an unblinded trial 
statistician who will help prepare the analyses for the eDMC will serve as a non-voting 
member of the committee. Details regarding the eDMC will be described in a charter 
document.
Power and Sample Size
Efficacy
The study will randomize 340 subjects into each treatment arm to achieve 90% power to 
demonstrate the primary hypothesis that MK-1439 100 mg q.d. is non-inferior to 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, at an overall one-sided 2.5% alpha level, as measured by the 
proportion of subjects achieving HIV-1 RNA <50 copies/mL at Week 48 using the Abbott 
RealTime HIV-1 Assay. The power calculation assumes a true response rate of 80% at Week 
48 for both MK-1439 100 mg q.d. arm and darunavir/ritonavir (800 mg/100 mg) q.d arm 
using the NC=F approach as defined by the FDA “snapshot” approach.  A margin of 10 
percentage points is used to define the non-inferiority of MK-1439 100 mg q.d. versus 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™. 
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Safety
MK-1439 Protocol 007 studied 4 doses of MK-1439 versus efavirenz, each in combination 
therapy with TRUVADATM, in HIV-1 infected treatment-naïve subjects. If we assume that 
darunavir/ritonavir has an effect on lipids at least as large as efavirenz, the treatment 
difference in mean change from baseline in fasting lipids observed in Protocol 007 can be 
used as an estimate for the power calculation for this study.
With 340 subjects in each treatment group, the study has >99% power to detect a between 
treatment difference of 14 mg/dL for mean change from baseline in fasting LDL-C. The 
study also has >99% power to detect a between treatment difference of 20 mg/dL for mean 
change from baseline in fasting non-HDL-C.
With 340 randomized subjects in each treatment group, the study has 90% power to declare, 
with 95% confidence, that the true difference between group proportions is no more than 9.9 
percentage points for a reasonably common adverse experience which occurs in 20% of 
subjects receiving either MK-1439 100 mg q.d. or darunavir/ritonavir (800 mg/100 mg) q.d., 
each in combination with TRUVADA™or EPZICOM™/KIVEXA™.
Interim Analysis
Two interim analyses will be performed in this study. The endpoints, timing, and purpose of 
the interim analyses are summarized in Table 9 below.
Although the assessment of neuropsychiatric adverse experiences is not a key objective in 
this study, a low rate of neuropsychiatric AEs associated with MK-1439 is expected to be an 
important attribute for the drug.  Therefore, for administrative reasons, the Sponsor has an 
interest in comparing the neuropsychiatric AE profile of MK-1439 with that of darunavir 
early in the study to determine if the profiles of the 2 drugs are observationally similar.  
Thus, the first interim analysis will occur after 200 subjects have completed Week 8 and will 
assess the overall neuropsychiatric adverse event profile for the MK-1439 group versus the 
control.  A selected list of neuropsychiatric adverse events will be examined.  These include
terms in the following 5 subcategories of events (1) dizziness, (2) sleep disorders and 
disturbances, (3) altered sensorium, (4) depression and suicide/self-injury, and (5) psychosis 
and psychotic disorders.  All such events will be pooled and evaluated as neuropsychiatric
events. Events in each separate subcategory will also be evaluated. MK-1439 and the control 
are expected to have similar neuropsychiatric AE profiles, and high rates of neuropsychiatric
AEs are not expected in this study.  Therefore, this analysis is not expected to lead to a 
termination of the study for safety reasons, and this interim analysis will be considered an 
administrative look at the data for purposes of making a program decision.  
The second interim analysis will be an efficacy analysis, which will be performed for the sole 
purpose of stopping the study for a lack of efficacy (futility). This interim analysis will be 
conducted when complete Week 24 data are available for ~ 340 subjects (i.e. 50% of subjects 
randomized in this study). Details of analysis and futility rule are described in 
Section 8.2.9.1.
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The eDMC will review the results for these 2 interim analyses and make a recommendation 
based on the data.
Table 9
Summary of Interim Analysis Strategy
Key Endpoints for 
Interim Analysis
Timing of 
Interim Analysis
Purpose of 
Interim Analysis
Proportion 
of 
Subjects 
with 
Neuropsychiatric Adverse Events by 
Week 8 
Approximately 200 of randomized 
subjects (~100 subjects on each 
treatment 
group) 
have 
either 
completed the Week 8 visit or 
discontinued before Week 8.
Administrative look
Proportion of Subjects Achieving 
HIV-1 RNA <50 copies/mL at Week 
24
Approximately 340 of randomized 
subjects (~170 subjects on each 
treatment 
group) 
have 
either 
completed the Week 24 visit or 
discontinued before Week 24.
Stop for futility
Statistical Analysis Plan
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee/Clinical Biostatistics department of the Sponsor.
The base study will be conducted as a double-blind study under in-house blinding 
procedures; study extensions 1, 2, and 3, for eligible subjects who elect to continue into these
extensions, will be conducted as open-label studies. At Week 48 of the base study (when the 
primary efficacy hypothesis will be evaluated), a copy of the database will be frozen after 
medical/scientific review has been completed, and data have been declared final and 
complete.  The study (after Week 48, when longer-term safety and efficacy data will be 
evaluated) will be unblinded to the Sponsor with the exception of a limited group of Sponsor 
personnel who will remain blinded at the subject level and continue to be responsible for the 
integrity of the database. All personnel who are unblinded at the subject level will be 
excluded from any future data review at the individual subject level.  The Week 96 analysis 
for the base study will follow the same approach as the Week 48 analysis.  For the purpose of 
the final analysis (after all subjects complete their final visit in study extension 1), the official 
clinical database will not be unblinded until medical/scientific review has been completed, 
and data have been declared final and complete.  Results from Week 96 (base study) and 
from study extension 1 will be presented in separate CSRs (separate from the CSR for the 
Week 48 analysis of the base study).
The designee/Clinical Biostatistics department will generate the randomized allocation 
schedule(s) for study treatment assignment.  Randomization will be implemented in an 
interactive voice response system (IVRS).
The planned interim analyses are described in Section 8.2.9.  Study enrollment is likely to be 
ongoing at the time of the interim analyses.  Blinding to treatment assignment will be 
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maintained at all investigational sites.  The results of the interim analysis will not be shared 
with the investigators prior to the completion of study extension 1.  Subject-level unblinding 
will be restricted to the designated external unblinded statistician and scientific programmer 
performing the interim analysis, who will have no other responsibilities associated with the 
study and are otherwise unaffiliated with the program.
Treatment-level results of the interim analysis will be provided by the designated external
unblinded statistician to the eDMC. Limited Sponsor personnel may be unblinded to the 
treatment-level results of the interim analysis, if required, in order to act on the 
recommendations of the eDMC.  The extent to which individuals are unblinded with respect 
to results of the interim analysis will be documented by the designated external unblinded 
statistician.
The eDMC will serve as the primary reviewer of the results of the interim analyses and will 
make recommendations for discontinuation of the study or protocol modifications to an 
Executive Oversight Committee (EOC) of the Sponsor, who will be responsible for 
implementing the recommendations of the eDMC.  Additional logistical details will be 
provided in the eDMC Charter. Key aspects of the planned interim analyses are described in 
Section 8.2.9.
Separate functional unblinding for pharmacokinetics will be done independent of the above 
interim analyses. Pharmacokinetic measurements will be conducted in support of 
pharmacokinetic evaluations. A small team as specified in a separate Modeling and 
Simulation (M&S) Modeling Analysis Plan, and who are separate from the study team, will 
be unblinded for the purpose of preparing the pharmacokinetic analyses. No interim data or 
results will be shared with the study team before the primary analyses at Week 48 have been 
completed. No decisions will be made based on this functional unblinding that will influence 
the conduct of the trial.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences for the base study and study extension 1 are listed below, followed by the 
descriptions of the derivations of selected endpoints.
An initial description of efficacy measures is provided in Section 4.2.3.
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Proportions of Subjects Achieving HIV-1 RNA <50 copies/mL, <40 copies/mL and 
<200 copies/mL
The proportions of subjects achieving HIV-1 RNA <50 copies/mL, <40 copies/mL and <200 
copies/mL will be estimated at each time point.  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. 
The primary hypothesis will be assessed based upon the proportion of subjects achieving 
HIV-1 RNA <50 copies/mL at Week 48.    
Change from Baseline in CD4 Cell Count
Change from baseline in CD4 cell count will be estimated at each time point at which CD4 
cell count is collected with a key interest at Week 48. 
For the calculations of change from baseline, baseline measurements are defined as the Day 1 
(Randomization) value for each subject. In the rare event when data for this visit are missing, 
the value obtained at the most recent screening visit will be used as baseline.  This rule will 
also be applied to define the baseline measurements for other laboratory tests.
Time to Loss Of Virologic Response (TLOVR)
For subjects who achieve HIV-1 RNA <50 copies/mL and subsequently have 2 consecutive 
HIV-1 RNA values (measured at least 1 week apart) ≥50 copies/mL, time to loss of virologic 
response is the time between Day 1 and the date of the first of the 2 consecutive values ≥50
copies/mL. For subjects who achieve and sustain HIV-1 RNA <50 copies/mL, time to loss of 
virologic response is censored at the time of the last available measurement. For subjects 
who do not achieve HIV-1 RNA values <50 copies/mL, time to loss of virologic response is 
0 weeks. 
Protocol-Defined Virologic Failure (PDVF)
Subjects with protocol-defined virologic failure (PDVF) as defined in Section 4.2.3.1 will be 
identified and summarized for each treatment group.
Resistance
Subjects with protocol-defined virologic failure and those who discontinue for any reason, 
who have blood samples available and potentially amplifiable (>400 copies/mL) for 
resistance testing, will be assessed for resistance to study drugs.
Resistance data from 
subjects with protocol-defined virologic failure and from subjects who discontinue from the 
study will be summarized.  
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For the population PK analysis, descriptive statistics will be provided for Cmin (defined as the 
minimum concentration for an individual subject collected predose). A population PK model 
has been developed utilizing the sparse PK data from Phase 2 and PK data from Phase 1 
studies.  This model will be updated with data from this study in order to assess individual 
exposure to MK-1439 (AUC, Cmax and C24hr) based on the sparse sampling data.
An initial description of safety measures is provided in Section 4.2.3.
Change From Baseline in Fasting Lipids
The change from baseline in fasting lipids (LDL-C, non-HDL-C, total cholesterol, HDL-C, 
and triglycerides) will be analyzed with primary interest in fasting LDL-C and non-HDL-C.
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.
Time to Discontinuation from Study Due to Adverse Experience
In addition to the counts of subjects who discontinued study therapy due to an adverse 
experience, the time to discontinuation from study due to an adverse experience will also be 
estimated.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory tests, subjects must have both a baseline and post-
randomization on-treatment measurement to be included. 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 (i.e., more abnormal in the direction of interest) than 
at baseline.  The criteria are adapted from DIVISION OF AIDS TABLE FOR GRADING 
THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS, PUBLISH DATE: 
AUGUST 2009 Version 1 (Appendix 12.5). A listing of the subjects who meet the criteria 
will be provided.
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Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all randomized subjects who:

receive at least one dose of study treatment and

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 data using the FAS population.  Details on the approach to handling 
missing data are provided in Section 8.2.5 (Statistical Methods).
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.
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 
8.2.5 (Statistical Methods).
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 8.2.5.2. Efficacy 
results that will be considered to be statistically significant after consideration of the strategy 
for controlling the Type-I error are described in Section 8.2.6 (Multiplicity). Nominal p-
values may be computed for other efficacy analyses as a measure of strength of association 
between the endpoint and the treatment effect rather than formal tests of hypotheses. Unless 
otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level.
The key objectives and hypotheses are to be addressed by the base study (double-blind with 
active comparator for 96 weeks).  Thus, between-treatment comparisons that address key 
efficacy and safety objectives will be limited to data from the base study.  Demography, 
efficacy and safety data from study extension 1, for those subjects who continue into 
extension 1, will be summarized separately using descriptive statistics only. Serious adverse 
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event data will be collected and summarized for study extension 2 and study extension 3 
separately.
Time Window
Table 10 lists the definition of time windows and the target relative day for the scheduled 
visits in the study which will be used for all analyses by timepoint. The measurement closest 
to the target date within a window will be used for analyses at a specific timepoint.
Table 10
Definition of Study Timepoint
Treatment 
Phase
Treatment 
Period
Protocol
Time
Day-Range Rules
Target 
Day
CSR Time
Pre-treatment
Baseline
Day 1 
(Baseline)
1
1
Day 1
Treatment
Double-
Blind
Week 2
2 and  21
15
Week 2
Week 4
22and  42
29
Week 4
Week 8
43 and 84
57
Week 8
Week 16
85 and  140
113
Week 16
Week 24
141and  210
169
Week 24
Week 36
211 and 294
253
Week 36
Week 48
295 and 378
337
Week 48
Week 60
379 and 462
421
Week 60
Week 72
463 and 546
505
Week 72
Week 84
547 and 630
589
Week 84
Week 96
631 and the last day of 
double-blind treatment 
period
673
Week 96
Treatment
Open-label 
Study 
Extension 
1
Week 100
first day of open-label 
extension 1 treatment period
and 756
701
Week 100
Week 116
757 and 868
813
Week 116
Week 132
869 and 980
925
Week 132
Week 148
981 and 1092
1037
Week 148
Week 164
1093 and 1204
1149
Week 164
Week 180
1205 and 1302
1261
Week 180
Week 192
1303 and last day of 
open-label extension 1 
treatment period
1345
Week 192
Relative days and target day are counted from the first day of study medication.  
  The clinical study report (CSR) time is the time label to be used in the analysis tables.
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Missing Values
There are 3 types of missing values:
intermittent missing values due to a missed or skipped visit or due to an inadequate 
sample;
non-intermittent missing values due to premature discontinuations because of treatment-
related reasons such as, “clinical adverse experience” (regardless of relationship to study 
drug), “laboratory adverse experience” (regardless of relationship to study drug), and 
“withdrew based on HIV-1 RNA results”;
non-intermittent missing values due to premature discontinuations because of other 
reasons which are not related to treatment such as loss to follow-up, protocol violation, 
subject withdrew consent, etc.
Two approaches will be used to handle missing values (Table 11). The primary approach for 
the analysis of the proportion of subjects achieving HIV-1 RNA <50 copies/mL is the Non-
Completer=Failure (NC=F) approach as defined by the FDA “snapshot” approach. Under 
this approach, only those subjects who 1) are on study assigned double-blind-treatment; 2) 
have HIV-1 RNA measurement(s) within the time window specified in Table 10; and 3) have 
the measurement closest to the target date of the time point <50 copies/mL, can be classified 
as virologic success at that time point. The other subjects, either with HIV-1 RNA 
measurement of ≥50 copies/mL or no virologic data within the time window due to 
intermittent missing or premature discontinuation regardless of reasons, will be considered as 
failures in the analyses of the proportion of subjects achieving HIV-1 RNA <50 copies/mL at 
that timepoint. 
In addition, the protocol allows a subject to switch from one of the study backbone NRTI 
regimens to the other (either from TRUVADA™ to EPZICOM™/KIVEXA™or from 
EPZICOM™/KIVEXA™to TRUVADA™) for management of toxic effects in the base 
study.  If the switch occurs after Week 2 and the subject has HIV RNA ≥50 copies/mL at the 
time of switch, the subject will be regarded as a failure at all timepoints after the switch in 
the base study.  During the open-label study extension, in order to address issues of drug 
access, tolerability, or subject convenience, a subject is allowed to switch from the NRTI 
backbone therapy used during the base study to another one of the allowed NRTI regimens 
permitted during the extension. A switch to another NRTI backbone regimen during study 
extension 1 for drug access, tolerability, or subject convenience reasons will not be counted 
as a failure in the efficacy analysis in the open-label extension, regardless of viral load at the 
time of the switch.
A second approach, the Observed Failure (OF) approach will be performed as a sensitivity 
analysis for the proportion of subjects achieving HIV-1 RNA<50 copies/mL at Week 48.
Under this approach, non-intermittent
missing data for subjects who prematurely 
discontinued assigned treatment due to lack of efficacy are considered as failures at 
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timepoints thereafter. Subjects with other reasons for missing data will be excluded from the 
analyses. 
The same approaches as described above will be used for the analysis of the proportion of 
subjects achieving HIV-1 RNA <40 copies/mL and <200 copies/mL.
Table 11
Summary of the Two Approaches to Handle Missing Values
Approaches§
Intermittent 
Missing
Non-intermittent Missing Not Related to 
Treatment
Non-intermittent Missing Related 
to Treatment
Success at Study 
Therapy 
Discontinuation
Failure at Study 
Therapy 
Discontinuation
Study Therapy 
Discontinuatio
n Due to 
Clinical/Lab 
Adverse 
Experience
Study Therapy 
Discontin-
uation Due to 
Lack of 
Efficacy
OF
Excluded
Excluded
Failures
Excluded
Failures
NC=F
Failure
Failures
Failures
Failures
Failures
§ OF (Observed Failure); NC=F (Non-Completer=Failure) is the primary approach.
Proportion of Subjects Achieving HIV-1 RNA <50 copies/mL
The proportion of subjects achieving HIV-1 RNA < 50 copies/mL will be summarized by 
treatment group at each time point, with primary interest at Week 48. For each time point of 
interest, the difference in proportions between treatment groups and the associated 95% 
confidence interval will be calculated using the stratum-adjusted Mantel-Haenszel method 
with the difference weighted by the harmonic mean of the sample size per arm for each 
stratum.
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 missing data will be treated as failures regardless of the reason.
To provide a full picture of virologic outcome at a timepoint, subjects who are not classified 
as virologic success will be further categorized as virologic failure (HIV-1 RNA ≥50 
copies/mL) or as having no virologic data at the time window with reasons of 1) discontinued 
study due to an AE, 2) discontinued study for other reasons (includes withdraw consent, loss 
to follow-up, moved, etc.), or 3) on study but missing data in window. The full categorization 
of virologic outcome at Week 48 and Week 96 will be summarized by treatment group.
A sensitivity analysis will be performed using the Observed Failure (OF) approach under 
which non-intermittent missing data for subjects who prematurely discontinued assigned 
treatment due to lack of efficacy are considered as failures at timepoints thereafter. This 
sensitivity analysis will be limited to the primary efficacy analysis only (i.e., the proportion 
of subjects achieving HIV-1 RNA <50 copies/mL at Week 48).
A margin of 10 percentage points is used to define the non-inferiority of MK-1439 100 mg
q.d. to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™.  MK-1439 100 mg q.d. will be concluded non-inferior to 
darunavir/ritonavir (800 mg/100 mg) q.d., if the lower bound of the two-sided 95% CI for the 
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difference in the proportion of subjects with HIV-1 RNA<50 copies/mL at Week 48 (MK-
1439 100 mg q.d. minus darunavir/ritonavir [800 mg/100 mg] q.d) is greater than -10 
percentage points. It can be further concluded that MK-1439 100 mg q.d. is superior to 
darunavir/ritonavir (800 mg/100 mg) q.d. if the lower bound of the two-sided 95% CI for the 
difference in response rates (MK-1439 100 mg q.d. minus darunavir/ritonavir [800 mg/100 
mg] q.d.) is greater than zero.
For the summary of virologic response over time, the difference in proportions between 
treatment groups at each time point will also be estimated and the associated two-sided 95% 
CI will be derived in a similar fashion to that described for the primary efficacy analysis.
Proportion of Subjects Achieving HIV-1 RNA <40 copies/mL and <200 copies/mL
The proportion of subjects achieving HIV-1 RNA <40 copies/mL and < 200 copies/mL will 
be analyzed using the same approach as described above for the proportion of subjects 
achieving HIV-1 RNA <50 copies/mL with the exception that no hypothesis will be assessed 
for these endpoints. 
Change from Baseline in CD4 cell counts
Change from baseline in CD4 cell counts will be summarized by treatment group at each 
time point at which CD4 cell count is collected, with a key interest at Week 48. The 
treatment difference in changes from baseline in CD4 cell count at each time point will be 
estimated between the 2 treatment groups. However, these estimates will not be subject to an 
absolute criterion for similarity. The clinical interpretation of the treatment difference is 
dependent upon the absolute value at baseline, and the magnitude and direction of the CD4 
changes seen in each treatment arm. 
The OF approach will be used for the calculations of 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.
Time to Loss Of Virologic Response (TLOVR)
TLOVR will be estimated using Kaplan-Meier product-limit estimates and graphically 
displayed. Log rank tests and Cox Proportional Hazards models may also be applied to this 
time-to-event data. 
Table 8 summarizes the key efficacy analyses of the study. The strategy to address 
multiplicity issues with regard to multiple treatment comparisons, multiple efficacy 
endpoints, multiple timepoints, and/or interim analyses is described in Section 8.2.6 
(Multiplicity) and Section 8.2.9 (Interim Analyses).
Protocol-Defined Virologic Failure (PDVF)
The number of subjects with PDVF will be summarized for each treatment group.
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Resistance
Resistance data from subjects with protocol-defined virologic failure and from subjects who 
discontinue from the study will be summarized.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests and vital signs.
The analysis of safety results will follow a tiered approach (Table 12).  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 predefined 
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 predefined 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 
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 predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs parameters 
will be considered Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, 
and change from baseline values will be provided by treatment group in table format.  
For this protocol, the Tier 1 events are the change from baseline in fasting LDL-C and non-
HDL-C.  Change from baseline in other fasting lipids (total cholesterol, HDL-C, 
triglycerides) will be Tier 2 events. The change from baseline in fasting lipids will be 
analyzed using ANCOVA models adjusted by baseline fasting lipids level and treatment 
group. The treatment differences and 95% confidence intervals will be provided for all lipid
parameters, and p-value for the between treatment comparison will be provided for LDL-C
and non-HDL-C. The significance of treatment difference for LDL-C will be tested first. 
Sequential testing for non-HDL-C will be done only if superiority is established for LDL-C.
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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 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. The difference in percentages between treatment groups and 
the associated 95% confidence interval will be calculated using Miettinen and Nurminen’s 
method [1].
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 method (1985) [1], an unconditional, asymptotic method.
The time to discontinuation from study due to an adverse experience will be estimated using 
Kaplan-Meier product-limit estimates and graphically displayed.
Table 12
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Change from baseline in fasting LDL-C, non-
HDL-C
X
X
X
Tier 2
Change from baseline in other fasting lipids
(total cholesterol, HDL-C, triglycerides)
X
X
Starting lipid-lowering therapy
X
X
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥4
subjects in one of the treatment groups)
X
X
Time to discontinuation from study due to AE
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4of
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital 
Signs)
X
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
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The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of descriptive statistics.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables (e.g., age, gender, race, region, etc.), baseline characteristics, primary 
and secondary diagnoses, and prior and concomitant therapies will be summarized by 
treatment using descriptive statistics for continuous or categorical variables, as appropriate. 
Summary statistics for baseline disease characteristics to be used as efficacy measures such 
as HIV-1 RNA and CD4 cell count will also be provided by treatment.
Summary statistics will be presented for sparsely sampled MK-1439 plasma concentrations. 
PK samples will also be used to update a previously developed population PK model and to 
explore possible PK/PD associations. 
Multiplicity
No multiplicity adjustment is needed in this study to account for multiple efficacy endpoints 
or multiple opportunities to declare success based on the test of the primary efficacy 
hypothesis.  Efficacy analyses other than the primary hypothesis test at Week 48 will be 
considered supportive and/or explanatory. The superiority of MK-1439 to darunavir/ritonavir 
with respect to the primary efficacy endpoint will be tested only if non-inferiority is first 
demonstrated. Due to the principles of closed testing, no adjustment for multiplicity is 
required for the superiority test since non-inferiority can always be concluded whenever the 
data also support superiority. 
The safety hypotheses on fasting LDL-C and non-HDL-C will be tested sequentially. The 
hypothesis for LDL-C will be tested first. Sequential testing for non-HDL-C will be done 
only if superiority is established for LDL-C. Due to the principles of closed testing, no 
adjustment for multiplicity is needed.
However, there are 2 interim analyses planned in the study (see Section 8.1.4). The first 
interim analysis of neuropsychiatric adverse events is not related to efficacy or fasting lipids 
and is considered an administrative look at the data for the purposes of making a program 
decision.  Therefore, it does not affect the Type-I error for the testing of the primary efficacy 
hypothesis or secondary lipid hypotheses. Although the second interim analysis is an efficacy 
analysis, the plan is to stop the study only for lack of efficacy; therefore, there is no need to 
adjust for multiplicity in this setting. However, as it is customary to spend a small amount of 
alpha for interim analyses, an alpha level of 0.00001 will be allocated for each interim 
analysis before testing the primary efficacy hypothesis or secondary lipid hypotheses.  Thus, 
both tests will be conducted at the 2-sided α=0.049998 level.
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Sample Size and Power Calculations
The study will randomize 340 subjects into each treatment arm to achieve 90% power to 
demonstrate the primary hypothesis that MK-1439 100 mg q.d. is non-inferior to darunavir
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™, at an overall one-sided 2.5% alpha level, as measured by the 
proportion of subjects achieving HIV-1 RNA <50 copies/mL at Week 48 using the Abbott 
RealTime HIV-1 Assay. The power calculation assumes a true response rate of 80% at Week 
48 for both the MK-1439 100 mg q.d. arm and darunavir/ritonavir (800 mg/100 mg) q.d arm 
using the NC=F approach as defined by the FDA “snapshot” approach.  A margin of 10 
percentage points is used to define the non-inferiority of MK-1439 100 mg q.d. versus 
darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™or 
EPZICOM™/KIVEXA™.  Given the non-inferiority margin of 10%, the assumed response 
rates in darunavir/ritonavir (800 mg/100 mg) q.d. group and the chosen sample size, non-
inferiority may be established when the observed difference in response rates (MK-1439 100 
mg q.d. minus darunavir/ritonavir [800 mg/100 mg] q.d.) is approximately -3.7% or larger; 
superiority may be concluded when the observed difference in response rates is 
approximately 5.7% or larger. The power calculation is based on an asymptotic method 
proposed by Farrington and Manning (1990) [2] and is carried out using SAS v9.3. Table 13
summarizes the power for the primary comparison under various assumptions for the control 
response rate and underlying difference in response rates. 
Table 13
Power (%) Under Various Assumptions (With 340 Subjects Randomized in 
Each Treatment Group)
Response Rate (%) in 
Darunavir/ritonavir 
(800 mg/100mg) q.d.
Underlying Difference in Response Rates (%)
(MK-1439 100 mg q.d. – Darunavir/ritonavir [800 mg/100mg] q.d.)
-3
-2
-1
0
1
2
3
74
54
65
76
84
91
95
98
77
56
68
79
87
93
96
98
80
60
72
83
90
95
98
99
83
65
77
87
93
97
99
>99
86
70
82
91
96
98
>99
>99
Note:  The power is calculated based on 340 subjects expected to be included in the analysis for each 
treatment group
Lipids
The change from baseline in fasting LDL-C and non-HDL-C at Week 48 will be analyzed 
using ANCOVA models adjusted by baseline fasting lipids level and treatment group. MK-
1439 100 mg q.d. will be concluded to be superior to darunavir/ritonavir (800 mg/100 mg) 
q.d. if the mean change from baseline in fasting LDL-C for the MK-1439 group is 
significantly lower than that for the darunavir/ritonavir group (the p-value for the between 
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treatment comparison is less than 0.04998). If superiority for LDL-C is established, 
sequential testing for non-HDL-C will be conducted at the same α level.
MK-1439 Protocol 007 studied 4 doses of MK-1439 versus efavirenz, each in combination 
therapy with TRUVADATM, in HIV-1 infected treatment-naïve subjects. If we assume that 
darunavir/ritonavir has an effect on lipids at least as large as efavirenz, the treatment 
difference in mean change from baseline in fasting lipids observed in Protocol 007 can be 
used as an estimate for the power calculation for this study.
The estimated between treatment differences in mean changes in fasting LDL-C and non-
HDL-C, based on the interim data from MK-1439 Protocol 007, were 14 mg/dL (standard 
deviation of 20 mg/dL) and 20 mg/dL (standard deviation of 25 mg/dL), respectively. With 
340 subjects in each treatment group, the study has >99% power to detect a between 
treatment difference of 14 mg/dL for mean change from baseline in fasting LDL-C. The 
study also has >99% power to detect a between treatment difference of 20 mg/dL for mean 
change from baseline in fasting non-HDL-C.
Adverse Experiences
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 
96.7% chance of observing at least one adverse experience among 340 subjects in any 
treatment group.  If no adverse experience of that type is observed among the 340 subjects in 
any treatment group, this study will provide 95% confidence that the underlying percentage 
of subjects with that particular adverse experience is <1.1% for the treatment group.
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 number of subjects 
with the AE within each treatment group are provided in Table 14.  These calculations are 
based on the exact binomial method proposed by Clopper and Pearson (1934) [3].
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Table 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers
of Subjects with AEs Among 340
Subjects 
Randomized in Each Treatment Group
Hypothetical Number of  Subjects 
With An Adverse Event
Estimate of Incidence
95% Upper Confidence Bound†
0
0%
1.1
5
1.5%
3.4
10
2.9%
5.3
15
4.4%
7.2
20
5.9%
8.9
25
7.4%
10.7
30
8.8%
12.4
† Based on the two-tailed exact confidence interval for a binomial proportion (Clopper and Pearson, 1934).
Table 15 gives the difference in the incidence of adverse experience (MK-1439 100 mg q.d. 
– darunavir/ritonavir [800 mg/100mg] q.d.) that can be ruled out with different power levels 
and 95% confidence when there are 340 subjects in each treatment group.  The underlying 
incidence of adverse experiences is assumed to be the same for the 2 treatment groups. For a 
reasonably common adverse experience which occurs in 20% of subjects either in the MK-
1439 100 mg q.d. arm or darunavir/ritonavir (800 mg/100mg) q.d. arm, the study has 90% 
power to declare with 95% confidence that the true difference between the treatment groups 
is no more than 9.9 percentage points. The calculations are based on an asymptotic method 
proposed by Farrington and Manning (1990) [2].
Table 15
Differences
in Incidences
of AEs
(MK-1439 100 mg q.d. minus 
Darunavir/ritonavir [800 mg/100mg] q.d.) That Can Be Ruled Out With 340
Subjects in Each Treatment Group
Difference† in Percentage Points That Can Be Ruled Out with Target 
Power Assuming the Underlying Incidence of the AE is
Target Power
10%
20%
30%
40%
50%
80
6.4
8.6
9.8
10.5
10.7
85
6.9
9.2
10.5
11.3
11.5
90
7.5
9.9
11.4
12.2
12.4
95
8.3
11.1
12.7
13.5
13.8
†The upper bound of the two-sided 95% confidence interval (Farrington and Manning (1990) for the 
difference in AE incidences (MK-1439 100 mg q.d. minus darunavir/ritonavir [800 mg/100mg] q.d.) 
assuming the incidences are the same.
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Subgroup Analyses and Effect of Baseline Factors (Base Study)
To determine whether the treatment effect is consistent across various subgroups, the
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be calculated and plotted within each category of the following classification 
variables:

Age category (≤median vs. >median)

Gender (female, male)

Region (North America, South America, Europe, Asia, Africa, etc.) 

Race (White, Black, Asian, Other)

Ethnicity (Hispanic/Latino, not Hispanic/Latino)

Screening HIV-1 RNA categories (HIV-1 RNA ≤100,000 copies/mL, HIV-1 RNA 
>100,000 copies/mL)

Baseline HIV-1 RNA categories (HIV-1 RNA ≤100,000 copies/mL, HIV-1 RNA 
>100,000 copies/mL)

Chronic Hepatitis B or C status (HBV/HCV-infected or HBV/HCV-uninfected)

Baseline CD4 categories (<50, 50-200, and >200 cells/mm3)

NRTI background therapy (TRUVADA™, EPZICOM™/KIVEXA™)
The Observed Failure approach will be used to handle missing values in these subgroup 
analyses.
Interim Analyses
One efficacy interim analysis will be performed for the sole purpose of stopping the study for 
a lack of efficacy (futility). Key aspects of this interim analysis are described in this section.  
Additional logistical details will be provided in the eDMC Charter.
Interim Futility Analysis at Week 24
The interim analysis will be performed when approximately 340 subjects randomized in the 
study (~170 subjects per treatment group) either complete Week 24 visit or discontinue 
before Week 24. There will be no pause in the enrollment for this interim analysis. Based on 
the observed proportion of subjects with HIV-1 RNA <50 copies/mL at Week 24, if the 
conditional power for demonstrating non-inferiority in the final analysis of the primary 
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hypothesis at Week 48 is <20%, the study may be stopped and all subjects in the MK-1439 
100 mg q.d. group will be switched to standard therapy.  For example, if at Week 24, the 
response rate in MK-1439 100 mg q.d. group is <74.4% and the response rate in the 
darunavir/ritonavir (800 mg/100 mg) q.d. group is 80%, the conditional probability of 
demonstrating non-inferiority in the final analysis will be <20% (assuming similar response 
rates are seen at Week 48) and the study may be stopped.  There is approximately a 9.8%
chance of stopping the study based on Week 24 data from 170 subjects per treatment group 
when in fact the true response rate in both treatment groups is 80%. 
Type-I/II Error Control for Interim Analyses
As the only purpose of the planned interim analyses is to stop the study for lack of efficacy, 
no adjustment for Type-I error is necessary.  However, as it is customary to spend a small 
amount of alpha for interim analyses, an alpha level of 0.00001 will be allocated to this 
interim analysis. On the other hand, as there is a chance that the study may be stopped early 
for lack of efficacy, albeit small, there is a reduction in the overall power (i.e., inflation of the 
Type II error) of the study. Using conditional power <20% as the stopping criterion at interim 
analysis, the overall power of the study will reduce to 86%.  If the stopping criterion is not 
met at the interim analysis, the conditional probability of demonstrating non-inferiority in the 
final analysis will increase to 94% (assuming 80% response rates for both treatment groups).
To supplement the routine safety monitoring outlined in this protocol, the eDMC will 
monitor ongoing safety data and provide recommendations to ensure the safety of study 
participants and the integrity of the trial to the EOC (see Section 7.3.3). The eDMC will 
monitor the trial at an appropriate frequency, with suggested periodic reviews to occur every 
~4-6 months. Details regarding the eDMC will be described in a charter document. 
One interim analysis will occur after 200 subjects (~100 subjects per treatment group) have 
completed Week 8 and will assess the overall neuropsychiatric adverse event profile for the 
MK-1439 group versus control.  A selected list of neuropsychiatric adverse events will be 
examined.  These include terms in the following 5 subcategories of events (1) dizziness, (2) 
sleep disorders and disturbances, (3) altered sensorium, (4) depression and suicide/self-
injury, and (5) psychosis and psychotic disorders. All such events will be pooled and 
evaluated as neuropsychiatric events. Events in each subcategory will also be evaluated 
separately.  
MK-1439 and the control are expected to have similar neuropsychiatric AE profiles, and high 
rates of neuropsychiatric AEs are not expected in this study. Therefore, this analysis is not 
expected to lead to a termination of the study for safety reasons, and this will be considered 
an administrative look at the data for purposes of making a program decision. No adjustment 
for Type-I error is necessary. However, as it is customary to spend a small amount of alpha 
for interim analyses, an alpha level of 0.00001 will be allocated to this interim analysis.
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Compliance (Medication Adherence)
Study Medication Diary Cards will be used to ensure and document the drug compliance.
Subjects are to take one pill once daily from each of 4 bottles/containers of study medication
during the base study.  For the main analysis of compliance in the base study, a day within 
the study will be considered an “On-Therapy” day if the subject takes at least one tablet from 
any bottle/container provided for this study. 
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:
Percent Compliance=
Number of Days on Therapy
x 100
Number of Days Should be on Therapy
Summary statistics will be provided on percent compliance by treatment group for the FAS
population.
A second analysis using a different definition of compliance will also be conducted for the 
base study.  In this analysis, a day within the study will be considered an “On-Therapy” day 
only if the subject takes the required number of tablets from all bottles/containers provided 
for this study (as noted in Section 7.1.5.2.1) will also be summarized.
During study extension 1, MK-1439 will be provided as study medication by the sponsor and 
2 NRTIs will be selected and supplied by investigator. Compliance with MK-1439 
administration will be summarized for study extension 1. A day within the study will be 
considered an “On-Therapy” day if the subject takes 1 tablet of MK-1439. 
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 for study 
extension 3.
Extent of Exposure
The extent of exposure to study therapy for all randomized and 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.
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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: Base Study and Study Extensions
Product Name & Potency
Dosage Form
Base Study
MK-1439 100 mg
Oral Compressed Tablet
Placebo to match MK-1439 100 mg
Oral Compressed Tablet
Darunavir 800 mg
Film-coated Tablet
Placebo to match darunavir 800 mg
Film-coated Tablet
Ritonavir 100 mg
Film-coated Tablet
Placebo to ritonavir 100 mg
Film-coated Tablet
TRUVADA™ (emtricitabine 200 mg and tenofovir 
disoproxil fumarate 300 mg)
Film-coated Tablet
EPZICOM™/KIVEXA™(abacavir sulfate 600 mg 
and lamivudine 300 mg)
Film-coated Tablet
Study Extensions
MK-1439 100 mg
Oral Compressed or Film-coated Tablet
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.
During the base study, subjects will receive both blinded (Bottles A, B and C) and open label
(Bottle D or Container E) bottles in accordance with the dispensing schedule. No kitting will 
be required. During the study extensions, subjects will receive Bottle F (oral compressed 
tablets) or, if subsequently available, Bottle G (film-coated tablets).
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment. 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 
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electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind subjects and to unmask treatment/vaccine identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
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.
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
For trials using Controlled Substances, all Federal, State, Province, Country, etc. regulations 
must be adhered to in regard to the shipping, storage, handling and dispensing of controlled 
substances. Additionally, the investigator should have the appropriate controlled drug 
license(s) as mandated by Federal, State, Province, Country, etc. laws in which the trial is 
being conducted.
Trial site personnel will have access to a central electronic 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 
drugs PREZISTA™(darunavir 800 mg) and NORVIR™(ritonavir 100 mg) as much as 
possible. You did not receive the active  drugs PREZISTA™(darunavir 800 mg) and 
NORVIR™(ritonavir 100 mg) as manufactured by Janssen Pharmaceuticals, Inc. and 
AbbVie, Inc., respectively.”
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.
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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 
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 
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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 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 discarding 
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 
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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 
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 
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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 
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. Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4:213-226.
2. 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.
3. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
binomial. Biometrika 1934; 26: 404-13.
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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 DNA and plasma specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug/vaccine.  The DNA and plasma
specimen(s) will be stored to provide a resource for future trials conducted by MSD
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 MSD or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
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 (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation, and plasma specimens will usually be 
obtained at a time when the subject is having blood drawn for other trial purposes. 
Specimens like tissue and bone marrow will usually be obtained at a time when the 
subject is having such a procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the MSD
approved policies and procedures for specimen handling and preparation.
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, MSD has developed secure policies and procedures.  All 
specimens will be de-identified 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.  
This first code will be replaced with a second code at a MSD designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the MSD designated facility to an Entrusted Keyholder at MSD.  The 
second code will be logged into the primary biorepository database at MSD and, in this 
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database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the MSD Entrusted Keyholder under strict security policies and procedures.  The MSD
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
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 MSD using the designated mailbox 
(clinical.specimen.management@MSD.com) and a form will be provided by MSD 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 MSD 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. 
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7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  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 MSD 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 MSD policies and procedures and this 
destruction will be documented in the biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by MSD on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
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 as 
to how to offer clinical diagnostic  testing (paid for by MSD) to subjects enrolled and will 
be advised that counseling should be made available for all who choose to participate in 
this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, MSD will publish the results without revealing specific 
subject information, inform all trial sites who participated in the MSD clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
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10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on MSD clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
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. 
MSD 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure MSD database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
14. 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
Screening through Week 48 (Base Study)
Week (Visit)
Screen
(V1)
Randomization 
Day 1
(V2)
2
(V3)
4
(V4)
8
(V5)
16
(V6)
24
(V7)
36
(V8)
48
(V9)
Hematology
2
2
2
2
2
2
2
2
2
CD4/CD8 cell count
2
2
2
2
Chemistry
12a
7
7
7
7
7
7
7 
7 
PT/INR and APTT
4.5
HLA
8.5   
HIV-1/HIV-2 Ab screen
8.5   
Hepatitis testing
8.5
Plasma viral RNA 
10
10
10
10
10
10
10
10
10
Plasma for viral resistance 
14  
Blood for Pharmacokinetics 
– Pop PK b
4  
4  
4  
8  
8  
Blood (DNA) for Future 
Biomedical Research
8.5
Plasma for Future 
Biomedical Research 
10
10
TOTAL for visit (mL)
69
43.5
19
23 
23  
19
29 
19
39  
Total (tablespoons) c
4.6
2.9  
1.3  
1.5  
1.5  
1.3   
1.9  
1.3   
2.6  
a Included Serum -human chorionic gonadotropin (hCG) test
b Sample(s) for population PK will be collected. At Day 1 and Week 4 the sample must be collect predose.  At weeks 24 and 48, the samples must be collected predose and 
within 0.5 to 2 hours postdose; and at Week 8, the samples may be collected irrespective of time of dose.
c One Tablespoon = 15 mL.
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Week 60 Through Post 14 Day Follow- up (Base Study)
Week
60
(V10)
72
(V11)
84
(V12)
96
(V13)
Viral Failure 
Confirmation 
(U)
Early 
Discontinuation 
(U)
Post 14-Day 
Follow-up 
(99)
Total Volume
in Base Study
Hematology
2
2
2
2
2
2
2
30
CD4/CD8 cell count
2
2
12 
Chemistry
7
7
7
7 
7
7
7 
110  
PT/INR and APTT
4.5
HLA
8.5
HIV-1/HIV-2 Ab screen
8.5
Hepatitis testing
8.5  
Plasma viral RNA 
10
10
10
10
10
10 
10 
150
Plasma for viral resistance 
14  
14  
42  
Blood for Pharmacokinetics –
Pop PK
28  
Blood 
(DNA) 
for 
Future 
Biomedical Research
8.5
Plasma for Future Biomedical 
Research 
10
30
Total for visit (mL)
19
21  
19
31
33
33
19
438.5  
Total (tablespoons) a 
1.3  
1.3  
1.3  
2.1  
2.2
2.2
  1.3
~29.2  
a One tablespoon = 15 mL
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Week 100 Through Post-Study 14-Day Follow-up (Study Extension 1)
Week (Visit)
100
(V14)
116
(V15)
132
(V16)
148
(V17)
164
(V18)
180
(V19)
192
(V20)
Viral Failure 
Confirmation
(U)
Early 
Discontinuation
(U)
Post-Study
14-Day 
Follow-up 
(99)
Total Vol. 
in Study 
Extension a
Hematology
2
2
2
2
2
2
2
2
2
2
18
CD4/CD8 cell count
2
2
2
6
Chemistry
7
7
7
7
7
7
7
7
7
7
63
Plasma viral RNA 
10
10
10
10
10
10
10
10
10
10
90
Plasma for viral 
resistance 
14
14
28 
Blood (DNA) for 
Future Biomedical 
Research 
0
Plasma for Future 
Biomedical Research
0
TOTAL for visit (mL)
21
19
19
21
19
19
21
33
33
19
203 
Total (tablespoons) b
1.4
1.3
1.3
1.4
1.3
1.3
1.4
2.2
2.2
1.2
13.5
a These samples are in addition to those collected during the base study.  Because an early discontinuation visit could potentially happen during the base study or study 
extension 1, but not both, and because there is no post-study follow-up visit after the base study for subjects who continue into the extension, the total volume for both base 
study and extension is less than the sum.
b One tablespoon = 15 mL.
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Guidelines for Grading Severity of Laboratory Adverse Experiences for Toxicity Management
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
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 
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 
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LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY 
LIFE-THREATENING
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).
Adapted from DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS, 
PUBLISH DATE: 28 Dec-04/Clarification Aug 09 DECEMBER.
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Plasma Assay—Sample Collection, Handling, Labeling, Storage, and Shipment
See Laboratory Manual.
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List of Abbreviations and Acronyms
3TC
Lamivudine
ABC
Abacavir
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 
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
CYP
Cytochrome
DAIDS
Division of Acquired Immunodeficiency Syndrome
DILI
Drug-Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECI
Event of clinical interest
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
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL-C
High-Density Lipoprotein Cholesterol
HIV-1
Human Immunodeficiency Virus Type 1
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IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization 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
IUD
Intrauterine Device
IVRS/IWRS
Interactive Voice Response System/Integrated Web Response System
LDL-C
Low-Density Lipoprotein Cholesterol
LOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
N(t)RTI
Nucleotide Reverse Transcriptase Inhibitor
NC=F
Non-Completer = Failure
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 
PT
Prothrombin Time 
q.d.
Once Daily
RBC
Red blood cell
RNA
Ribonucleic acid
SOC
System Organ Class
(s)SAP
(supplemental) Statistical Analysis Plan
SoA
Schedule of Assessments
TAF
Tenofovir Alafenamide Fumarate  
TDF
Tenofovir Disoproxil Fumarate
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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