Clinical trial NCT02629822
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-01-14; Completion date: 2020-10-28
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objectives of this study are to evaluate the antiretroviral activity and the safety/tolerability of open-label doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF; MK-1439A; DELSTRIGO™) consisting of a single fixed-dose combination (FDC) tablet of DOR/3TC/TDF 100 mg/300 mg/300 mg in treatment-naïve HIV-1 infected participants with select non-nucleoside reverse transcriptase inhibitor (NNRTI) transmitted resistance-associated mutations.

Detailed description:
This study had a Base Study (Day 1 to Week 96) and an optional Study Extension (Week 96 to Week 192).

Arms: arm 1: Treatment-naïve HIV-1 infected participants with NNRTI transmitted resistance-associated mutations were treated with open-label MK-1439A (DOR/3TC/TDF 100mg/300mg/300mg) as a FDC tablet taken once daily by mouth for 96 weeks in the Base Study. In addition, eligible participants continued to receive the same MK-1439A regimen from Week 96 to Week 192 during the Extension Study.
Interventions: intervention 1: Doravirine/lamivudine/tenofovir disoproxil fumarate
Intervention descriptions: intervention 1: FDC tablet containing MK-1439 (doravirine) 100 mg / lamivudine 300 mg / tenofovir disoproxil fumarate 300 mg taken by mouth.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02629822  
Document Date: 
05-Jun-2017
A Phase IIa Multicenter, Open-Label Clinical Trial to Evaluate the 
Safety and Efficacy of MK-1439A in Treatment-Naïve HIV-1 
Infected Subjects with Selected Non-Nucleoside Reverse 
Transcriptase Inhibitor (NNRTI) Transmitted Resistance Mutations


Product:  MK-1439A 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as the 
Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase IIa Multicenter, Open-Label Clinical Trial to Evaluate the Safety and Efficacy of 
MK-1439A in Treatment-Naïve HIV-1 Infected Subjects with Selected Non-Nucleoside 
Reverse Transcriptase Inhibitor (NNRTI) Transmitted Resistance Mutations
IND NUMBER:  124997
EudraCT NUMBER:  2015-003616-20
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
TRIAL SUMMARY.................................................................................................. 13
1.0
TRIAL DESIGN........................................................................................................ 13
2.0
Trial Design ........................................................................................................... 13
2.1
Trial Diagram........................................................................................................ 15
2.2
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16
3.0
Primary Objective(s) & Hypothesis(es) .............................................................. 16
3.1
Base Study .......................................................................................................... 16
3.1.1
Secondary Objective(s) & Hypothesis(es)........................................................... 16
3.2
Base Study .......................................................................................................... 16
3.2.1
Exploratory Objectives......................................................................................... 17
3.3
Base Study .......................................................................................................... 17
3.3.1
Study Extension .................................................................................................. 17
3.3.2
BACKGROUND & RATIONALE.......................................................................... 17
4.0
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Rationale................................................................................................................ 19
4.2
Rationale for the Trial and Selected Subject Population .................................... 19
4.2.1
Rationale for Study Design................................................................................. 21
4.2.2
Rationale for Dose Selection/Regimen............................................................... 21
4.2.3
Rationale for Endpoints ...................................................................................... 23
4.2.4
4.2.4.1
Efficacy Endpoints....................................................................................... 23
4.2.4.2
Safety Endpoints .......................................................................................... 23
4.2.4.3
Pharmacokinetic Endpoints ......................................................................... 24
4.2.4.4
Planned Exploratory Biomarker Research................................................... 24
4.2.4.5
Future Biomedical Research........................................................................ 24
Rationale for Study Extension ............................................................................ 24
4.2.5
Benefit/Risk ........................................................................................................... 25
4.3
 
 
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METHODOLOGY ................................................................................................... 25
5.0
Entry Criteria........................................................................................................ 25
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 25
5.1.1
Subject Inclusion Criteria.................................................................................... 25
5.1.2
Subject Exclusion Criteria .................................................................................. 28
5.1.3
Trial Treatment(s) ................................................................................................ 29
5.2
Dose Selection .................................................................................................... 30
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 30
5.2.1.2
Dose Modification/Interruption During the Base Study or the Study 
Extension ..................................................................................................... 30
Timing of Dose Administration .......................................................................... 31
5.2.2
Trial Blinding/Masking....................................................................................... 31
5.2.3
Randomization or Treatment Allocation............................................................ 31
5.3
Stratification.......................................................................................................... 31
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 31
5.5
Rescue Medications & Supportive Care............................................................. 33
5.6
Diet/Activity/Other Considerations..................................................................... 33
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 33
5.8
Subject Replacement Strategy............................................................................. 35
5.9
Beginning and End of the Trial ........................................................................... 35
5.10
Clinical Criteria for Early Trial Termination ................................................... 35
5.11
TRIAL FLOW CHART ........................................................................................... 36
6.0
TRIAL PROCEDURES ........................................................................................... 43
7.0
Trial Procedures ................................................................................................... 43
7.1
Administrative Procedures.................................................................................. 43
7.1.1
7.1.1.1
Informed Consent......................................................................................... 43
7.1.1.1.1
General Informed Consent.................................................................... 43
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 43
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 44
7.1.1.3
Subject Identification Card .......................................................................... 44
7.1.1.4
Medical History ........................................................................................... 44
 
 
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7.1.1.5
Prior and Concomitant Medications Review ............................................... 44
7.1.1.5.1
Prior Medications.................................................................................. 44
7.1.1.5.2
Concomitant Medications..................................................................... 44
7.1.1.6
Assignment of Screening Number............................................................... 44
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 45
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 45
Clinical Procedures/Assessments........................................................................ 45
7.1.2
7.1.2.1
Physical Examination................................................................................... 45
7.1.2.2
Height Assessment....................................................................................... 46
7.1.2.3
Vital Signs and Weight ................................................................................ 46
7.1.2.4
12-Lead ECG (performed locally) ............................................................... 46
7.1.2.5
Adverse Events ............................................................................................ 47
7.1.2.6
Toxicity Management .................................................................................. 47
7.1.2.7
Birth Control Confirmation.......................................................................... 47
Laboratory Procedures/Assessments .................................................................. 48
7.1.3
7.1.3.1
Serum/Urine Pregnancy Test ....................................................................... 48
7.1.3.2
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 48
7.1.3.3
HIV/Hepatitis Screening.............................................................................. 49
7.1.3.4
Virology Test ............................................................................................... 49
7.1.3.5
Viral Resistance Testing .............................................................................. 49
7.1.3.6
CD4 Cell Counts.......................................................................................... 50
7.1.3.7
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 50
7.1.3.8
Planned Genetic Analysis Sample Collection.............................................. 51
7.1.3.9
Future Biomedical Research Sample Collection ......................................... 51
Other Procedures................................................................................................. 51
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 51
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 51
7.1.4.2
Blinding/Unblinding .................................................................................... 52
7.1.4.3
Calibration of Critical Equipment................................................................ 52
Visit Requirements.............................................................................................. 52
7.1.5
7.1.5.1
Screening...................................................................................................... 52
7.1.5.2
Treatment Period Visits (Visits 2 – 14) ....................................................... 53
 
 
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7.1.5.3
Treatment Period Visits for Study Extension (Visit 15-20)......................... 54
7.1.5.4
Virologic Failure Confirmation Visit........................................................... 55
7.1.5.5
Early Discontinuation Visit.......................................................................... 56
7.1.5.6
Post-Trial...................................................................................................... 56
Assessing and Recording Adverse Events .......................................................... 56
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 57
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 57
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 58
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 58
7.2.3.2
Events of Clinical Interest............................................................................ 59
Evaluating Adverse Events ................................................................................. 60
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 63
7.2.5
STATISTICAL ANALYSIS PLAN ........................................................................ 63
8.0
Statistical Analysis Plan Summary ..................................................................... 63
8.1
Responsibility for Analyses/In-House Blinding ................................................. 65
8.2
Hypotheses/Estimation ......................................................................................... 65
8.3
Analysis Endpoints ............................................................................................... 65
8.4
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..................................... 65
8.4.1
Safety Endpoints ................................................................................................. 66
8.4.2
Analysis Populations............................................................................................. 66
8.5
Efficacy Analysis Populations ............................................................................ 67
8.5.1
Safety Analysis Populations ............................................................................... 67
8.5.2
Statistical Methods................................................................................................ 67
8.6
Statistical Methods for Efficacy Analyses .......................................................... 67
8.6.1
Statistical Methods for Safety Analyses ............................................................. 71
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 71
8.6.3
8.6.3.1
Demographic and Baseline Characteristics ................................................. 71
8.6.3.2
Population PK Analyses .............................................................................. 72
Interim Analyses ................................................................................................... 72
8.7
Multiplicity ............................................................................................................ 72
8.8
Sample Size and Power Calculations .................................................................. 73
8.9
 
 
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Sample Size and Power for Efficacy Analyses ................................................... 73
8.9.1
Sample Size and Power for Safety Analyses ...................................................... 73
8.9.2
Subgroup Analyses and Effect of Baseline Factors (Base Study)..................... 73
8.10
Compliance (Medication Adherence).................................................................. 74
8.11
Extent of Exposure................................................................................................ 74
8.12
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
9.0
SUPPLIES ................................................................................................................. 74
Investigational Product ........................................................................................ 74
9.1
Packaging and Labeling Information ................................................................. 75
9.2
Clinical Supplies Disclosure................................................................................. 75
9.3
Storage and Handling Requirements.................................................................. 75
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 75
9.5
Standard Policies................................................................................................... 75
9.6
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 76
10.0
Confidentiality....................................................................................................... 76
10.1
Confidentiality of Data ....................................................................................... 76
10.1.1
Confidentiality of Subject Records..................................................................... 76
10.1.2
Confidentiality of Investigator Information........................................................ 76
10.1.3
Confidentiality of IRB/IEC Information............................................................. 77
10.1.4
Compliance with Financial Disclosure Requirements....................................... 77
10.2
Compliance with Law, Audit and Debarment ................................................... 77
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 79
10.4
Quality Management System............................................................................... 79
10.5
Data Management................................................................................................. 79
10.6
Publications ........................................................................................................... 80
10.7
LIST OF REFERENCES......................................................................................... 81
11.0
APPENDICES........................................................................................................... 82
12.0
Merck Code of Conduct for Clinical Trials........................................................ 82
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 84
 
 
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Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 88
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................... 99
Plasma Assay – Sample Collection, Handling, Labeling, Storage, and 
12.5
Shipment.............................................................................................................. 102
List of Abbreviations and Acronyms ................................................................ 103
12.6
Division of AIDS Table for Grading the Severity of Adult and Pediatric 
12.7
Adverse Events.................................................................................................... 105
Child-Pugh Score for Cirrhosis Mortality........................................................ 112
12.8
SIGNATURES......................................................................................................... 113
13.0
Sponsor's Representative ................................................................................... 113
13.1
Investigator.......................................................................................................... 113
13.2
 
 
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LIST OF TABLES
    
Table 1  Antiviral Activity IC50 (nM), in 100% NHS Viking Assay...................................... 20
Table 2  Trial Treatment During Base Study and Study Extension........................................ 30
Table 3  Prohibited Medications/Therapy Due to MK-1439 Interactions.............................. 33
Table 4  Laboratory Tests ....................................................................................................... 48
Table 5  Pharmacokinetic Sampling Timepoints.................................................................... 51
Table 6  Evaluating Adverse Events....................................................................................... 61
Table 7  Definition of Study Timepoint.................................................................................. 68
Table 8  Summary of the Two Approaches to Handle Missing Values.................................. 69
Table 9  Analysis Strategy for Key Efficacy Variables.......................................................... 70
Table 10  Product Descriptions............................................................................................... 74
 
 
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LIST OF FIGURES
          
Figure 1 Trial Design for Base Study .................................................................................... 15
Figure 2  Trial Design for Study Extension............................................................................ 16
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Multiple (Specified below)
Multiple
Enrollment discontinued after 
10 subjects were enrolled.
Enrollment stopped due to an 
assessment of lack of feasibility 
of recruiting enough subjects 
who met the study entry criteria 
in a reasonable period of time.
8.0
8.1 
8.7 
8.9.1
Statistical Analysis
Interim Analysis
Sample 
Size 
for 
Efficacy 
Analysis
As the enrollment target was 
changed from 60 to 10, the 
following 
changes 
to 
the 
statistical analysis were made: 
The first futility analysis will 
be conducted with all evaluable 
subjects.
The criterion for excluding 
subjects 
who 
were 
non-
compliant 
with 
study 
medication from the second 
futility analysis was added.
The sample size and power 
calculations were updated.
Updated due to change in
number of subjects enrolled.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
Trial Summary
Section updated to reflect the 
change in target enrollment 
(number of subjects to be 
enrolled was changed from 60 
to 10).
Enrollment stopped due to an 
assessment of lack of feasibility 
of recruiting enough subjects 
who met the study entry criteria 
in a reasonable period of time.
2.1
Trial Design
The rationale for amendment -
01 was removed. The rationale 
for -02 amendment (change in 
number of subjects enrolled) 
was added. 
Removed language regarding 
stratification.
Updated due to change in 
number of subjects enrolled. 
Given an updated number of 
subjects enrolled, the initial 
stratification plan is no longer 
applicable.
2.2
Trial Diagram
Statement 
added 
indicating 
subjects who continue into the 
study extension will have a 
single 14 day follow-up visit at 
the end of the study extension 
only and not in the base study.
Clarification that subjects who 
continue in the extension only 
need the 14-day follow-up at 
the end of the study extension.
2.2
Trial Diagram
Figure 1 “Trial Diagram for 
Base Study” was updated to 
reflect the number of subjects 
enrolled. 
Updated due to change in 
number of subjects enrolled.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.2.1
Rationale for the Trial and 
Selected Subject Population
Table 1, second row, the term 
“MK-1495” was changed to 
“MK-1439.” 
Typographical error corrected.
5.4 
Stratification 
Removed language regarding 
stratification.
Given the number of subjects 
enrolled, 
the 
initial 
stratification plan is no longer 
applicable.
7.1.2.5
Adverse Event 
Updated 
instructions 
for 
documenting adverse events.
To 
clarify 
evaluation 
for
relationship/causality of IRIS.
 
 
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TRIAL SUMMARY
1.0
Abbreviated Title
MK-1439A in treatment-naïve HIV-1 infected subjects with NNRTI 
transmitted resistance
Trial Phase
Phase IIa
Clinical Indication
Treatment of HIV-1 Infection
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-1439A q.d.
Number of trial subjects
Approximately 10 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 5 years 
from the time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
Duration of Participation
For subjects who participate in the base study only, but do not 
continue into the study extension, each subject will participate in the 
trial for approximately 104 weeks, from the time the subject signs the 
Informed Consent Form (ICF) through the final contact.  For subjects 
who do continue into the study extension, each subject will participate 
for approximately 200 weeks from the time the subject signs the ICF 
through the final contact.  
After a screening phase of up to 45 days, each subject will receive 
assigned treatment for approximately 96 weeks in the base study; for 
subjects who continue into the study extension, study treatment will 
continue for an additional 96 weeks, approximately, through a total of 
approximately 192 weeks of treatment.  After the end of treatment,
each subject will be followed for 14 days. Subjects who do not
continue into the study extension will be followed through 14 days
after the Week 96 treatment visit, while subjects who continue into
the study extension will be followed through 14 days after the
Week 192 visit.
A list of abbreviations used in this document can be found in Section 12.6.
TRIAL DESIGN
2.0
Trial Design
2.1
This is a multicenter, open-label trial to evaluate the safety and efficacy of MK-1439A once 
daily (q.d.) in antiretroviral treatment-naïve subjects with human immunodeficiency virus 
type 1 (HIV-1) infection with selected non-nucleoside reverse transcriptase inhibitor 
(NNRTI) transmitted resistance mutations.  The study includes a 96 week base study and a 
96 week study extension to collect long-term efficacy and safety data with MK-1439A.  The 
study is to be conducted in conformance with Good Clinical Practice.
 
 
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MK-1439A is a single tablet fixed-dose combination (FDC) that combines MK-1439, an 
investigational NNRTI with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), 2 
approved and marketed nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).  A 
single tablet of MK-1439A contains a full daily HIV treatment regimen of MK-1439 100 mg 
+ lamivudine 300 mg + TDF 300 mg. 
Subjects are considered evaluable if they receive study treatment and have one of the three 
NNRTI resistance mutations confirmed by the central laboratory and present as a single 
mutation (i.e., subjects with multiple mutations are not eligible to enroll).  The duration of 
treatment for a given subject is 96 weeks in the base study.  The primary efficacy endpoint of 
the study is the proportion of subjects with HIV-1 RNA <50 copies/mL (by the Abbott 
RealTime HIV-1 Assay) at Week 48.  
At Study Week 96 (visit 14 flow chart A) subjects who meet the following criteria will be
eligible to enter the study extension: (1) completed the Week 96 (visit 14) study visit, (2) 
considered by the investigator to have derived benefit from participation in the base study,
(3) further treatment with MK-1439A is considered
clinically appropriate by the
investigator, and (4) have provided informed consent to continue into the study extension,
thus continuing study treatment for approximately 96 weeks beyond the base study.
The total duration of treatment for a given subject in the base study will be 96 weeks 
(approximately 2 years); for subjects
who continue into the study extension, the total
duration of treatment will be 192 weeks (approximately 4 years).
Two interim futility analyses will be performed during the base study.  Both analyses will be 
conducted and evaluated by the study team.  No external data monitoring committee will be 
used in this study.  If futility criteria are satisfied, the study team will discuss the analysis 
results with Sponsor management to make the final determination for stopping the study.  
Refer to Section 8.7 (Interim Analyses) for further information regarding the two futility 
analyses.
Subjects who meet virologic failure criteria during the base study or study extension (see 
Section 4.2.4.1) will return to the site for repeat viral RNA testing between one week and 4 
weeks (≥1 and ≤4 weeks) later (at a virologic failure confirmation visit).  If virologic failure 
is confirmed and the viral load meets the criteria for resistance testing (>400 copies/mL), 
viral resistance testing will be performed.  
For subjects in the base study with confirmed virologic failure, plasma samples collected for 
resistance testing from the virologic failure visit and from the confirmation visit will be sent 
for resistance testing.  For subjects in the study extension with confirmed virologic failure, 
the plasma sample from the virologic failure confirmation visit will be sent for resistance 
testing.  In addition, plasma samples for resistance testing collected at the early 
discontinuation visit from subjects who discontinue, from either the base study or the study 
extension, for reasons other than virologic failure will be sent for testing.  (Note that if a 
sample from the early discontinuation visit is not available, a sample from the most recent 
previous visit will be sent in the base study.)
Blood samples will be collected to support the evaluation of MK-1439 population 
pharmacokinetics (PK) from all subjects at Day 1 and Weeks 4, 8, 24 and 48. 
 
 
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During the study extension, subjects will continue to be monitored for safety, and 
maintenance of virologic suppression.  Long-term safety and efficacy data will be collected 
during the extension phase of the study and summarized descriptively.  No formal hypothesis 
testing will be conducted for the safety or for efficacy for the study extension.
Initially 60 subjects were to be enrolled in this study.  However, enrollment was discontinued 
after 10 subjects were enrolled due to an assessment of lack of feasibility of recruiting 
enough subjects who met the study entry criteria in a reasonable period of time.
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.
Trial Diagram
2.2
The trial design is depicted in Figure 1 (base study) and Figure 2 (study extension). Note the 
subjects who continue into the study extension will have a single 14 day follow-up visit at the 
end of the study extension only and not in the base study.
Figure 1 Trial Design for Base Study
 
 
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Figure 2  Trial Design for Study Extension
OBJECTIVE(S) & HYPOTHESIS(ES)
3.0
Primary Objective(s) & Hypothesis(es)
3.1
As this is an open-label, non-comparative study for estimation purposes only, there will be 
no formal hypotheses testing.
Base Study
3.1.1
(1) Objective:  To evaluate the antiretroviral activity of MK-1439A as measured by the 
proportion of subjects achieving HIV -1 RNA <50 copies/mL (by the Abbott RealTime 
HIV-1 Assay) at Week 48.
(2) Objective: To evaluate the safety and tolerability of MK-1439A, as assessed by review 
of the accumulated safety data by Week 48 and Week 96.
Secondary Objective(s) & Hypothesis(es)
3.2
Base Study 
3.2.1
(1) Objective: To evaluate the antiretroviral activity of MK-1439A as measured by the 
proportion of subjects achieving HIV-1 RNA <50 copies/mL at Week 96.
(2) Objective: To evaluate the antiretroviral activity of MK-1439A as measured by the 
proportion of subjects achieving HIV-1 RNA below the limit of quantification (BLoQ) 
of the Abbott RealTime HIV-1 Assay (<40 copies/mL) at Week 48 and Week 96.
(3) Objective: To evaluate the immunologic effect of MK-1439A, as measured by the 
change from baseline in CD4 cell count at Week 48 and Week 96.
 
 
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(4) Objective: To evaluate the antiretroviral activity of MK-1439A as measured by the 
time-to-loss-of-virologic-response (TLOVR).
Exploratory Objectives 
3.3
Base Study
3.3.1
(1) Objective: To evaluate the pharmacokinetics of MK-1439, when administered as a 
component of MK-1439A, and the pharmacokinetic-pharmacodynamic association, if 
supported by the data.
(2) Objective: To assess the development of resistance to MK-1439A (including 
assessments through deep sequencing) in subjects who have virologic failure.
(3) Objective:  To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study
Study Extension 
3.3.2
(1) Objective: To assess long-term efficacy and safety of MK-1439A administered for
up to 192 weeks in subjects enrolled in the extension phase of the study.
BACKGROUND & RATIONALE
4.0
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-1439A.
Pharmaceutical and Therapeutic Background
4.1.1
HIV infection, which causes Acquired Immunodeficiency Syndrome (AIDS) and for many 
years was associated with substantial morbidity and mortality, has now become a chronic 
disease that can be controlled through life-long combination antiretroviral therapy (ART) 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 five distinct mechanistic classes known as reverse transcriptase 
inhibitors (nucleos[t]ide reverse transcriptase inhibitors [N(t)RTIs] and non-nucleoside 
reverse transcriptase inhibitors [NNRTIs]), protease inhibitors (PIs), fusion inhibitors, entry 
inhibitors (CCR5 co–receptor antagonists), and integrase strand transfer inhibitors (InSTIs).  
Successful combinations of antiretroviral medications generally utilize 3 agents from at least 
2 different mechanistic classes.  The goal of HAART is to suppress HIV to undetectable 
levels so that immune function is preserved or restored.  Yet, while HAART can delay 
disease progression and death, as well as reduce the risk of HIV transmission, it does not cure 
the infection.  As a result, lifelong treatment must be maintained, which may lead to therapy 
fatigue and to noncompliance if the treatment regimen is difficult to adhere to (e.g., pill 
burden, frequency of treatment) and/or associated with intolerable side-effects.  This can 
potentially lead to treatment failures with possible development of resistant virus.  
 
 
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HIV resistance mutations can be transmitted from infected individuals to uninfected 
individuals.  Thus, “HIV infection with transmitted resistance” occurs when a previously 
uninfected, HIV-treatment-naïve individual is infected with virus that already has mutations 
that make it resistant to certain HIV treatments.  The presence of Transmitted Drug 
Resistance (TDR) increases the risk for subsequent regimen failure.
The prevalence of infection with transmitted resistance varies by geographic region, drug 
class and HIV transmission group.  The risk of transmitted resistance is heightened in regions 
of the world without routine viral load monitoring, as patients are maintained on failing 
regimens.  This is compounded by the reality that routine baseline resistance testing is not 
feasible in many parts of the world, particularly those most burdened by the problem of TDR, 
thus increasing the risk that a patient might be started on a regimen to which they are already 
resistant.  NNRTI transmitted resistance has proven to be the most common for a number of 
reasons.  For many years, NNRTI-based therapy has been the most common regimen type 
used in treatment-naïve patients.  NNRTIs have also been key components of prophylactic 
regimens designed to prevent maternal-to-child transmission of HIV.  Finally, there are 
virologic reasons that transmission of NNRTI resistant virus is more common than that for 
other drug classes.  The fitness of prevalent NNRTI resistant mutants such as K103N and 
Y181C is comparable to that of wild type (WT) virus; thus, when these mutations are 
selected for, they often persist for more than a year.  These resistant variants are also highly 
transmissible.  The prevalence of transmitted NNRTI resistance has increased over time, 
though it has slowed with the introduction of new drug classes.  Men who have Sex with 
Men (MSM) have generally been shown to have higher rates of transmitted resistance than 
People Who Inject Drugs (PWID) or heterosexuals.  This largely relates to the size and scope 
of the social networks from which new infections originate.  
A systematic review of the peer-reviewed English literature on TDR (1999–2013) was 
published in 2014 including a total of 212 studies [1].  The areas with the greatest TDR 
prevalence were North America [MSM: 13.7%, PWID: 9.1%, heterosexuals: 10.5%]; 
followed by Western Europe (MSM: 11.0%, PWID: 5.7%, heterosexuals: 6.9%) and South 
America (MSM: 8.3%, PWID: 13.5%, heterosexuals: 7.5%).  Disproportionately high TDR 
burdens were noted in MSM in Oceania (Australia 15.5%), eastern Europe/central Asia 
(10.2%) and East Asia (7.8%).  The risk of TDR infection was significantly greater in MSM 
than that in heterosexuals and PWID.  Increasing trends of resistance to non-nucleoside 
reverse transcriptase and PIs were noted in general among MSM.
In Europe, a continuous program (SPREAD) has been in place for ten years to study the 
transmission of drug resistant HIV [2].  The prevalence TDR was highest in MSM 
(prevalence of 11.1%), followed by heterosexuals (6.6%) and injection drug users (IDU) 
(5.1%, p<0.001).  TDR was predominantly ascribed to NRTIs with a prevalence of 6.6% in 
MSM, 3.3% in heterosexuals and 2.0% in IDU (p = 0.001).  A significant increase in 
resistance to NNRTIs and a decrease in resistance to PIs was observed in MSM (p = 0.008 
and p = 0.006, respectively) but not in heterosexual patients (p = 0.68 and p = 0.14, 
respectively).  MSM were shown to have significantly higher TDR prevalence compared to 
heterosexuals and IDU.  The increasing NNRTI resistance in MSM is likely to negatively 
influence the response to first-line therapy, as many include regimens based upon NNRTI 
drugs.
 
 
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For initiation of combination antiretroviral therapy for HIV infection, currently available 
NNRTIs have, for many years, been an important option for use as anchor agents along with 
two NRTIs.  Efavirenz and rilpivirine are the most widely-used NNRTIs and both are 
included as potential therapies for treatment initiation according to multiple guidelines [3, 4].  
However, both have resistance liabilities that have led to the selection for and persistence of 
specific resistance mutations that are commonly transmitted to uninfected individuals.  
Virologic failure to EFV is frequently associated with K103N mutations, and virologic 
failure with rilpivirine is commonly associated with Y181C mutations.  The G190A mutation 
is associated with nevirapine use, either as treatment or as part of prevention of maternal to 
child transmission regimens.
MK-1439 is a novel NNRTI being studied for the treatment of HIV-1 infection in 
antiretroviral-naïve HIV-infected subjects.  MK-1439 is a potent inhibitor of HIV-1 
replication in vitro and has a favorable preclinical toxicity profile.  Clinical pharmacology 
studies indicate that MK-1439 can be dosed once daily, without regard to food and that 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-naive HIV-infected patients demonstrate that MK-1439 in combination 
with TDF/emtricitabine has a favorable safety and tolerability profile and potent efficacy, 
with ~76% of patients receiving MK-1439 achieving undetectable viral load at week 24 (see 
Section 4.2.3).  Based on these data, both MK-1439 and the FDC, MK-1439A, are currently 
being studied in Phase 3 clinical trials.  
In addition to displaying excellent potency against WT HIV with an IC 50 of 12 nM in the 
presence of 100% normal human serum (NHS), MK-1439 has been observed in preclinical 
studies to have a favorable in vitro resistance profile that is distinct from other NNRTIs, with 
IC50’s of 21, 31, and 55 nM against mutants containing the most frequently transmitted 
NNRTI mutations, K103N, Y181C and G190A, respectively, under the same conditions.  
Thus, MK-1439 may be a unique NNRTI that can be used to treat HIV infection in the 
setting of NNRTI resistance.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
MK-1439 is highly active against the 3 most common NNRTI transmitted resistant viruses in 
in vitro multiple cycle infectivity assays conducted in the presence of 100% normal human 
serum (Table 1).
 
 
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Table 1  Antiviral Activity IC50 (nM), in 100% NHS Viking Assay
NNRTI
WT
K103N
Y181C
G190A
Protein 
Binding (%)
MK-1439
12
21
31
55
26
NPV
246
11520
>21000
NA
62
RPV
56
56
169
88
99.6
EFV
31
1166
92
826
99.6
Results from modeling and simulation based on available clinical data for NNRTIs suggest 
that the target trough level to achieve maximum viral load reduction with monotherapy is 
>6*IC50.  The clinical trough concentration is 830 nM in plasma for MK-1439 at a daily dose 
of 100 mg, which is the dose being studied in the Phase 3 clinical trials, and the trough 
concentrations of EFV and RPV are 5600 nM and 260 nM at 24 hours at doses of 600 mg 
and 25 mg, respectively.  Inhibitory quotient (IQ) has been used as a clinical efficacy 
predictor for antivirals with higher IQ correlating with better efficacy.  It is derived from the 
ratio of trough concentration over the IC50 of the drug candidate.  The IC50 that was 
determined in the presence of 100% human serum with the top 11 prevalent NNRTI-mutant 
viruses was used to calculate the IQ.  MK-1439 displayed an IQ of 39, 26 and 16 against 
K103N, Y181C, and G190A mutants, respectively.  In addition, MK-1439 also showed IQ 
>6 against all other mutants except the Y188L mutant.  There are only two mutants (Y181C 
and G190A) that showed IQ >6 with EFV.  The IQ are all <6 with RPV including for WT 
virus.  Furthermore, there are 5 and 7 mutants that have IQ <1 with EFV and RPV, 
respectively.  With higher IQ values against most of the prevalent NNRTI-associated mutants 
compared to EFV and RPV, MK-1439 may have a higher resistance barrier than EFV and 
RPV in clinical settings.  
Furthermore, in in vitro resistance selection experiments with mutant viruses, no additional 
mutation was observed at clinically relevant concentrations of MK-1439 with K103N and 
Y181C (and G190A) mutants, whereas breakthrough viruses were detected in the selection 
with clinically relevant concentrations of RPV (with both the K103N and Y181 mutants) and 
EFV (with the K103N mutant).  Altogether these in vitro data provide confidence that the 
levels of MK-1439 achieved with the selected Phase 3 dose should provide good activity 
against common transmitted resistant variants.  
Patients who have more than one of these selected mutations will not be eligible for this 
proof-of-concept study.  The presence of more than one mutation can be suggestive of 
infection with a virus from a patient with adherence issues.  This heightens the concern that 
there may be minor variants present as well which could make the overall MK-1439-based 
regimen less effective.  Subjects with resistance mutations other than K103N, Y181C and 
G190A (as single mutations) will also be excluded from this study as the objective of the 
study is to assess the efficacy of MK-1439 against the most prevalent NNRTI-associated 
mutants, i.e. K103N, Y181C, and G190A.  The inclusion of other mutations would 
complicate the interpretation of the clinical results.
 
 
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The purpose of this study is to demonstrate that the in vitro resistance profile of MK-1439 
translates to clinical efficacy (proof-of-concept), to further define the efficacy profile of MK-
1439 against TDR mutants, and to investigate the potential for MK-1439 to be used in the 
presence of selected baseline NNRTI resistance which may be particularly helpful in settings 
where baseline genotyping is not standard practice.
Rationale for Study Design
4.2.2
Given the novelty of treating patients who have selected NNRTI resistance mutations with an 
NNRTI that has projected activity against those mutations, this protocol has been designed to 
include extra precautions.  It is open-label in design with frequent early study visits to allow 
close monitoring of HIV RNA and safety, and it also includes follow-up of subjects (in the 
base study only) who discontinued due to virologic failures at approximately 24 weeks after 
the early discontinuation visit to assess whether or not subjects who fail with MK-1439A are 
successful on subsequent treatment.
Rationale for Dose Selection/Regimen
4.2.3
The investigational FDC, MK-1439A, contains 100 mg of MK-1439, a potent investigational 
NNRTI, and standard doses of 2 marketed and commonly-used NRTIs, TDF (300 mg) and 
lamivudine (300 mg).  
A 100 mg dose of MK-1439 was selected for Phase 3 development based on Phase 1b and 2 
data and several other factors.
In a Phase 1b study (Protocol 005), q.d. oral administration of 25 mg and 200 mg of MK-
1439 as monotherapy for 7 days to treatment-naïve HIV-infected patients reduced plasma 
vRNA (viral ribonucleic acid) burden as compared to placebo-treated controls.  The mean 
change from baseline in log10 HIV RNA copies/mL on Day 7 (24 hours post-dose) was -1.52 
for the MK-1439 25 mg group and was -1.41 for the MK-1439 200 mg group, while that for 
the placebo group was -0.15.  The mean differences between MK-1439 25 mg and 200 mg 
versus placebo in change from baseline in log10 HIV RNA copies/mL were -1.37 and -1.26, 
respectively.
Protocol 007 (Part 1) is a Phase 2 study designed to assess MK-1439 at doses of 25, 50, 100 
and 200 mg q.d. versus efavirenz at 600 mg q.d., both in combination with the fixed-dose
combination of TDF/FTC (TRUVADA™) in treatment-naïve HIV-1 infected subjects.  The 
MK-1439 dose range was selected based upon projections from in vitro data as well as the 
Phase 1b data in HIV-1 infected treatment naïve individuals, which showed comparable 
virologic suppression at the 25 mg and 200 mg doses given once daily for 7 days.
In Protocol 007 (Part 1) 208 treatment-naïve HIV-1 infected subjects were treated with study 
drug (MK-1439 or efavirenz).  At Week 24, all MK-1439 doses had rates of virologic 
suppression comparable to efavirenz for the key efficacy endpoints including the proportion 
of subjects with HIV-1 RNA levels <40 copies/mL (primary) or <200 copies/mL 
(secondary).  All MK-1439 doses showed numerically higher response rates compared to 
efavirenz (80.0%, 76.2%, 71.4%, 78.0% versus 64.3% of patients with <40 copies/mL for the 
MK-1439 25 mg, 50 mg, 100 mg, 200 mg versus efavirenz arms, respectively) [5, 6].  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 
 
 
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dose) achieved <40 copies/mL compared with 64.3% for efavirenz. In addition, 
approximately 30% of subjects in the study had baseline HIV RNA above 100,000 
copies/mL, and, in this subgroup, MK-1439 at all dosing levels showed virologic responses 
comparable to efavirenz.  It should be acknowledged that this high viral load subgroup was 
relatively small, with approximately 12 subjects per dosing group.  However, the totality of 
these efficacy data strongly support that the dose range studied (25-200 mg daily) was on the 
plateau of the dose response curve.
Similarly, the data from Protocol 007 showed an overall favorable safety and tolerability 
profile for MK-1439 compared with efavirenz, with no differentiation among MK-1439 
doses (25 mg - 200 mg daily) with regard to safety.  Based upon the 24 week results of 
Protocol 007, MK-1439 at doses ranging from 25-200 mg was generally well-tolerated, with 
no apparent dose related toxicity.  Fewer drug related AEs were observed for MK-1439 than 
for efavirenz (34.9% for MK-1439 overall vs. 57.1% for EFV), and fewer neuropsychiatric 
AEs were reported both at Week 8 and Week 24 (20.5% for MK-1439 overall vs. 33.3% for 
EFV at Week 8 and 23.4% for MK-1439 overall vs. 33.3% for EFV at Week 24) [7].   
Because the safety and efficacy data from Protocol 007 did not distinguish among the doses 
tested, the selection of the MK-1439 100-mg daily dose for study in Part 2 of Protocol 007 
and in the Phase 3 studies has taken into consideration a number of additional factors.  
Firstly, MK-1439 is a substrate of CYP3A metabolism and is subject to induction and 
inhibition of CYP3A by other concomitant medications.  Consequently, the 100 mg dose is 
more likely than the lower doses to provide adequate MK-1439 exposures even in the setting 
of moderate metabolic inducers, and it allows for a safety margin in the setting of moderate 
metabolic inhibitors (since acceptable safety and tolerability were seen at the 200 mg dose in 
the Phase 2 study as well as at multiple doses and single doses as high as 750 mg and 1200 
mg, respectively, in Phase 1 studies).  Secondly, the 100-mg dose may provide forgiveness in 
the setting of the occasional missed dose.  Thirdly, based on modeling and simulation, the 
100-mg dose is predicted to provide adequate exposures and Ctrough concentrations in the 
setting of certain common NNRTI resistance mutations against which MK-1439 is 
considered to be active in vitro, including the K103N, Y181C, and G190A mutations, as well 
as the dual K103N/Y181C mutation. 
Patients receiving MK-1439 at 25, 50 or 200 mg in Part 1 of Protocol 007 were switched to 
100 mg after dose selection.  An additional 132 patients were randomized in Part 2, 66 to 
receive MK-1439 100 mg and 66 to receive EFV 600 mg. Combining Part 1 and 2, a total of 
108 patients received MK-1439 100 mg, and 108 patients received EFV. By Week 8, at least 
one neuropsychiatric AE was reported in 22.2% of the MK-1439 group and 43.5% of the 
EFV group (p<0.001).  The most commonly-reported neuropsychiatric AEs were dizziness 
(in 9.3% of patients receiving MK-1439 and 27.8% of patients receiving EFV), insomnia (in 
6.5% of patients receiving MK-1439 and 2.8% of patients receiving EFV), abnormal dreams 
(in 5.6% of patients receiving MK-1439 and 16.7% of patients receiving EFV), and 
nightmares (in 5.6% of patients receiving MK-1439 and 8.3% of patients receiving EFV). 
Standard marketed doses of lamivudine and TDF were selected for inclusion in MK-1439A 
because these dose levels have demonstrated efficacy and safety in treatment-naive subjects, 
and no antagonism was observed between MK-1439 and either of these drugs in in vitro 
studies.
 
 
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Rationale for Endpoints
4.2.4
4.2.4.1
Efficacy Endpoints
The primary efficacy parameter in the study is viral load as measured by HIV-1 RNA, which 
is consistent with other clinical trials in HIV-infected patients and the current regulatory 
guidance.  Suppressing HIV-1 RNA to low levels preserves the immune system and prevents 
the development of opportunistic infections and progression of the disease.  Clinical trials of 
antiretroviral agents in multiple classes have demonstrated that suppression of HIV RNA to 
levels below 50 copies/mL is a clinically meaningful endpoint.  Therefore, the primary 
efficacy endpoint of this study is the proportion of subjects achieving HIV-1 RNA <50 
copies/mL by the Abbott RealTime HIV-1 Assay. Week 48 was chosen as the primary 
efficacy time point, as recommended by regulatory agencies for HIV treatment-naïve studies.
Secondary and exploratory measurements for efficacy include HIV RNA <40 copies/mL (the 
lower limit of quantification of the Abbott RealTime HIV-1 Assay), change from baseline in 
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 (PDVF) for this study is defined as one of the following:
1) Confirmed (two 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
OR
2) Confirmed (two consecutive measures at least one week apart) HIV-1 RNA ≥200 
copies/mL at Week 24 or Week 36 
OR 
3) Confirmed (two consecutive measures at least one week apart) HIV-1 RNA ≥50 
copies/mL at Week 48.
Subjects should be discontinued, regardless of compliance with study therapy, if they meet 
the protocol defined virologic failure criteria.
4.2.4.2
Safety Endpoints
Safety evaluations in the base study will include physical examinations (including vital signs) 
and laboratory tests (blood) performed at the visits indicated in the Trial Flow Chart A 
(Section 6.0).  For subjects who continue into the study extension, safety evaluations will 
include physical examinations (including vital signs) and laboratory test (blood) performed at
each of the study visits, and if applicable, at the early discontinuation visit and/or a
virologic failure confirmation visit and at a 14-day follow-up visit as shown in Trial Flow 
Chart B.  Adverse experiences will be evaluated at each visit and graded according to the 
guidelines provided in Section 7.2.  Subjects may be asked to return for unscheduled visits in 
order to perform additional safety monitoring.
 
 
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Primary and exploratory measurements for safety include clinical and laboratory adverse 
experiences and predefined limits of change in laboratory parameters.  
4.2.4.3
Pharmacokinetic Endpoints
Pharmacokinetic (PK) samples to be assayed for MK-1439 plasma concentrations will be 
collected on the Day 1 visit as a predose sample.  Population PK samples will also be taken 
at Weeks 4, 8, 24 and 48.  At Week 4, the sample is to be collected predose.  At Weeks 24 
and 48, the samples are to be collected predose and within 0.5 to 2 hours postdose; at Week 
8, the sample may be collected irrespective of time of dose (time of last dose and time of PK 
sample collection must be documented).
4.2.4.4
Planned Exploratory Biomarker Research 
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.4.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting 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 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Rationale for Study Extension  
4.2.5
This protocol was previously amended to provide MK-1439A to subjects who have 
completed the base study (96 weeks of treatment for PN030) for an additional 96 weeks, and 
to collect long-term efficacy and safety data with MK-1439A.  MK-1439A is being evaluated 
as a potential treatment option for subjects infected with HIV-1, including those with one of 
 
 
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the following NNRTI mutations:  K103N, Y181C, or G190A.  It is important to assess its 
long-term safety and efficacy since HIV infection is chronic, with treatment generally
lasting for years.  Thus, after the 96 week period (base study) to evaluate the key primary 
and secondary objectives, there will be an extension for an additional 96 week period where 
all eligible subjects can continue to receive MK-1439A.  
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
MK-1439 is a promising new NNRTI for the treatment of HIV-1 infection.  It is a potent 
inhibitor of HIV-1 replication in vitro and is active against both wild type virus and most 
common NNRTI resistant variants at concentrations achieved with once daily dosing.  In 
early studies, MK-1439 has been shown to be efficacious in combination with other ARTs in 
treatment-naïve patients.  MK-1439 is not expected to have many of the safety concerns 
associated with EFV (especially neuropsychiatric AEs and dyslipidemia).  In addition, MK-
1439 is not expected to have major drug-drug interactions that would limit its utility in 
clinical practice.  Therefore, MK-1439 could represent a valuable addition to the HIV 
armamentarium for treatment-naïve patients.  Additionally, the FDC, MK-1439A, which is 
used in this protocol, is a simplified regimen that could result in increased adherence, thereby 
potentially decreasing the risk of virologic failure.
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.
METHODOLOGY
5.0
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male and female subjects 18 years of age or older who are HIV-1 positive, naïve to 
antiretroviral therapy (ART) and have transmitted resistance to selected NNRTI mutations 
will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be at least 18 years of age on the day of signing the informed consent.
2. Understand the study procedures and voluntarily agree to participate by giving 
written informed consent (or have a legal representative provide written informed 
consent, if considered acceptable by local regulatory agencies and/or ERCs/IRBs) for 
the trial.  The subject or his/her legal representative (if considered acceptable by local 
regulatory agencies and/or ERCs/IRBs) may also provide consent for Future 
Biomedical Research.  However, the subject may participate in the main trial without 
participating in Future Biomedical Research.
 
 
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3. Be HIV-1 positive as determined by a positive result on an enzyme-immunoassay, 
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. Have a screening CD4 cell count ≥100 cells/mm3 (completed by the central 
laboratory) within 45 days prior to the treatment phase of this study.
5. 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.
6. Prior to screening, have documentation of genotype performed confirming the 
presence of one and only one of the following NNRTI mutations:  K103N, Y181C, or 
G190A. An additional sample must be obtained and analyzed by the central 
laboratory as a part of the screening process to establish a baseline resistance profile.  
The results of the central laboratory test results must be available prior to subject 
enrollment. If, upon receipt of the central laboratory results, a discordance between 
the local sample drawn prior to screening and central laboratory results is identified, 
such that exclusion criterion #4 is met using the central laboratory results, the subject 
should not be enrolled in the study.  In addition, if the central laboratory test results 
do not confirm inclusion criteria 6, the subject should not be enrolled.
7. Have the following laboratory values during the screening period of the trial:
a.
Alkaline phosphatase ≤3.0 x upper limit of normal.
b. AST (SGOT) and ALT (SGPT) ≤5.0 x upper limit of normal.
c.
Hemoglobin ≥9.0 g/dL (if female) or ≥10.0 g/dL (if male).
Note:  A single repeat of a laboratory screening test will be allowed for test 
results that are unexpected based on documented prior laboratory results.
8. Have a calculated creatinine clearance at the time of screening ≥50 mL/min, based on 
the Cockcroft-Gault equation which is as follows:
For males:
Clcr(mL/min) = (140-age) x weight (in kg)
                                                  72 x serum creatinine (mg/dL)
For females:
Clcr(mL/min) = (140-age) x weight (in kg)            x0.85
                                                  72 x serum creatinine (mg/dL)
9. In the opinion of the investigator, be considered clinically stable with no signs or 
symptoms of active infection at the time of entry into the study (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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10. Be highly unlikely to become pregnant or to impregnate a partner since the subject 
falls into at least one of the following categories:
a.
The subject is a male who is not of reproductive potential, defined as a male who 
has azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).  
b. The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) is postmenopausal (defined as at least 12 months with no menses 
in women ≥45 years of age); (2) has had a hysterectomy and/or bilateral 
oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at 
least 6 weeks prior to screening; OR (3) has a congenital or acquired condition 
that prevents childbearing.
c.
The subject is a female or a male who is of reproductive potential and agrees to 
avoid becoming pregnant or impregnating a partner while receiving study drug 
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.  
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 two 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)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
contraceptive rod implanted into the skin or subcutaneous contraceptive injection
Use of barrier methods of contraception is strongly encouraged to reduce the risk of 
HIV-1 transmission during sexual contact.
†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. 
 
 
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‡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 order to be eligible for participation in the study extension at the Week 96 visit, the
subject must:
11. Have completed the Week 96 visit.
12. Be considered, in the opinion of the investigator, to have derived benefit from study
participation through Week 96. 
13. Be considered, in the opinion of the investigator, a clinically appropriate  candidate
for an additional 2 years (additional 96 weeks) of treatment with MK-1439A.
14. Understand the procedures in the study extension and provide written informed
consent to enter the study extension, thus continuing for approximately  2 years
beyond the base study.
Subject Exclusion Criteria
5.1.3
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 this 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 (MK-1439, lamivudine, and/or 
tenofovir) as defined below:

Resistance to MK-1439 for the purpose of this study is considered to include 
mutant viruses containing any of the following NNRTI-associated mutations.  
o
L100I K101E, K101P, K103S, V106A, V106I, V106M, V108I, E138K, 
E138A, E138G, E138Q E138R, V179L, Y181I, Y181V, Y188C, Y188H, 
Y188L, G190S, H221Y, P225H, F227C, F227V, F227L, M230I and 
M230L.  
o
Any double or triple NNRTI mutation that includes mutations from the 
above in combination with K103N, Y181C, or G190A.
 
 
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
Resistance to lamivudine or tenofovir  for the purpose of this study is considered 
to include following NRTI-associated mutations:

M41L, A62V, K65R, D67N, K70E, K70R, L74V, V75I, F77L, Y115F, 
F116Y, Q151M, M184I, M184V, L210W. T215F, T215Y, K219E, and 
K219Q as well as the T69S insertion complex.
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 the study.
6. Has any medical condition requiring, or likely to require, chronic systemic 
administration of corticosteroids, TNF antagonists, or other immunosuppressant drugs 
during the course of the trial.
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 drug as determined by the investigator.
9. Has a current (active) diagnosis of acute hepatitis due to any cause.
Note:  Subjects with chronic hepatitis 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. Has evidence of decompensated liver disease manifested by the presence of or a 
history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or 
other signs or symptoms of advanced liver diseases 
or 
has liver cirrhosis and a Child-Pugh Class C score or Pugh-Turcotte (CPT) score >9.
Note: To calculate the CPT score and associated Child-Pugh Class, refer to the 
following website: http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality 
(see Section 12.8).
11. Is pregnant, breastfeeding, or expecting to conceive.
12. .Is female and 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).
13. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
5.2
Following completion of the Day 1 procedures and confirmation of eligibility, the site will 
contact the IVRS/IWRS for assignment of the study drug.  Sites should not call IVRS/IWRS 
to dispense study drug until the subject has met all criteria for the study and is ready to 
 
 
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receive the first dose of study medication on Day 1.  The treatment to be used in this trial is 
outlined below in Table 2.  
Table 2  Trial Treatment During Base Study and Study Extension
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
MK-1439A
Single tablet FDC containing 
MK-1439 100 mg, lamivudine 
300 
mg, 
and 
tenofovir 
disoproxil fumarate (TDF) 300 
mg
QD
PO
Subjects will receive study medication at the Day 1 visit and should take the first dose of 
medication the same day.
MK-1439A is to be taken once daily without regard to food at approximately the same time 
each day.
MK-1439A for the base study and for the study extension (provided that development of 
MK-1439A is continuing) will be provided centrally by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
5.2.1.2
Dose Modification/Interruption During the Base Study or the Study Extension
Dose Modification
No dose modification of study therapy is allowed during the study.
Dose Interruption:
Consideration should be given to interrupting study therapy for toxicity management (see 
Section 7.1.2.6).
Interruptions from the protocol specified treatment plan that are expected to be 7 days or 
greater require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on subject management.
 
 
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Timing of Dose Administration
5.2.2
Subjects will be instructed to take one tablet of MK-1439A once a day (q.d.) orally, with or 
without food at the approximately the same time each day. 
If a subject misses a dose of study drug and it is less than 12 hours before the next dose, the 
missed dose should be skipped and the normal dosing schedule resumed.  The subject should 
not double the next dose in order to compensate for what has been missed.  If a subject 
misses a dose and it is greater than 12 hours before the next dose, the missed dose should be 
taken and the normal dosing schedule resumed.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Treatment allocation will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS).  There is one treatment arm.  Subjects 
participating in this trial will be assigned to MK-1439A by non-random assignment.
Stratification
5.4
In the original protocol, enrollment of eligible subjects were to be stratified by mutation type 
(K103N, Y181C, and G190A), however as enrollment was discontinued at 10 subjects, no 
stratification will occur.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
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.
1. Use of oral or other hormonal contraception is permitted.
 
 
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2. Newly approved regimens for the treatment of HCV infection are permitted, as long as 
there are no known potential drug-drug interactions between those treatments and any of 
the study medications.  The Merck Clinical Director or designee should be contacted if 
there are any questions about whether there is a potential drug-drug interaction with a 
specific treatment that the Investigator is planning to give the subject.
Prohibited Concomitant Medications/Therapies
In general, concomitant use of immune therapy agents or other immunosuppressive therapy 
is not allowed during the course of the study.  Important exceptions to this rule include:

Short courses of corticosteroids (e.g., as for asthma exacerbation) are allowed.

Intralesional or localized electron beam therapy for cutaneous Kaposi’s sarcoma is 
permitted.

If a subject develops a malignancy (for example lymphoma) after treatment allocation, 
the subject may receive chemotherapy (including cancer immunotherapy) and remain in 
the study if, in the opinion of the investigator, the benefits outweigh the risks.  Depending 
on the type of chemotherapy, study medication may need to be interrupted until 
completion of the chemotherapy.

If a subject requires interferon-based treatment for hepatitis after treatment allocation, the 
subject may receive treatment and remain in the study if, in the opinion of the 
investigator, the benefits outweigh the risks.  If it is possible, interferon-based therapy 
should be deferred until the completion of the study.
Antiretroviral therapies other than those used in the study (MK-1439A) are also not 
permitted during the course of the study.  Subjects who discontinue study therapy due to 
virologic failure may initiate antiretroviral therapy in the time period between virologic 
failure confirmation and the contact which occurs approximately 24 weeks after study 
discontinuation.  
Investigational agents must be discontinued30 days prior to signing consent in this study and 
are not permitted during the course of the study.
Prohibited Concomitant Therapy Due to Potential Interactions with MK-1439A
MK-1439 is expected to be eliminated mainly via CYP (cytochrome)-mediated oxidation.
The medications and/or substances below are prohibited in this study because they are 
moderate or potent inducers of CYP3A4 and their coadministration with MK-1439A could 
possibly result in reduced drug levels of MK-1439 or has the potential for additional drug-
drug interactions.  Since this list is not comprehensive, the investigator should use his/her 
medical judgment when a subject presents with a medication not on the list or call the 
Sponsor Clinical Director or Designee for clarification.  Prohibited medications/therapy due 
to MK-1439 interactions are listed in Table 3.  
 
 
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Table 3  Prohibited Medications/Therapy Due to MK-1439 Interactions
Prohibited Medication/Therapy Due to  
MK-1439 Interactions
Carbamazepine
Phenobarbital
Phenytoin
Rifabutin
Rifampin
Herbal remedies
St. John’s Wort
Modafinil
Bosentan
Nafcillin
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
Diet
MK-1439A can be taken without regard to food and should generally be taken at 
approximately the same time each day.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
Note:  Please provide additional detail for the reason the subject withdrew consent on 
the Subject Disposition eCRF.
 
 
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
The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol; these may include but are not limited to:
o
clinical or laboratory findings suggestive of lactic acidosis or pronounced 
hepatotoxicity 
(which 
may 
include 
symptomatic 
hyperlactataemia, 
metabolic/lactic acidosis, progressive hepatomegaly, rapidly elevating 
aminotransferase levels, and hepatomegaly and steatosis even in the absence 
of marked transaminase elevations).

The subject has a confirmed positive serum/urine pregnancy test.
Note: Subjects who become pregnant during the study will be asked to join a 
pregnancy registry which collects information about the outcome of the pregnancy.

The subject fails to comply with the dosing, evaluations, or other requirements of the 
trial.

A physician investigator feels it is in the best interest of the subject to discontinue.

The subject has an adverse experience or tolerability issue related to study medication 
which requires discontinuation of the medication. 

Subject  has a creatinine clearance of <50 mL/min (confirmed by repeat 
measurement) based on the Cockcroft-Gault equation:
Male: 
Clcr (mL/min) =   (140-age) x weight (in kg)
  
                72 x serum creatinine (mg/dL)
Female:
Clcr (mL/min) =   (140-age) x weight (in kg)          X    0.85
   
                72 x serum creatinine (mg/dL)

Subject has serum phosphorous <0.32 mmol/L.

The subject requires discontinuation of study therapy for a reason other than virologic 
failure.
Subjects who discontinue the trial prior to the last scheduled treatment visit should have an 
Early Discontinuation visit and a 14-day follow up visit conducted.
A subject must be discontinued from study therapy, regardless of compliance; if they meet 
the protocol defined virologic failure criteria in Section 4.2.4.1.  Subjects who discontinue 
study therapy due to virologic failure will complete an Early Discontinuation visit and a 14-
day follow-up visit.  In addition, subjects who discontinue study therapy due to virologic 
failure will be contacted by the site approximately 24 weeks after the Early Discontinuation 
visit.  The subject will no longer attend any other scheduled study visits following 
discontinuation.  At this contact, information will be collected on the subjects’ subsequent 
HIV regimens (following discontinuation of the study treatment) and virologic outcome.  
Details regarding the regimens used and virologic outcome will be recorded on the eCRF.
 
 
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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 the study extension.  
A subject who completes the base study and does not elect to participate in the study 
extension is considered to have completed the study.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
If the futility criterion is met for either of the two interim futility analyses, the study may stop 
due to lack of efficacy.  Refer to Section 8.7 (Interim Analyses) for further information 
regarding the two futility analyses.  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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Trial Period:
Screening
Treatment
Post-treatment
Visit Number/Title:
1
Screen
-ing
2
3
4
5
6
7
8
9
10
11
12
13
14
U (Virologic 
Failure 
Confirmation
)
U (Early 
Discon-
tinuation)k, 
l
U 
Virologic 
Failure 
Follow 
Up
99
Scheduled Weeks/Days:
Screen
Fastinga
Day 1b
W
K
2
WK
4
W
K
8
Fas
tin
ga
W
K
12
W
K
16
WK
24
W
K
36
Fast-
inga
WK
48
WK 
60
W
K 
72
W
K 
84
Fast-
inga
WK 
96
≥ 1 to ≤ 4 
weeks after 
initial 
virologic 
failure
At time 
of Discon
24 Weeks 
Post 
Virologic 
Failure
Post 
study 
14 
day 
follo
w up
Visit Windowsm
+/- 3 days
+/- 7 days
- 2 
days
Virology Test Plasma HIV RNA 
quantification test (Abbott Real 
Time HIV-1)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect 
Blood for CD4 Cell Counto
X
X
X
X
X
X
Collect Blood for MK-1439 PKj
X
X
X
X
X
Collect 
Plasma 
for 
Viral 
Resistance Test
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect 
Blood 
for 
Genetic 
Analysisc
X
Collect 
Blood 
for 
Deep 
Sequencing Analysis
X
X
Collect 
Plasma 
for 
Future 
Biomedical Researchp
X
X
X
 
 
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a.
Fasting for at least 8 hours.  
b.
Within 45 days of screening visit and prior to the first dose on Day 1.
c.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR 
is approved and consent is given, this sample will be collected for the purpose of FBR. 
d.
A local ECG should be performed prior to the subject’s first dose of study medication (within 7 days prior to the study Day 1 visit).
e.
For women of childbearing potential.
f.
Results of test must be available prior to enrolling the subject.
g.
Refer to Table 4 for listing of specific blood safety tests.
h.
Hemostatic Function Test includes: Prothrombin time (PT), Activated Partial Thromboplastic Time (APTT), and International Normalized Ratio (INR).
i.
HIV/Hepatitis Screen tests 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 polymerase chain reaction (PCR) quantitative test will be performed if the Hepatitis C antibody test is 
positive.
j.
One sample for assay of MK-1439 plasma concentrations will be collected at Day 1 (Pre-dose), Week 4 (Pre-Dose), Week 8 (random).  At Weeks 24 and 48, two samples will 
be collected, pre-dose and 30 mins to 2 hours postdose (the subject should be fasting for the Week 48 samples).
k.
If virologic failure is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for resistance need not 
be collected again at the early discontinuation visit.  All other early discontinuation tests should be performed at the early discontinuation visit.
l.
Subjects who discontinue due to virologic failure, will no longer attend scheduled study visits, but will be followed at approximately 24 weeks after study discontinuation to 
determine virologic outcome and regimen used.
m.
The timing of visits 3 through 14 is relative to the Day 1 visit.  Every attempt must be made to keep subjects on schedule.  
n.
Subjects should have a documented genotype performed by local lab prior to screening.  An additional sample will be obtained and analyzed by the central lab as a part of the 
screening process to establish a baseline resistance profile.  If, upon receipt of the central laboratory results, a discordance between the local sample drawn prior to screening 
and central laboratory results is identified, such that exclusion criterion #4 is met using the central laboratory results, the subject should not be enrolled in the study.  In 
addition, if the central laboratory test results do not confirm inclusion criteria 6, the subject should not be enrolled.
o.
If the investigator believes more frequent CD4 counts are necessary for clinical care or are required per local treatment guidelines, then he/she has the option to add additional 
CD4 counts at a scheduled visit.  The samples should be sent to the central lab for testing.
p.
Plasma samples for FBR should be collected at Day 1, and at Weeks 48 and 96 if the subject signs the FBR consent.
q.
If the subject is eligible and elects to enter the study extension, he/she will be considered to have completed the base study and will, after providing informed consent, 
immediately enter the study extension.
 
 
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Flow Chart B: Week 112 Through Week 192  Plus 14 Days Follow-up (Study Extension)
Trial Period
Treatment
Post-Treatment
Visit Number/Title:
15a
16
17
18
19
20
U
(Virologic
Failure
Confirmation)
U
(Extension
Early
Discontinuation)
99
Trial Period:
Extension: Treatment b
Post-
Treatment c
TRIAL PROCEDURES
Wk 112
Wk 128
Fasting
Wk144
Wk 160
Wk 176
Fasting
Wk 192
1 to 4 weeks
after initial
virologic failure
At time of
Discontinuation
14 Day
Follow-up
Visit Windowsj
+/- 7 days
-2 days
Administrative Procedures
Concomitant Medication Review
x
x
x
x
x
x
x
x
Register Study Visit via Interactive
Voice/Web Response System (IVRS/IWRS)
x
x
x
x
x
x
x
Dispense Study Therapy d
x
x
x
x
x
Provide/ Review Study Medication Diary
x
x
x
x
x
x
x
Clinical Procedures/Assessments
Directed Physical Examination
x
x
x
x
x
x
x
x
Vital Signs (including pulse rate, blood
pressure, respiratory rate, and body
temperature) and weight
x
x
x
x
x
x
x
x
Adverse Events Monitoring
x
x
x
x
x
x
x
x
Birth Control Confirmation
x
x
x
x
x
x
x
x
Laboratory Procedures/Assessments
Collect Blood for Safety Laboratory Tests
(Hematology/Chemistry) e
x
x
x f
x
x
x f
x
x
x
Urine Pregnancy Test (if applicable) g
x
x
x
x
x
x
x
x
Virology Test Plasma HIV viral RNA
quantification test (Abbott Real Time HIV-1)
x
x
x
x
x
x
x
x
x
 
 
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Trial Period
Treatment
Post-Treatment
Visit Number/Title:
15a
16
17
18
19
20
U
(Virologic
Failure
Confirmation)
U
(Extension
Early
Discontinuation)
99
Trial Period:
Extension: Treatment b
Post-
Treatment c
TRIAL PROCEDURES
Wk 112
Wk 128
Fasting
Wk144
Wk 160
Wk 176
Fasting
Wk 192
1 to 4 weeks
after initial
virologic failure
At time of
Discontinuation
14 Day
Follow-up
Visit Windowsj
+/- 7 days
-2 days
Collect Blood for CD4 Cell Counth
x
x
Viral Resistance Test (Plasma)
x
x i
a.
Subjects who enter the study extension are considered enrolled in the extension upon providing written informed consent at the Week 96 study visit.
b. The visit windows are approximately +/- 14 days for all visits from Week 112 through Week 192. The timing of each visit is relative to the (Day 1) visit.
Every attempt must be made to keep subjects on schedule.
c.
The visit window for the post-study 14-day follow-up visit is approximately – 2 to 0 days.
d. IVRS/IWRS will be used to allocate drug and to manage distribution of MK-1439A.
e.
Refer to Table 4 for listing of specific blood safety tests.
f.
Fasting for at least 8 hours. Fasting is required at these visits for lipids measurement.
g. For women of childbearing potential
h. If the investigator believes more frequent CD4 counts are necessary for clinical care or are required per local treatment guidelines, then he/she has the option to add additional 
CD4 counts at a scheduled visit.  The samples should be sent to the central lab for testing.
i.
If virologic failure or relapse is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for resistance
need not be collected again at the early discontinuation visit. All other early discontinuation tests should be performed at the early discontinuation visit.
j.
The timing of visits 15 through 20 is relative to the Day 1 of base study  visit.  Every attempt must be made to keep subjects on schedule.  
 
 
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TRIAL PROCEDURES
7.0
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
 
 
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performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  A review of these criteria should occur at the 
Screening visit and on the Day 1 visit.  For subjects who wish to continue into the study
extension, the additional inclusion criteria (11 to 14 Section 5.1.2) are to be reviewed at the
Week 96 study visit.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  The medical 
history should include information pertaining to the diagnosis of HIV infection and the year 
diagnosed.  If a subject has previously been diagnosed with any AIDS defining condition, or 
a CD4 count <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, for calculation of Framingham cardiovascular risk, should be obtained and 
recorded on the appropriate eCRF.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the subject within 30 days before starting the trial. 
Investigational agents must be discontinued 30 days prior to signing Informed Consent.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication and the reason for therapy, if 
any, for medications taken by the subject during the trial.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
 
 
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subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
The site must access the IVRS/IWRS system to register each screening subject. 
Specific details on the screening visit requirements are provided in Section 7.1.5.1.
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.   Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Subject Diary Cards will be used to ensure and document drug compliance.
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 number on the subject diary card prior to giving the diary card to the 
subject. The subject should follow the instructions on the diary card for recording study drug.  
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 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 4 visits to ascertain if there are problems with non-compliance 
as early as possible, to access whether the subject is taking study medication as directed and 
to ensure that subjects experiencing difficulties are re-educated, as appropriate.
Interruptions from the protocol specified  treatment plan that are expected to be 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
7.1.2
7.1.2.1
Physical Examination
All physical examinations should be performed as indicated in the Trial Flow Chart (Section 
6.0). All physical examinations must be performed by the principal investigator or sub-
investigator (physician, physician assistant or nurse practitioner). 
A complete (full) physical examination (including vital signs [weight, pulse, respiratory rate, 
blood pressure, and body temperature]) must be obtained at the Screening visit. A complete 
 
 
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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 on 
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 AEs and entered on the AE eCRF. 
If the subject is discontinued for any reason during the treatment phase, every attempt should 
be made to perform a final physical examination.
7.1.2.2
Height Assessment
The subject's height should be assessed as indicated in the Trial Flow Chart A (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 AE on the eCRF.
7.1.2.3
Vital Signs and Weight
Vital signs, including pulse rate, respiratory rate, blood pressure and body temperature, and 
weight should be assessed as indicated in the Trial 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 AE on the eCRF.
7.1.2.4
12-Lead ECG (performed locally)
A local 12-Lead ECG should also be performed prior to the subject’s first dose of study 
medication (within 7 days prior to the Study Day 1 visit), as indicated in the Trial Flow Chart 
A (Section 6.0), and any abnormalities should be documented.  Results must be available 
prior to the subject receiving study medication.  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 pre- Day 1/Day 1 ECG must be documented in the subject's 
chart and captured on the medical history eCRF.
If an ECG is performed for any medical reason while the patient 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.
 
 
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7.1.2.5
Adverse Events
When evaluating an adverse event, the investigator should document in the eCRF if there is a 
likely causality relationship to immune reconstitution syndrome (IRIS).
If a subject has been diagnosed with an AIDS defining condition following initiation of study 
medication, the condition must be reported as an AE.  
Due to the use of lamivudine and tenofovir in this trial, subjects should be monitored for 
symptoms of hyperlactataemia.
Details on assessing and recording AEs can be found in Section 7.2.
7.1.2.6
Toxicity Management
Guidelines for grading the severity of laboratory AEs are based on Division of Acquired 
Immunodeficiency Syndrome (DAIDS) criteria for grading severity of AEs (Section 12.7). 
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 AEs 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 Merck 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 
advance approval of re-challenge is not required by local regulations, the IEC/IRB will 
receive notification for information only.
If, after re-initiation of study therapy, there is a recurrence of the laboratory abnormality or 
clinical AE, consideration should be given to permanently discontinuing all study therapy. 
Whenever study drugs are interrupted, the Merck Clinical Director or Designee should be 
notified.
7.1.2.7
Birth Control Confirmation
Care must be taken to avoid pregnancy in female subjects of childbearing potential and in the 
female partners of 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
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.4.
7.1.3.1
Serum/Urine Pregnancy Test
For women of childbearing potential, serum pregnancy is to be done at the Screening visit, 
and urine pregnancy is to be done at the Day 1 visit prior to dispensing study drug.  Urine 
pregnancy tests must also be subsequently done at each study visit, including the  Early 
Discontinuation Visit (if applicable) and 14 day Follow-up Visits in both the base study and
the study extension. Results must be documented in the subject’s chart. A subject found to be 
pregnant must be discontinued from the study.
7.1.3.2
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 4.
Table 4  Laboratory Tests
Hematology
Chemistry
Other
Hematocrit
Alkaline phosphatase
Prothrombin time (PT)3
Hemoglobin
Alanine aminotransferase (ALT, 
SGPT)
Activated partial 
thromboplastin time 
(APTT)3
Platelet count
Aspartate aminotransferase 
(AST, SGOT)
International Normalized 
Ratio (INR)3
Red Blood Cell Count
Creatine Kinase
Hepatitis B Virus surface 
antigen 3
Erythrocyte Mean corpuscular 
volume
Total Bilirubin
Hepatitis B Virus surface 
antibody 3
White Blood Cell Count (Total 
and Differential)
Direct Bilirubin
Hepatitis B e-Antigen 3
CD4% and Absolute 
CD4/Lymphocytes
Indirect Bilirubin
Hepatitis C Antibody 3
CD8% and Absolute 
CD8/Lymphocytes
Amylase
Plasma hepatitis C virus 
PCR quantitative4
CD4/CD8 ratio
Lipase
Enzyme immunoassay HIV 
antibody (with confirmation 
WB)3
Glucose, fasting1
HIV viral RNA 
Quantification
Glucose, non-fasting2  
Serum -human chorionic 
gonadotropin (hCG) test5
Blood Urea Nitrogen
Urine -human chorionic 
gonadotropin (hCG) test6
Creatinine8
HIV Viral resistance7
Phosphorus
Magnesium
Calcium
Protein
Albumin
 
 
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Hematology
Chemistry
Other
Sodium
Potassium
Chloride
Bicarbonate
High-density lipoprotein 
cholesterol (HDL-C) (fasting1)
Low-density lipoprotein 
cholesterol (LDL-C) (fasting1)
Triglycerides (fasting1)
Total Cholesterol (fasting1)
1.
Perform at the Day 1, Week 12, 48, and 96 visits and, for subjects who continue into the extension, at
the Week 144 and 192 visits.  Subjects should be fasting for 8 hours. 
2.
Perform at the Screening visit, Day 1 and the Weeks 2, 4, 8, 16, 24, 36, 60, 72 and 84 visits, and, in the
extension, at the Study Week 112, 128,160 and 176 visits and the 14 day follow-up visit. 
3.
Perform at the screening visit only.
4.
If the result of the Hepatitis C Antibody testing is positive, then a plasma hepatitis C virus PCR 
quantitative test will also be performed.
5.
Serum hCG test at the Screening visit to be performed by central laboratory.
6.
Urine hCG test to be performed at the investigator site at Day 1 and every study visit  thereafter.
7.
Perform at the Screening visit, Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84 and 96 visits, the Virologic 
Failure confirmation visit, and the Early Discontinuation visit (if not collected at Virologic Failure 
confirmation visit).  In the extension, resistance sample will be collected only at Virologic Failure and 
Discontinuation Visit.
8.
Creatinine clearance will be computed at every visit by the central laboratory and provided to the site in 
the report that the site receives from the central laboratory.
7.1.3.3
HIV/Hepatitis Screening
At the Screening visit, serum HIV/Hepatitis screening tests will be performed including:  
Enzyme immunoassay HIV antibody (with confirmation WB), serum Hepatitis B surface 
antigen, serum Hepatitis B surface antibody, serum Hepatitis B e-antigen and serum Hepatitis 
C antibody.  A plasma hepatitis C virus PCR quantitative test will be performed if the 
Hepatitis C antibody test is positive.
7.1.3.4
Virology Test
Plasma HIV-1 RNA quantification will be performed at all visits.  The testing will be 
performed at the central laboratory using the Abbott RealTime HIV-1 assay.
7.1.3.5
Viral Resistance Testing
Blood samples will be collected for genotypic HIV viral resistance testing at the Screening 
visit for study inclusion purposes and to determine MK-1439, tenofovir, and lamivudine 
resistance. Additional resistance testing on screening samples may be performed.  Blood 
samples will also be collected for HIV viral resistance testing at Weeks 4, 8, 12, 16, 24, 36, 
48, 60, 72, 84 and 96, in the base study and at the Virologic Failure Confirmation visit or the 
Early Discontinuation Visit (if not already obtained at Virologic Failure Confirmation visit) 
in both the base study and the study extension.  
Prior to screening, subjects must have documentation of genotype performed confirming the 
presence of one and only one of the following NNRTI mutations:  K103N, Y181C, or 
G190A. An additional sample must be obtained and analyzed by the central laboratory as a 
 
 
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part of the screening process to establish a baseline resistance profile. The results of the 
central laboratory test results must be available prior to subject enrollment. If, upon receipt of 
the central laboratory results, a discordance between the local sample drawn prior to 
screening and central laboratory results is identified, such that exclusion criterion #4 is met 
using the central laboratory results, the subject should not be enrolled in the study.  In 
addition, if the central laboratory test results do not confirm inclusion criteria #6, the subject 
should not be enrolled.  All other resistance testing will be performed by the central 
laboratory only.  
7.1.3.6
CD4 Cell Counts
CD4 cell count (absolute and percentage) will be determined at Screening, Day 1, and at 
Weeks 24, 48, 72 and 96, for subjects who continue into the study extension, CD4 cell count
will also be determined at the Study Week 144 and 192 visits.  The testing will be 
performed at the central laboratory using a commercially available assay.  If the investigator 
believes that more frequent CD4 cell counts are necessary for clinical care or are required per 
local treatment guidelines, then he/she has the option to add additional CD4 counts at a 
scheduled visit.  The samples should be sent to the central lab for processing.
7.1.3.7
Pharmacokinetic/Pharmacodynamic Evaluations
MK-1439 population PK samples will be collected from all subjects as outlined in Table 5.  
The exact time the dose of study medication was taken prior to the sample collection will be 
recorded on the appropriate eCRF. The type of meal (full, medium, light or no meal) 
consumed with the last dose of study medication prior to the collection of the PK sample will 
also be recorded on the appropriate eCRF. The type of meal is defined as the following:

No Meal - the subject did not have a meal

Light Meal - the subject consumed a snack (less than 250 calories)

Medium Meal - the subject consumed a small meal (from 250 to 750 calories)

Full Meal - the subject consumed a large meal (greater than 750 calories)
Note:  At Weeks 24 (Visit 8) and 48 (Visit 10), two PK samples will be collected, one pre-
dose and one 0.5-2.0 hours post dose.  Subjects should be fasting for the collection of the 
Week 48 samples. Subjects will be given their dose of MK-1439A in the office following the 
collection of the pre-dose sample and may stay in the office or return to the office for the 
collection of the post dose sample.  
 
 
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Table 5  Pharmacokinetic Sampling Timepoints
Visit Number
Study Day/Week
Time Relative to MK-1439A Dose
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
8
Week 24
Sample to be collected predose and within 0.5 to 2 
hours postdose.
10
Week 48
Sample to be collected predose and within 0.5 to 2 
hours postdose (Subject should remain fasting 
until the postdose PK sample is collected).
Sample collection, storage and shipment instructions for the PK samples will be provided in 
the operations/laboratory manual.
7.1.3.8
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
7.1.3.9
Future Biomedical Research Sample Collection
The following specimens are to be obtained as a part of Future Biomedical Research:

Leftover DNA for future research

Plasma for future research
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
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.  In addition all 
investigative products must be retrieved from the subject.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.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 
 
 
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be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
A centrifuge and -20 degrees Celsius freezer will be required for the processing and storage 
of lab samples.
Please refer to the central laboratory manuals for equipment requirements and necessary 
maintenance or calibration.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Written informed consent/assent must be obtained from the subject prior to performing any 
study-specific procedures. Potential subjects will be evaluated to determine if they fulfill the 
Inclusion/Exclusion entry requirements 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 up to 45 days.

All procedures listed for the Screening visit (Visit 1) in the Trial Flow Chart A  
(Section 6.0) must be completed and the subjects eligibility confirmed by the 
investigator prior MK-1439A administration on Day 1.
 
 
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
Blood will be collected for safety laboratory evaluations, Hemostatic function tests, 
HIV/Hepatitis Screen, HIV-1 RNA quantification, CD4 cell counts, and viral 
resistance testing.  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.
7.1.5.2
Treatment Period Visits (Visits 2 – 14)
Study Day 1 (Visit 2)

Procedures listed for Day 1 (Visit 2) on the Trial Flow Chart A (Section 6.0) should 
be performed prior to the dispensing study drug 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 remainder of the pretreatment 
(Day 1) testing/procedures will be performed.  If the urine pregnancy test result is 
positive, the subject must be discontinued from further participation.

Blood will be collected for safety laboratory evaluations, HIV-1 RNA quantification, 
CD4 cell counts, and PK measurements.  These samples will be sent to the 
appropriate central laboratory(ies) following the procedure(s) set forth in the 
manual(s).

Following completion of the Day 1 pretreatment procedures and confirmation of 
eligibility, the site pharmacist or study coordinator will contact the IVRS/IWRS for 
assignment of the drug to be administered. Sites should not call IVRS/IWRS for drug 
administration until the subject has met all criteria for the study and are ready to 
receive the first dose of study medication on Day 1.  Eligible subjects will receive a 
4-week supply of MK-1439A on Day 1 (Visit 2).  Subjects will be instructed to take 
their first dose of 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.
 
 
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Drug Administration

Subjects will be dispensed a bottle of study drug and will be instructed to take one 
tablet of MK-1439A q.d. orally, with or without food at approximately the same time 
each day.  The MK-1439A tablets must be kept in the bottle prior to taking study 
medication since the formulation being used in this study is moisture sensitive.
Week 2 (Visit 3) to Week 96 (Visit 14)

All procedures for treatment Week 2 (Visit 3) to Week 96 (Visit 14) listed on the 
Trial 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 Trial Flow Chart.  These samples will be sent to the appropriate 
central laboratory(ies) following the procedure(s) set forth in the manual(s).

For a female subject who is of childbearing potential, a urine pregnancy test will be 
performed at all study visits. If the urine pregnancy test result is positive, the subject 
must be discontinued.

Subjects will be required to fast for at least 8 hours prior to study visits at Weeks 12, 
48 and 96.

All bottles of study drug will be returned to the study coordinator at each visit, at 
which time the drug supplies for the following time period will be dispensed.  The 
number of tablets remaining in the bottle will be counted and recorded in the source 
documentation.  The primary source of adherence data, however, will be the subjects 
study medication diary.

Subjects will receive a 4-week supply of study drug at Week 4 (Visit 4), Week 8 
(Visit 5) and Week 12 (Visit 6); an 8-week supply at Week 16 (Visit 7) and a 12-
week supply at Week 24 (Visit 8), Week 36 (Visit 9), Week 48 (Visit 10), Week 60 
(Visit 11), Week 72 (Visit 12) and Week 84 (Visit 13) and, for subjects who are
considered eligible and elect to enter the study extension, a 16-week supply at
Study Week 96 (Visit 14).

At each treatment visit, the study coordinator and subject will review the study 
medication diary information.
7.1.5.3
Treatment Period Visits for Study Extension (Visit 15-20)

All procedures for Study Week 112 (Visit 15), Week 128 (Visit 16), Week 144
(Visit 17), Week 160 (Visit 18), Week 176 (Visit 19), and Week 192 (Visit 20)
listed on the Trial Flow Chart B (Section 6.0) should be performed.

Blood will be collected for safety laboratory evaluations and HIV-1 RNA
quantification at the time points specified in the Trial Flow Chart B. Samples for
CD4 counts will also be collected at the Study Week 144 and 192 visits. Subjects
will be required to fast for at least 8 hours prior to the Study Week 144 and 192
visits. Samples for HIV viral resistance will be collected only at the virologic
failure confirmation visit or, for subjects who
discontinue due to any other
 
 
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reason, at the early discontinuation visit. These samples will be sent to the
appropriate central laboratory(ies) following the procedure(s) set forth in the
manual(s).

For a female subject who is of childbearing potential, a urine pregnancy test
will be performed at all study visits. If the urine pregnancy test result is positive,
the subject must be discontinued.

All bottles of study drug will be returned to the study coordinator at each visit, at
which time the drug supplies for the following time period will be dispensed. The
number of tablets remaining in the bottle will be counted and recorded in the source
documentation.
The primary source of adherence data, however, will be the
subject’s study medication diary.

Site staff will access the IVRS/IWRS for registration of visits. Subjects will
receive a 16-week supply of study drug at each study visit through Week 192.

At each study visit the study coordinator and subject will review the study
medication diary information.
7.1.5.4
Virologic Failure Confirmation Visit

When a subject has a virologic failure confirmation visit performed, all procedures 
for the virologic failure confirmation visit listed on the Trial Flow Charts should be 
performed.
Protocol defined virologic failure (PDVF) for this study is defined as one of the following:
1) Confirmed (two 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
OR
2) Confirmed (two consecutive measures at least one week apart) HIV-1 RNA ≥200 
copies/mL at Week 24 or Week 36 
OR
3) Confirmed (two consecutive measures at least one week apart) HIV-1 RNA ≥50 
copies/mL at Week 48.
The virologic failure confirmation visit should be done between 1 and 4 weeks after the first 
measurement of HIV-1 RNA ≥50 copies/ml.
Subjects should be discontinued, regardless of compliance with study therapy, if they meet 
the protocol defined virologic failure criteria.  Subjects who discontinue study therapy due to 
virologic failure will complete an Early Discontinuation visit and a 14-day follow-up visit.  
In addition, subjects who discontinue study therapy due to virologic failure in the base study 
will be contacted approximately 24 weeks after the Early Discontinuation visit.  During this 
contact, information will be collected on the subjects’ subsequent HIV regimens (following 
discontinuation of the study treatment) and virologic outcome.  Details regarding the 
regimens used and virologic outcome will be recorded on the eCRF.
 
 
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7.1.5.5
Early Discontinuation Visit

When a subject discontinues/withdraws from participation in the trial, all procedures 
for the Early Discontinuation visit listed on the Trial Flow Charts should be 
performed.

At a minimum, the following information should be collected when a subject 
discontinues: 
o
The reason the subject discontinued
o
The date of the last dose of study medications from the trial
o
The date of the last assessment and/or contact
o
All Adverse events (AEs)  (including any Serious Adverse Events)

Any AEs which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 -
Assessing and Recording Adverse Events.

Subjects who discontinue early from the study are expected to return for a 14-day 
post therapy follow-up visit.
7.1.5.6
Post-Trial

Following the completion of study therapy (in the base study or study extension) or 
in the event of early discontinuation, subjects will be required to return to the clinic 
approximately 14 days after the last dose of study drug for the post-study visit as 
outlined in the Trial 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 AEs have occurred since the post-study clinic visit.

Follow-up of virologic failures in the base study at approximately 24 weeks after the 
early discontinuation visit to assess whether or not subjects who fail with MK-1439A 
are successful on subsequent treatment.
Assessing and Recording Adverse Events
7.2
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.  
 
 
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Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. 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 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than twice the recommended daily dose in a 
calendar day.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
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
7.2.2
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.
 
 
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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 6 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 
 
 
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be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
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
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 6. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 6 and Appendix 12.7 for instructions in evaluating 
adverse events.
 
 
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Table 6  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 a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AND IF REQUIRED, BY THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.  IF 
ADVANCED APPROVAL OF RECHALLENGE IS NOT REQUIRED BY LOCAL REGULATIONS, THE IRB/IEC WILL RECEIVE 
NOTIFICATION FOR INFORMATION ONLY.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
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. 
STATISTICAL ANALYSIS PLAN
8.0
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to data base lock, will be 
documented in a supplemental Statistical Analysis Plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Separate analysis plans (i.e., separate documents from the 
sSAP) will be developed to detail other planned analyses (e.g., analysis of PK data and future 
biomedical research).  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.  Analysis of data from the study extension does not require
changes to the SAP: all data from the extension will be summarized descriptively only, as
will be described in the sSAP.  These data will be summarized separately from data
generated from the base study.
Study Design Overview
A Phase IIa Multicenter, Open-Label, Clinical Trial to Evaluate 
the Safety and Efficacy of MK-1439A in Treatment-Naïve HIV-1 
Infected 
Subjects 
with 
Selected 
Non-Nucleoside 
Reverse 
Transcriptase 
Inhibitor 
(NNRTI) 
Transmitted 
Resistance 
Mutations
Treatment Assignment
Subjects meeting screening criteria were to be allocated to receive 
MK-1439A until the 20 evaluable subject minimums are met for 
both the K103N and Y181C single mutations or until a total of 60 
evaluable subjects are enrolled (whichever comes first). However, 
the study discontinued enrollment early with only 10 subjects.
Analysis Populations
Efficacy: mFAS 
Evaluability criteria for a modified Full Analysis Set (mFAS) 
population require that subjects take at least one dose of MK-
1439A and meet eligibility criteria regarding the presence of 
selected NNRTI resistance mutations based on central lab 
confirmation of the local lab results used for screening purposes.
Safety: All Patients as Treated (APaT)
Note, although subjects will be contacted for status after 
discontinuation due to virologic failure this data will not be used in 
the planned analysis populations but summarized separately.
Primary Endpoint(s)
1.
Proportion of subjects with HIV-1 RNA <50 copies/mL (by 
the Abbott RealTime HIV-1 Assay) at Week 48.
2.
Safety and tolerability by Week 48 and Week 96.
 
 
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Key Secondary Endpoints
1.
Change from baseline in CD4 cell count at Week 48 and 
Week 96.
2.
The proportion of subjects achieving HIV-1 RNA< 40 
copies/mL (BLoQ) (by the Abbott RealTime HIV-1 Assay) at 
Week 48 and Week 96.
3.
The proportion of subjects achieving HIV-1 RNA< 50 
copies/mL (by the Abbott RealTime HIV-1 Assay) at week 
96.
4.
Time-to-Loss-Of-Virologic-Failure (TLOVR) 
Statistical Methods for Key 
Efficacy Analyses
The observed failure (OF) missing data approach will be the 
primary approach to handling missing data.
Descriptive statistics will be provided with regard to the key 
efficacy endpoints including 95% confidence intervals.  The mFAS 
population using the OF missing data approach (primary) will be 
used wherein only subjects with observed viral loads post 
treatment at Week 48 or subjects who have previously 
discontinued due to lack of efficacy (imputed as failures) will be 
included.  Key efficacy analyses will also be summarized by 
mutation type.  
Statistical Methods for Key 
Safety Analyses
Safety and tolerability will be assessed by clinical review of all 
relevant parameters including adverse experiences (AEs), 
laboratory tests and vital signs.  Descriptive statistics will be 
provided for these safety parameters.
Interim Analyses
Two interim futility analyses will be performed in this study. The 
interim futility analyses are summarized below. Details are 
provided in Section 8.7. Both futility analyses will be performed 
using the mFAS population.
1st Futility Analysis
This analysis was originally to be performed when the first 10 
evaluable subjects belonging to the mFAS population have Week 4 
HIV-1 RNA data. Given the study discontinued enrollment early 
this analysis will be conducted with the evaluable subjects 
remaining on study.
2nd Futility Analysis
An ongoing assessment of the number of subjects belonging to the 
mFAS population who fail to achieve HIV-1 RNA <200 
copies/mL by Week 24 or who discontinue due to lack of efficacy 
(not otherwise attributed to non-compliance to study medication) 
at any time point up to and including Week 24.
Multiplicity
No multiplicity adjustment is necessary as there are no statistical 
hypothesis tests for this protocol.
Sample Size and Power 
There are no hypotheses in this study and all objectives will be 
addressed through summary statistics. The primary objective will 
be assessed based on the proportion of subjects with HIV-1 RNA 
<50 copies/mL at Week 48. Assuming an observed response rate 
of 80%, a sample size of 10 would provide a 2-sided exact 95% CI 
of [44.4%, 97.5].
 
 
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Responsibility for Analyses/In-House Blinding
8.2
Although the trial is open label, analyses or summaries generated by either the overall single-
arm cohort or by the cohort’s mutation type will be limited and documented. The interim 
futility analyses will be conducted by the Clinical Biostatistics department of the SPONSOR.
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. 
This trial is being conducted as a single-arm, open-label study, i.e., subjects, investigators, 
and SPONSOR personnel will be aware of subject treatment assignment after each subject is 
allocated and treatment is assigned.
The Clinical Biostatistics
department will generate
the allocation schedule for
study
treatment assignment. Allocation numbers will be assigned via an interactive voice 
response system (IVRS).  
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
8.4.1
An initial description of efficacy measures is provided in Section 4.2.4.
Proportions of Subjects with HIV-1 RNA <50 and <40 copies/mL 
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 proportions of subjects with HIV-1 RNA <50 and <40 copies/mL will be 
estimated at each time point.
The primary objective assesses the proportion of subjects achieving HIV-1 RNA <50
copies/mL at Week 48. The secondary objectives assess the proportion of subjects achieving 
HIV-1 RNA<50 copies/mL at Week 96 and <40 copies/mL (BLoQ of the Abbott RealTime 
HIV-1 Assay) at Week 48 and Week 96.
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 
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.
 
 
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Time to Loss Of Virologic Response (TLOVR)
For subjects who achieve HIV-1 RNA <50 copies/mL and subsequently have two 
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 two 
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 PDVF as defined in Section 4.2.4.1 will be summarized.
Change from Baseline in log10 HIV-1 RNA 
Change from baseline in log10 HIV-1 RNA at Week 4 (Week 4 – baseline) will be calculated 
for the first interim futility analysis.  The use of this endpoint will provide a more sensitive 
measure of study drug activity at an early timepoint than the proportion of patients falling 
below a threshold (e.g., <50 copies/mL).
Safety Endpoints
8.4.2
An initial description of safety measures is provided in Section 4.2.4.
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 discontinue
study therapy due to an adverse experience. Specific adverse experiences by system organ
class tests will also be summarized.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory tests, subjects must have both a baseline and 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 (Section 12.7).  A listing of the subjects who meet the criteria
will be provided.
Analysis Populations
8.5
Eligible subjects enter the trial when the treatment allocation number is centrally assigned 
using IVRS/IWRS (see Section 5.3).
 
 
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Efficacy Analysis Populations
8.5.1
The modified Full Analysis Set (mFAS) population will serve as the primary population for
the analysis of efficacy data in this study. The modified FAS population consists of all 
allocated subjects who:

receive at least one dose of study treatment,

have baseline data for those analyses that require baseline data, meet eligibility 
criteria regarding the presence of NNRTI resistance mutations based on central lab 
results

Details on the approach to handling missing data are provided in Section 8.6
Statistical Methods.
Safety Analysis Populations
8.5.2
The All Patients as Treated (APaT) population will be used for the analysis of safety data in 
this study. The APaT population consists of all allocated subjects who received at least 
one dose of study treatment.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose
of study treatment is required for inclusion in the analysis of each specific parameter. To
assess change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in
Section 8.6 Statistical Methods.
Statistical Methods
8.6
As this is an open-label, single arm study, only descriptive summary statistics and confidence 
intervals will be provided for both efficacy and safety endpoints with no tests of hypotheses. 
Demography, efficacy and safety data from the study extension, for those subjects who 
continue into the extension, will be summarized separately using descriptive statistics only. 
Statistical Methods for Efficacy Analyses
8.6.1
Time Window
Table 7 lists the definition of time windows and the target day relative to Day 1 for the
scheduled visits in the study that 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.
 
 
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Table 7  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
  
Open-
Label
Week 2
2 and  21
15
Week 2
Week 4
22and  42
29
Week 4
Week 8
43 and 70
57
Week 8
Week 12
71 and 98
85
Week 12
Week 16
99 and  140
113
Week 16
Week 24
141 and  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 728
673
Week 96
Treatment 
Extension
Open 
Label
Week 112
≥729 and ≤840
785
Week 112
Week 128
≥841 and ≤952
897
Week 128
Week 144
≥953 and ≤1064
1009
Week 144
Week 160
≥1065 and ≤1176
1121
Week 160
Week 176
≥1177 and ≤1288
1233
Week 176
Week 192
≥1289
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.
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 8). The primary approach for 
the analysis of the proportion of subjects achieving HIV-1 RNA <50 copies/mL is the 
Observed Failure (OF) approach. Under this approach, non-intermittent missing data for 
subjects who prematurely discontinued assigned treatment due to lack of efficacy are 
considered as failures at timepoints thereafter. Subjects with other reasons for missing data
will be excluded from the analyses.  
 
 
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A second supportive approach will use a Non-Completer=Failure (NC=F) approach
as defined by the FDA “snapshot” approach. Under this approach, only subjects meeting
the following can be classified as virologic success at a given time point: 1) subject is on
study-assigned treatment, 2) subject has HIV-1 RNA measurement(s) within the time
window specified in  Table 7, and Table 3) subject has the measurement closest to the
target date of the time point <50 copies/mL. The other subjects, either with an 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.  
The same approaches as described above will be used for the analysis of the proportion of
subjects achieving HIV-1 RNA <40 copies/mL.
Table 8  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 
Discontinuation 
Due to 
Clinical/Lab 
Adverse 
Experience
Study Therapy 
Discontinuation 
Due to Lack of 
Efficacy
OF
Excluded
Excluded
Failures†
Excluded
Failures†
NC=F
Failure
Failures
Failures
Failures
Failures
§ OF (Observed Failure) is the primary approach; NC=F (Non-Completer=Failure).
† Subjects will be excluded in the OF approach if central lab test results based on baseline samples indicate 
NNRTI mutant types for a subject that are resistant to MK-1439.
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 
mutation type at each time point, with primary interest at Week 48. A 95% confidence 
interval will be calculated using the exact binomial method proposed by Clopper and Pearson 
(1934) [8] for the proportion of subjects achieving HIV-1 RNA <50 copies/mL at each time 
point.
The primary analysis approach will be based on the OF approach under which subjects with
non-intermittent missing data because they prematurely discontinued assigned treatment
due to lack of efficacy are considered as failures at timepoints thereafter. The NC=F
approach as defined by FDA “snapshot” approach will be used as the secondary 
approach to analysis wherein 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 within 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 will be summarized.
 
 
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Proportion of Subjects Achieving HIV-1 RNA <40 copies/mL
The proportion of subjects achieving HIV-1 RNA <40 will be analyzed using the same 
approach as described above for the proportion of subjects achieving HIV-1 RNA <50 
copies/mL.
Change from Baseline in CD4 cell counts
Change from baseline in CD4 cell counts will be summarized at each time  point  at  
which CD4 cell  count  is  collected, with  a key interest  at  Week  48.  
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. 
Protocol Defined Virologic Failure (PDVF)
The number of subjects with PDVF will be summarized.
Resistance
Genotypic and phenotypic resistance data from subjects with protocol defined virologic 
failure will be summarized.
Table 9 summarizes the key efficacy analyses.
Table 9  Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary 
vs. 
Supportive 
Approach
†
Statistical Method
Analysis
Populatio
n
Missing Data 
Approach
Primary Objective
Proportion of subjects achieving 
HIV-1 RNA <50 copies/mL at
Week 48
P
Descriptive statistics 
overall and by mutant 
type
mFAS
OF approach
Proportion of subjects achieving 
HIV-1 RNA <50 copies/mL at
Week 48
S
Descriptive statistics 
overall and by mutant 
type
mFAS
NC=F approach
Secondary Objectives
Proportion of subjects achieving 
HIV-1 RNA <40 copies/mL at
Week 48 and Week 96
P
Descriptive statistics 
overall and by mutant 
type
mFAS
OF approach
Proportion of subjects achieving 
HIV-1 RNA <40 copies/mL at
Week 48 and Week 96
S
Descriptive statistics 
overall and by mutant 
type
mFAS
NC=F approach
Proportion of subjects achieving 
HIV-1 RNA <50 copies/mL at 
Week 96
P
Descriptive statistics 
overall and by mutant 
type
mFAS
OF approach
 
 
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Endpoint/Variable
(Description, Time Point)
Primary 
vs. 
Supportive 
Approach
†
Statistical Method
Analysis
Populatio
n
Missing Data 
Approach
Change from baseline in CD4
cell counts at Week 48 and 
Week 96
P
Descriptive statistics 
overall and by mutant 
type
mFAS
OF approach 
assuming baseline-
carried-forward
Time-to-Loss-Of- Virologic-
Failure (TLOVR)
P
Kaplan-Meier product 
limit estimates and 
graph overall and by 
mutant type
mFAS
Not applicable
† P=Primary approach; S=Secondary approach.
Descriptive statistics will be number and percent (95% CI) for binary endpoints and mean (95% CI) for continuous
endpoints.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple timepoints, and/or interim analyses is described in Section 8.7, Interim Analyses and 
in Section 8.8, Multiplicity. As described in Section 8.8, no multiplicity adjustment is 
necessary as there are no statistical hypothesis tests for this protocol.
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests and vital signs.  Descriptive statistics will be 
provided for these safety parameters.  Summary statistics will be number and percent (95%
CI) for incidence of adverse experiences and mean (SD) for change from baseline in 
laboratory test.
The proportions of patients with clinical or laboratory adverse experiences of the following
types will be tabulated overall and by mutant type: (1) at least one adverse experience; (2)
a drug-related adverse experience; (3) a serious adverse experience; (4) serious and drug-
related adverse experiences; (5) adverse experience leading to discontinuation.
The percentage of patients with specific adverse experiences by system organ class and the
number and percentage of patients with laboratory tests that exceed the Pre-Defined Limit
of Change in laboratory tests will also be summarized in the same fashion.
Summary statistics for baseline, on-treatment, and change from baseline values in laboratory
parameters will be provided overall and by mutant type.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
8.6.3.1
Demographic and Baseline Characteristics
Baseline characteristics for all allocated and treated patients will be summarized by the 
use of descriptive statistics. No statistical hypothesis tests will be performed on these
characteristics. The number and percentage of patients screened, allocated, the primary
reasons for screen  failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age, gender and race, history of AIDS, mutant type),
primary and secondary diagnoses, prior and concomitant therapies will be summarized
using descriptive statistics for continuous or categorical variables, as appropriate. 
 
 
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Summary statistics for baseline efficacy measures such as HIV RNA and CD4 cell count will
also be provided.
8.6.3.2
Population PK Analyses
Based on pharmacokinetic data
obtained within this study, a separate population 
Pharmacokinetics (PK) analysis will be performed. The prospective details of this analysis 
will be specified in a separate population PK analysis plan.
Interim Analyses
8.7
Two interim futility analyses will be performed. Both analyses will be conducted and 
evaluated internally by the study team.  No external data monitoring committee will be used 
in this study.  If futility criteria are satisfied the study team will discuss the analysis results 
with management at the Sponsor to make a final determination for stopping the study.
1st Futility Analysis
Initially, the first futility analysis was planned that after the first 10 evaluable mFAS-
allocated subjects complete their Week 4 visit and have HIV-1 RNA data available, an 
interim futility analysis would be performed. Given enrollment was halted at 10 subjects, 
this analysis will be performed using all evaluable subjects.
If the mean change from baseline in log10 HIV-1 RNA at Week 4 is not a decline of 1.5 or 
more, the study may stop for futility.  If the viral load dynamics in this study are the same as 
those observed in Protocol 007, there is 0.1% chance to possibly stop for futility.  Week 24 
data from the MK-1439 100 mg treatment group in Protocol 007 were used to determine the 
expected log decline in HIV-1 RNA at Week 4.  Based on an analysis of these data, the mean 
(SD) change from baseline (log10 HIV-1 RNA, Week 4 – Baseline) was -2.09 (0.53).  Under 
a conservative assumption that the true mean is -2.04 (mean + 1SE), by simulation, the 
likelihood of stopping for futility (i.e. observing a mean ≥-1.5) at Week 4 is <0.1%.  
2nd Futility Analysis
This analysis is an ongoing assessment of the number of subjects belonging to the mFAS 
population who fail to achieve HIV-1 RNA <200 copies/mL by Week 24 or who discontinue 
due to lack of efficacy (not attributed to non-compliance) at any time up to and including 
Week 24.  The percentage of subjects in the MK-1439 100 mg treatment group of Protocol 
007 who failed to achieve HIV-1 RNA <200 copies/mL by Week 24 or who discontinued 
due to lack of efficacy at any time up to and including Week 24 was 3.7% (4/108).  
Therefore, it is expected that 3.7% of 10 evaluable subjects (1 subject, rounding up), would 
meet this criterion in Protocol 030 if complete data on 10 subjects were available.  Based on 
this expected number, simulation was used to determine the likelihood of stopping for futility 
using >1 subject out of 10 as the criterion.  The criterion of >1 was chosen based on the low 
likelihood of stopping (5%) when the expected number is <1. 
Multiplicity
8.8
No multiplicity adjustment is necessary as there are no statistical hypothesis tests for this 
protocol.
 
 
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Sample Size and Power Calculations
8.9
Sample Size and Power for Efficacy Analyses
8.9.1
The primary objective will be assessed based on the proportion of subjects with HIV-1 RNA 
<50 copies/mL at Week 48. This is an estimation study only with no hypotheses. The 
expected response rate is ~80% based on previous treatment-naïve clinical trials. MK-1439A 
is expected to be similarly active against each of the mutant types. Subjects meeting 
screening criteria were allocated to receive MK-1439A until the 20 evaluable subject 
minimums are met for both the K103N and Y181C single mutations or until a total of 60 
evaluable subjects are enrolled (whichever comes first).  However, enrollment was stopped 
after only 10 subjects were enrolled.  Assuming an observed response rate of 80%, a sample 
size of 10 would provide a 2-sided exact 95% CI of [44.4%, 97.5%].
Sample Size and Power for Safety Analyses
8.9.2
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 
<10.0% chance of observing at least one adverse experience of that type among 10 subjects.  
If no adverse experience of that type is observed among the 10 subjects, this study will 
provide 95% confidence that the underlying percentage of subjects with that particular 
adverse experience is <31%.   
Subgroup Analyses and Effect of Baseline Factors (Base Study)
8.10
To characterize the efficacy response across various subgroups, the primary endpoint will be
summarized 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)

NNRTI mutation type (K103N, Y181C and G190A)

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 C status (HCV-infected or HCV-uninfected)

Baseline CD4 categories (100-200, and >200 cells/mm3)
 
 
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The Observed Failure approach will be used to handle missing values in these subgroup 
analyses.
Compliance (Medication Adherence)
8.11
Study Medication Diary Cards will be used to ensure and document drug compliance.
Subjects are to take one pill of study medication once daily. For the main analysis of
compliance in this study, a day within the study will be considered an “On-Therapy” day if
the subject takes study drug.
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: 
Summary statistics will be provided for percent compliance for the mFAS population.
Data from the study medication diary, rather than the returned pill count will serve as the
primary data for compliance.
Extent of Exposure
8.12
The extent of exposure to study therapy for all treated subjects will be summarized. The 
number of subjects exposed to various doses (actual total daily dose) for defined periods of 
time will be listed, along with a summary of the mean (range) duration subjects were exposed 
to various doses.
LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
9.0
SUPPLIES
Investigational Product 
9.1
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 10.
Table 10  Product Descriptions
Product Name & Potency
Dosage Form
MK-1439A 100 mg/Lamivudine 300 
mg/Tenofovir Disoproxil Fumarate 300 mg
Tablet
 
 
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Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label monthly bottles.  No kitting is required.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
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
9.5
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
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
 
 
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ADMINISTRATIVE AND REGULATORY DETAILS
10.0
Confidentiality
10.1
Confidentiality of Data
10.1.1
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
10.1.2
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
10.1.3
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;
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.
 
 
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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
10.1.4
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
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
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 Merck, is provided in Section 12.1 -
Merck 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.
 
 
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
 
 
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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, Merck, 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
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow 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
10.5
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
10.6
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.
 
 
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
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. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
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 
 
 
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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.
LIST OF REFERENCES
11.0
1. Pham QD, Wilson DP, Law MG, Kelleher AD, Zhang L.  Global burden of transmitted 
HIV drug resistance and HIV-exposure categories:  a systematic review and meta-
analysis.  AIDS  2014; 28:  2751-2762.
2. Frentz D, van de Vijver D, Abecasis A, Albert J, Hamouda O, et al.  Patterns of 
Transmitted HIV Drug Resistance in Europe Vary by Risk Group.   PLoS ONE  2014;  
9(4):  e94495.
3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and 
Human 
Services. 
April 
8, 
2015; 
1-288. 
Available 
at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.
4. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV 
infection - recommendations for a public health approach.  Department of Health and 
Human 
Services. 
 
April 
8, 
2015; 
1-11. 
 
Available 
at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/aa_recommendations.pdf 
5. Anderson M, Gilmartin J, Cilissen C, etc., Safety, Tolerability, and Pharmacokinetics of 
Single and Multiple Doses of MK-1439, a Novel HIV Non-Nucleoside Reverse 
Transcriptase Inhibitor, in Healthy Subjects, Abstract presented at Conference on 
Retroviruses and Opportunistic Infections, March 3 – 6, 2014, Boston, MA 
6. Morales-Ramirez JO, Gatel JM, Hagins DP, Thompson M, Arasteh K, Hoffman C, C. 
Harvey C, Xu X, Teppler H. Safety and antiviral effect of MK-1439, a novel NNRTI, 
(+Truvada®) in ART-Naïve HIV infected patients.  Presented at Conference on 
Retrovirus and Opportunistic Infections (CROI) March 3-6, 2014 
7. Gatell JM, Morales-Ramirez JO, Hagins DP, Thompson M, Keikawus A, et al.  Forty-
eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a 
novel NNRTI, with TDF/FTC in ART-naïve HIV-positive patients.  JIAS 2014; 17(Suppl 
3):  19532.
8. 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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APPENDICES
12.0
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.9 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Table B: Approximate Blood Volume Drawn From Week 112 Through Week 144 Plus 14 Days Follow-up (Study Extension)
Week (Visit)
WK
112
(V15)
WK
128
(V 16)
WK
144
(V 17)
WK
160
(V 18)
WK
176
(V 19)
WK
192
(V 20)
Virologic
Failure
Confirmation
(U)
Extension
Early
Discontinuation
(U)
14 Day
Follow-up
(Post Treatment)
(99)
Total
Volume
Hematology
2
2
2
2
2
2
2
2
2
18
Chemistry
7
7
7 a
7
7
7 a
7
7
7
63
Plasma for HIV Viral RNA
10
10
10
10
10
10
10
10
10
90
CD4 Cell Count
2
2
4
Plasma for Viral Resistance
14
14b
28
TOTAL (mL)
19
19
21
19
19
21
33
33
19
203
Total (tablespoons) c
1.3
1.3
1.4
1.3
1.3
1.4
2.2
2.2
1.3
~13.5
a.    Fasting is required at these visits for lipids measurement.
b.    If viral failure or relapse is confirmed (with a confirmatory HIV-1 RNA at least one week later), and the decision is made to discontinue the subject, plasma for resistance need
not be collected again at the early discontinuation visit.
c.    One tablespoon = 15 mL.
 
 
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Plasma Assay – Sample Collection, Handling, Labeling, Storage, and Shipment
12.5
See Laboratory Manual.
 
 
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List of Abbreviations and Acronyms
12.6
3TC
lamivudine
β-hCG
β-human chorionic gonadotropin
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
AMA
American Medical Association
APaT
All Patients as Treated
APTT
Activated partial thromboplastin time
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
BLoQ
Below the limit of quantification
CCR5
Chemokine Receptor Type 5
CI
Confidence Interval
Clcr
Creatinine clearance
CSR
Clinical study report
CYP
cytochrome
DAIDS
Division of acquired immunodeficiency syndrome
DNA
Deoxyribonucleic acid
ECG
electrocardiogram
ECI
Event of clinical interest
eCRF
Electronic case report form
EFV
efavirenz
ERC
Ethical review committee
EU
European union
FAS
Full analysis set
FBR
Future Biomedical Research
FDA
Food & Drug Administration
FDAAA
Food & Drug Administration Amendments Act
FDAMA
Food & Drug Administration Modernization Act
FDC
Fixed dose combination
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 immune deficiency virus type 1
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International conference on harmonization
IDU
Injection drug users
IEC
Independent ethics committee
INR 
International normalized ratio
InSTI
Integrase strand transfer inhibitors
IQ
Inhibitory Quotient
IRB
Institutional Review board
IRIS
Immune reconstitution syndrome
IUD
Intrauterine device
 
 
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IVRS/IWRS
Interactive voice response system/Integrated web 
response system
LDL-C
Low-density lipoprotein cholesterol
LOQ
Lower limit of reliable quantification
mFAS
Modified full analysis set
MSM
Men who have sex with men
NC=F
Non-completer = failure
NHS
Normal human serum
NNRTI
Non-nucleotide reverse transcriptase inhibitor
NRTI
Nucleotide reverse transcriptase inhibitor
N(t)RTI
Nucleotide reverse transcriptase inhibitor
OF
Observed failure
PCR
Polymerase chain reaction
PDLC
Predefined limit of change
PDVF
Protocol defined virologic failure
PI
Protease inhibitor
PIN
Personal Identification number
PK
pharmacokinetics
PO
Per oral
PT
Prothrombin time
PWID
People who inject drugs
q.d.
Once daily
RNA
Ribonucleic acid
SAE
Serious adverse event
siDMC
Standing internal data monitoring committee
SOP
Standard operating procedure
sSAP
Supplemental statistical analysis plan
TDF
Tenofovir disoproxil fumarate
TDF/FTC
Tenofovir 
disoproxil 
fumarate/Emtricitabine 
(TRUVADA™)
TDR
Transmitted drug resistance
TLOVR
Time to loss of virologic response
vRNA
Viral ribonucleic acid
WT
Wild Type
 
 
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Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events
12.7
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 
Pediatric 1 year – 14 years 
3.0 – 3.5 mg/dL 0.97 –
2.5 – 2.9 mg/dL 0.81 –
1.5 – 2.4 mg/dL 0.48 –
< 1.50 mg/dL < 0.48 mmol/L 
 
 
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Product:  MK-1439A 
110
Protocol/Amendment No.: 030-02 
MK-1439A-030-02 Final Protocol
5-Jun-2017
Confidential
LABORATORY
PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 SEVERE
GRADE 4 POTENTIALLY 
LIFE-THREATENING
1.13 mmol/L 
0.96 mmol/L 
0.80 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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Product:  MK-1439A 
111
Protocol/Amendment No.: 030-02 
MK-1439A-030-02 Final Protocol
5-Jun-2017
Confidential
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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Product:  MK-1439A 
112
Protocol/Amendment No.: 030-02 
MK-1439A-030-02 Final Protocol
5-Jun-2017
Confidential
Child-Pugh Score for Cirrhosis Mortality
12.8
Measure
1 point
2 points
3 points
Total bilirubin, μmol/l (mg/dl)
<34 (<2)
34-50 (2-3)
>50 (>3)
Serum albumin, g/dl
>3.5
2.8-3.5
<2.8
Prothrombin time, prolongation 
(secs)
<4.0
4.0-6.0
>6.0
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed 
with medication)
Grade III-IV (or 
refractory
 
 
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Product:  MK-1439A 
113
Protocol/Amendment No.: 030-02 
MK-1439A-030-02 Final Protocol
5-Jun-2017
Confidential
SIGNATURES
13.0
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
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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