Clinical trial NCT03552536
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-10-07; Completion date: 2019-03-11
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study aims to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-retroviral therapy (ART) activity of the tenofovir prodrug, MK-8583 monotherapy in ART-naïve, HIV-1 infected participants. The primary hypothesis is that at a dose that is sufficiently safe and generally well tolerated, MK-8583 has superior anti-retroviral activity compared to historical placebo, as measured by change from baseline in plasma HIV-1 ribonucleic acid (RNA) (log10 copies/mL) at 168 hours post-dose.

Detailed description:

Arms: arm 1: After fasting, a single oral dose of 100 mg MK-8583 in capsule form. arm 2: After fasting, a single oral dose of ≤ 150 mg MK-8583 in capsule form, with the dose based on the results from earlier treatments arm 3: After fasting, a single oral dose of ≤ 150 mg MK-8583 in capsule form, with the dose based on the results from earlier treatments
Interventions: intervention 1: MK-8583
Intervention descriptions: intervention 1: A single oral dose of MK-8583 in capsule form

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03552536 
Document Date: 
09-Mar-2018
A Single-Dose Clinical Trial to Study the Safety, Tolerability, 
Pharmacokinetics, and Anti-Retroviral Activity of MK-8583 
Monotherapy in Anti-Retroviral Therapy (ART)-Naïve, HIV-1 
Infected Patients


Product: MK-8583 
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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
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 Single-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Anti-
Retroviral Activity of MK-8583 Monotherapy in Anti-Retroviral Therapy (ART)-Naïve, 
HIV-1 Infected Patients
  
EudraCT NUMBER:  2017-004017-92 
 
 
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................... 9
2.0
TRIAL DESIGN.......................................................................................................... 9
Trial Design ............................................................................................................. 9
2.1
Trial Diagram........................................................................................................ 11
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 11
Primary Objective(s) & Hypothesis(es) .............................................................. 11
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 12
3.2
Exploratory Objectives......................................................................................... 12
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 12
Background ........................................................................................................... 12
4.1
Pharmaceutical and Therapeutic Background .................................................... 12
4.1.1
MK-8583............................................................................................................. 13
4.1.2
Rationale................................................................................................................ 15
4.2
Rationale for the Trial and Selected Subject Population .................................... 15
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 15
4.2.2
Starting Dose for This Trial ......................................................................... 16
4.2.2.1
Maximum Dose/Exposure for This Trial..................................................... 17
4.2.2.2
Rationale for Dose Interval.......................................................................... 18
4.2.2.3
Rationale for Endpoints ...................................................................................... 19
4.2.3
Safety Endpoints .......................................................................................... 19
4.2.3.1
Pharmacokinetic Endpoints ......................................................................... 19
4.2.3.2
Pharmacodynamic Endpoints....................................................................... 19
4.2.3.3
Planned Exploratory Biomarker Research................................................... 20
4.2.3.4
Future Biomedical Research........................................................................ 20
4.2.3.5
Benefit/Risk ........................................................................................................... 21
4.3
5.0
METHODOLOGY ................................................................................................... 21
Entry Criteria........................................................................................................ 21
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 21
5.1.1
Subject Inclusion Criteria.................................................................................... 21
5.1.2
Subject Exclusion Criteria .................................................................................. 22
5.1.3
 
 
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Trial Treatment(s) ................................................................................................ 24
5.2
Dose Selection/Modification .............................................................................. 24
5.2.1
Dose Selection (Preparation) ....................................................................... 24
5.2.1.1
Dose Modification (Escalation/Titration/Other).......................................... 25
5.2.1.2
Timing of Dose Administration .......................................................................... 25
5.2.2
Trial Blinding...................................................................................................... 25
5.2.3
Randomization or Treatment Allocation............................................................ 25
5.3
Stratification.......................................................................................................... 26
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 26
5.5
Rescue Medications & Supportive Care............................................................. 27
5.6
Diet/Activity/Other Considerations..................................................................... 27
5.7
Diet and Fruit Juice Restrictions......................................................................... 27
5.7.1
Diet............................................................................................................... 27
5.7.1.1
Fruit Juice Restrictions ................................................................................ 27
5.7.1.2
Alcohol, Caffeine, Tobacco, Activity ................................................................. 28
5.7.2
Alcohol Restrictions..................................................................................... 28
5.7.2.1
Caffeine Restrictions.................................................................................... 28
5.7.2.2
Smoking Restrictions................................................................................... 28
5.7.2.3
Activity Restrictions .................................................................................... 28
5.7.2.4
Contraception and Pregnancy Testing ................................................................ 28
5.7.3
Contraception............................................................................................... 28
5.7.3.1
5.7.3.1.1
Pregnancy Testing................................................................................. 29
Subject Withdrawal/Discontinuation Criteria................................................... 29
5.8
Discontinuation................................................................................................... 29
5.8.1
Withdrawal from the Trial .................................................................................. 29
5.8.2
Subject Replacement Strategy............................................................................. 29
5.9
Beginning and End of the Trial ........................................................................... 30
5.10
Clinical Criteria for Early Trial Termination ................................................... 30
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 32
7.0
TRIAL PROCEDURES ........................................................................................... 35
Trial Procedures ................................................................................................... 35
7.1
Administrative Procedures.................................................................................. 35
7.1.1
 
 
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Informed Consent......................................................................................... 35
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 35
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 35
Inclusion/Exclusion Criteria ........................................................................ 36
7.1.1.2
Subject Identification Card .......................................................................... 36
7.1.1.3
Medical History ........................................................................................... 36
7.1.1.4
Prior and Concomitant Medications Review ............................................... 36
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 36
7.1.1.5.2
Concomitant Medications..................................................................... 36
Assignment of Screening Number............................................................... 36
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 36
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other) ................................... 37
7.1.1.8
Clinical Procedures/Assessments........................................................................ 37
7.1.2
Laboratory Procedures/Assessments .................................................................. 39
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 39
7.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 40
7.1.3.2
7.1.3.2.1
Blood Collection for Plasma TFV and MK-8583................................. 40
7.1.3.2.2
Blood Collection for PBMC ................................................................. 40
7.1.3.2.3
Blood Collection for HIV-1 Viral RNA and Viral Resistance ............. 40
Planned Genetic Analysis Sample Collection.............................................. 40
7.1.3.3
Future Biomedical Research Samples ......................................................... 41
7.1.3.4
Other Procedures................................................................................................. 41
7.1.4
Withdrawal/Discontinuation........................................................................ 41
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 41
7.1.4.1.2
Lost to Follow-up.................................................................................. 42
Subject Blinding/Unblinding ....................................................................... 42
7.1.4.2
Domiciling ................................................................................................... 42
7.1.4.3
Calibration of Critical Equipment................................................................ 42
7.1.4.4
Visit Requirements.............................................................................................. 43
7.1.5
Screening...................................................................................................... 43
7.1.5.1
Treatment Period.......................................................................................... 43
7.1.5.2
7.1.5.2.1
Pre-dose Procedures (All Panels) ......................................................... 43
 
 
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7.1.5.2.2
Treatment Procedures (All Panels)....................................................... 43
Post-Trial...................................................................................................... 43
7.1.5.3
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 44
7.1.5.4
Trial 
Design/Dosing/Procedures Modifications Permitted 
within 
7.1.5.5
Protocol Parameters ..................................................................................... 45
Assessing and Recording Adverse Events .......................................................... 46
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 46
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 47
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 47
7.2.3
Serious Adverse Events ............................................................................... 47
7.2.3.1
Events of Clinical Interest............................................................................ 48
7.2.3.2
Evaluating Adverse Events ................................................................................. 49
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 52
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 52
Statistical Analysis Plan Summary ..................................................................... 52
8.1
Statistical Analysis Plan ....................................................................................... 53
8.2
Hypotheses.......................................................................................................... 53
8.2.1
Analysis Endpoints ............................................................................................. 53
8.2.2
Approaches to Analyses...................................................................................... 54
8.2.3
Statistical Methods.............................................................................................. 54
8.2.4
Multiplicity ......................................................................................................... 56
8.2.5
Sample Size and Power....................................................................................... 56
8.2.6
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 56
Investigational Product ........................................................................................ 56
9.1
Packaging and Labeling Information ................................................................. 57
9.2
Clinical Supplies Disclosure................................................................................. 57
9.3
Storage and Handling Requirements.................................................................. 57
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 57
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 58
Confidentiality....................................................................................................... 58
10.1
 
 
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Confidentiality of Data ....................................................................................... 58
10.1.1
Confidentiality of Subject Records ..................................................................... 58
10.1.2
Confidentiality of Investigator Information........................................................ 58
10.1.3
Confidentiality of IRB/IEC Information............................................................. 59
10.1.4
Compliance with Financial Disclosure Requirements....................................... 59
10.2
Compliance with Law, Audit and Debarment ................................................... 59
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 61
10.4
Quality Management System............................................................................... 61
10.5
Data Management................................................................................................. 61
10.6
Publications ........................................................................................................... 62
10.7
11.0
LIST OF REFERENCES......................................................................................... 63
12.0
APPENDICES........................................................................................................... 64
Merck Code of Conduct for Clinical Trials........................................................ 64
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 66
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.3
by Sample Types ................................................................................................... 70
Algorithm for Assessing Out-of-Range Laboratory Values ............................. 71
12.4
List of Abbreviations Used in this Document..................................................... 72
12.5
13.0
SIGNATURES........................................................................................................... 75
Sponsor's Representative ..................................................................................... 75
13.1
Investigator............................................................................................................ 75
13.2
 
 
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LIST OF TABLES
    
Table 1
Dose Plan................................................................................................................ 11
Table 2
Exposure predictions for the starting dose of 100 mg ............................................ 17
Table 3
Trial Treatment ....................................................................................................... 24
Table 4
Sample Allocation Schedule................................................................................... 26
Table 5
Laboratory Tests ..................................................................................................... 39
Table 6
PK (Blood)/PBMC/Viral Load Collection Windows ............................................. 44
Table 7
Post-dose Standard Safety Evaluations Collection Windows................................. 44
Table 8
Evaluating Adverse Events..................................................................................... 50
Table 9
Product Descriptions............................................................................................... 57
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design Diagram ......................................................................................... 11
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-8583 Single Dose Study in HIV-1 Infected Patients
Sponsor Product Identifiers
MK-8583
Trial Phase
Phase Ib
Clinical Indication
Treatment of HIV-1 Infection
Trial Type
Interventional
Type of control
Historical placebo control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Up to three panels (Panel A, B, and C) of 6 subjects each will receive 
a single dose of MK-8583.
Number of trial subjects
Approximately 18 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 7 
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 8 weeks
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of approximately 4 
weeks, each subject will be receiving assigned treatment for 1 day.  
After the end of treatment each subject will be followed for
approximately 28
days.
Subjects choosing to forgo follow-on 
combination anti-retroviral therapy (ART) may also be asked if they 
wish to continue to participate in observational monitoring beyond 28 
days.
A list of abbreviations used in this document can be found in Section 12.5.
2.0 TRIAL DESIGN
Trial Design
2.1
This is an open-label, single-dose, multiple panel trial to evaluate the safety, tolerability, 
pharmacokinetics (PK), and anti-retroviral therapy (ART) activity of MK-8583 monotherapy 
in ART-naïve, Human Immunodeficiency Virus type 1 (HIV-1) infected subjects. The 
primary study endpoints are the safety and tolerability of MK-8583 and the change in plasma 
HIV-1 RNA (log10 copies/mL) compared with historical placebo data.  This study will be 
conducted in conformance with Good Clinical Practices.
Up to three panels of 6 subjects each will be enrolled in a sequential manner. All doses of 
study drug will be administered following at least an 8-hour fast. In each panel, subjects will 
receive a single dose of MK-8583. Safety procedures and biological specimen collections 
will occur at designated time points. Subjects in Panel A will receive a single oral dose of 
MK-8583 100 mg. The exact dose administered in Panels B and C will be selected following 
review of all available safety, PK and viral dynamic data from prior panel(s); the dose will 
not exceed 150 mg. There will be an interval of time between dosing of panels to allow for 
 
 
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review of safety, PK, and viral dynamic data to inform dose selection in the following panel. 
It is estimated that this review will take approximately 30-40 days. 
Initiation of ART: At a designated time following administration of study drug, subjects 
will be encouraged to initiate an ART regimen. The exact timing and regimen will be decided 
by the subject in consultation with his/her physician, but ART initiation will not occur before 
Day 10 post-dose (see Section 5.5). Once initiated, the duration of suppressive ART is 
recommended to be at least ~25 days, or approximately 5 half-lives of tenofovir diphosphate 
(TFV-DP) in peripheral blood mononuclear cells (PBMCs). To lessen the chance of HIV 
resistance mutations, the Sponsor recommends that ART initiation occurs on or before Day 
14 post-dose. The Sponsor will not provide this therapy.
The initiation of follow-on ART is not a requirement for participation in the study. All 
subjects will be followed for safety monitoring for a maximum of approximately 28 days 
after dosing of MK-8583. If subjects start ART as planned, on Day 10 through 14 after 
dosing, the final blood draw for viral load (VL), viral resistance, or PK will occur on the day 
of ART initiation (prior to receiving the first dose of ART).
If subjects do not initiate ART, the Investigator may ask to continue regular blood draws for 
PK assessments, VL changes, and viral resistance for up to ~28 days post-dose. Subjects 
choosing to forgo follow-on ART may also be asked if they wish to continue to participate in 
observational monitoring of VL and viral resistance beyond 28 days. The timing of these 
blood draws beyond Day 28 will first be discussed with the Sponsor.
If subjects initiate an ART regimen that does not include tenofovir disoproxil fumarate 
(TDF) or tenofovir alafenamide fumarate (TAF), the Investigator may ask to continue regular 
blood draws for PK assessments for up to ~28 days post-dose. The timing of these blood 
draws beyond Day 28 will first be discussed with the Sponsor.
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.
Because this is a Phase I assessment of MK-8583 in humans, the pharmacokinetic, 
pharmacodynamic and safety profiles of the compound are still being elucidated. This 
protocol is therefore written with some flexibility to accommodate the inherent dynamic 
nature of Phase I clinical trials. Please refer to Section 7.1.5 – Visit Requirements for 
examples of modifications permitted within the protocol parameters.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1 and Table 1.
All 
Panels 
A - C
~Day -28 
to -1
Day -1
Day 1
Day 10-
14
~Day 
28
Screening 
procedures
Domiciled overnight 
pre- and post-dose 
for monitoring and 
blood PK sampling
Follow up 
monitoring and 
sampling for PK 
and viral load
Planned 
ART 
start
Post-
trial 
visit
Figure 1
Trial Design Diagram
Table 1
Dose Plan
Panela
Doseb
Panel A
100 mg
Panel B
150 mg
Panel Cc
150 mg
a In each panel, 6 subjects will receive a single dose of MK-8583.
b The dose administered in Panels B and C will be determined following review of safety, PK, and viral 
load data from the previous panel(s) and will not exceed 150 mg. At least approximately 30-40 days 
will separate the administration of doses between panels to allow time for review of the previous panel 
safety, PK and viral load data.
c A decision to enroll Panel C will be made upon completion of the previous panels and review of 
safety, PK, and viral load data.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:To evaluate the anti-retroviral activity of MK-8583 in HIV-1 infected 
subjects relative to historical subjects receiving placebo.
Hypothesis: At a dose that is sufficiently safe and generally well tolerated, MK-8583
has superior anti-retroviral activity compared to placebo, as measured by change from 
baseline in plasma HIV-1 RNA (log10 copies/mL) at 168 hours post-dose. That is, 
the true mean difference in the plasma HIV -1 RNA reduction from baseline between 
MK-8583 and placebo is at least 0.5 log10 copies/mL.
 
 
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2) Objective: To evaluate the safety and tolerability of MK-8583 in HIV-1 infected 
subjects.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To evaluate the intracellular PK profile of TFV-DP and to determine PK 
parameter values (including AUC0-168hr, Tmax, Cmax, C168hr, and apparent 
terminal t1/2) in PBMCs after administration of single oral doses of MK-8583 to 
HIV-1 infected subjects.
Hypothesis: The true geometric mean (GM) TFV-DP PBMC C168hr is ≥0.1 μM for 
at least one dose level that also exhibits an acceptable safety and tolerability profile.
2) Objective: To characterize the single dose plasma PK profile of MK-8583 and to 
determine the PK parameter values (including AUC0-last, AUC0-inf, Tmax, Cmax, 
apparent terminal t1/2, CL/F and Vz/F) after administration of MK-8583 to HIV-1 
infected subjects.
3) Objective: To obtain the single dose plasma PK profile of TFV and to determine the 
PK parameter values (including AUC0-last, AUC0-inf, Tmax, Cmax, and apparent 
terminal t1/2) after administration of MK-8583 to HIV-1 infected subjects.
4) Objective:  To evaluate the PK-PD association of TFV-DP with viral load reduction.
Exploratory Objectives
3.3
1) Objective: To evaluate the relationship between dose and anti-retroviral activity of 
MK-8583.
2) Objective: To quantify PBMC levels of tenofovir monophosphate (TFV-MP).
3) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered and mechanisms of disease. Variation across the human 
genome may be analyzed for association with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-8583.
Pharmaceutical and Therapeutic Background
4.1.1
As treatment for HIV-1 has improved, HIV-1 infection has shifted from being an acute 
disease to being a chronic, manageable condition. There is now a clear medical need for new 
treatment regimens and dosing strategies that are both highly effective and very well 
tolerated. In particular, increased tolerability and ease of administration are expected to 
improve long-term adherence. A highly-potent nucleoside reverse transcriptase inhibitor
(NRTI) with superior tolerability and ease of administration would be a valuable addition to 
the HIV-1 armamentarium.
 
 
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MK-8583 is a novel, potent tenofovir prodrug (TFV PD) that belongs to the class of HIV-1
NRTIs.
Marketed
NRTIs
include
lamivudine,
emtricitabine,
abacavir,
didanosine,
stavudine, and zidovudine, as well as 2 TFV PDs, TDF and TAF.
TFV PDs have an acyclic nucleoside phosphonate on an adenine base. The phosphorylated
moiety, TFV-DP competes with the natural substrate, deoxyadenosine, for incorporation by 
reverse transcriptase into newly synthesized cDNA strands. Once incorporated, TFV-DP 
terminates strand elongation, inhibiting viral replication.
TDF (VIREAD®) is a TFV PD, currently marketed by Gilead Sciences, Inc., that has been
available since 2001. Following absorption, TDF is rapidly converted to TFV, which is then
taken up by cells and converted intracellularly to the active anabolite, TFV -DP. After 
over 15 years in clinical use, TDF has been associated with small but significant decreases in 
kidney function (mean decrease in eGFR of 3.9 mL/ min, 95% confidence interval 2.1 - 5.7) 
[1] [2]and mild decreases in bone marrow density (BMD) [3], (approximate 2% loss in BMD 
in the spine and hip) in chronically treated patients. These effects are directly associated with 
high levels of TFV in circulation. TAF (VEMLIDY®), a more recently approved TFV PD,
exhibits greater stability than TDF and is more efficiently taken up by target cells (i.e. 
PBMCs) thereby rendering lower levels of TFV in systemic circulation and lower levels 
of TFV available to cause toxicity to non-target cells (i.e. renal tubule cells and 
bone). The lower concentration of circulating TFV is believed to contribute to TAF’s
improved safety profile compared to TDF, although both compounds display similar
efficacy in longer term clinical studies when administered as part of a complete
treatment regimen.
Currently recommended first-line treatment of HIV infection in naïve patients calls for 3
agents and generally includes 2 NRTI agents in combination with either an integrase strand
transfer inhibitor, a protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor.
While the currently approved NRTIs represent a cornerstone of modern ART, there are
significant class associated toxicities including loss of bone mineral density, new or
worsening renal impairment, severe lactic acidosis, and serious hypersensitivity reactions.
Because tolerability issues are one of the most common reasons for lack of adherence and
subsequent viral failure, a need exists for new, highly potent NRTIs, like MK-8583, with
improved safety and tolerability. Furthermore, reducing the frequency that patients need to 
take anti-retroviral therapy from daily to weekly would remove a significant barrier to 
adherence and thereby improve health outcomes.
MK-8583
4.1.2
MK-8583 is a TFV PD that inhibits HIV-1 reverse transcriptase (RT). In vitro, MK-8583 
demonstrated potent inhibition of HIV-1 R8 virus in PBMCs. TFV PDs are taken up by 
target cells and converted into TFV, which is then phosphorylated to the active antiviral 
TFV-DP. Extracellular TFV is also generated through prodrug metabolism and leakage out 
of target cells and must be renally cleared. Plasma TFV levels correlate with renal 
accumulation and toxicity. Therefore, prodrugs that are transported into leukocytes and 
converted to TFV-DP more readily will generate less plasma TFV and will have lower 
toxicity potential. In vitro, MK-8583 generates approximately 3-fold higher concentrations of 
intracellular TFV-DP than TAF. The more efficient conversion of MK-8583 into the active 
 
 
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metabolite leads to lower circulating levels of TFV, the metabolite responsible for toxicity, 
and therefore MK-8583 is expected to have a more favorable safety profile than TAF.
MK-8583 was evaluated in genetic toxicity assays, safety pharmacology models, and in 
repeat dose oral toxicity and toxicokinetic studies of up to 3 months in duration in rats and 
dogs. In both species, TFV was the major metabolite in plasma and excreta, which is 
consistent with in vitro studies that indicate hydrolysis to TFV is the primary elimination 
pathway of MK-8583.
MK-8583 is not expected to be a victim of CYP-mediated drug interactions. MK-8583 is a 
substrate of human P-gp and could be a victim of P-gp-mediated drug interactions. TFV is 
eliminated by renal excretion and is a substrate of OAT1, OAT3 and MRP4 in vitro. 
Therefore, TFV may be affected by drugs that reduce renal transport. In vitro, MK-8583 is an 
inhibitor of CYP3A, OATP1B1, and OATP1B3, and therefore MK-8583 has the potential to 
perpetrate drug interactions on substrates of these enzymes.
In preclinical safety studies, the primary toxicological effects of MK-8583 were noted in the 
gastrointestinal tract and in the kidneys. These changes were similar to those reported for 
other TFV PDs (TDF and TAF) at similar systemic exposures of the TFV metabolite. Based 
on the consistency of preclinical findings with MK-8583, TDF, and TAF, no specific 
preclinical findings were attributed to the novel prodrug, MK-8583.
MK-8583 was assessed in a single rising-dose study in healthy subjects. Following oral 
administration, MK-8583 was rapidly absorbed (time to maximum plasma concentration
[Tmax] ~ 0.5 hour) and rapidly eliminated from the plasma (terminal half-life [t1/2] of 0.2 to 
0.4 hours). Prodrug exposure was dose-proportional at doses 40 mg. Plasma TFV exposure 
was also dose-proportional, with a Tmax of 1 to 4 hours and a t1/2 in the range of 19 to 30 
hours. TFV-DP in PBMCs exhibited a median Tmax of 4 to 24 hr and a terminal t1/2 ranging 
from 65 to 136 hours. The PBMC TFV-DP AUC increased approximately dose-
proportionally, and the Cmax increased somewhat more than dose-proportionally. Food 
somewhat lowered peak and extent of exposure of PBMC TFV-DP (GM fed/fasted ratio of 
0.83 for AUC0-inf, 0.32 for maximum concentration [Cmax], 0.47 for C168hr). Elimination 
of plasma MK-8583 was monophasic, while elimination of plasma TFV was biphasic. PBMC 
TFV-DP presented monophasic elimination, but showed signs of biphasic elimination at 
higher doses.
Single oral doses of MK-8583 up to 150 mg were generally well tolerated. No SAEs, events 
of clinical interest (ECIs), or deaths were reported. A total of 24 subjects enrolled in the trial. 
No trends were observed between AE incidence and increasing dose levels, and there were 
no AE findings consistent with renal or bone toxicity. No clinically meaningful trends were 
observed for changes in clinical laboratory values, vital signs (VS), or ECGs as a function of 
dose or treatment.
Please refer to the Investigator’s Brochure (IB) for more detailed information on MK-8583.
 
 
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Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
MK-8583 has a promising preclinical and clinical profile and has potential to be an effective 
long acting TFV PD. This study is being conducted to assess the short-term anti-retroviral
activity of MK-8583 monotherapy. Proof-of-concept trials demonstrate that agents that 
robustly suppress the VL as short-term monotherapy can be expected to deliver long-term 
efficacy as combination therapy [4]. This study’s design and objectives conform to the EMA 
Guideline describing appropriate clinical development for anti-retroviral
agents as 
monotherapy [5]. As described in this Guideline, the purpose of a monotherapy study is to 
characterize the relationship between dose, plasma concentration, and the short-term in vivo 
anti-retroviral activity.
Infected subjects who are therapy naïve will be enrolled in this study in order to decrease the 
presence of TFV resistant mutations. Prior to enrollment, subjects will be screened for the 
presence of common NRTI resistance mutations (International AIDS Society - USA 
(IASUSA) [6] to set a baseline standard for MK-8583-sensitivity to the viral variants present 
in each subject. Subjects identified with common mutations known to affect susceptibility to 
TFV (e.g., K65R, K70E, M184V/I, or combinations of three or more thymidine analog 
mutations (TAMs) including M41L, L210W, T215Y, D67N, K70R, K219Q/E/N) will be 
excluded from the study. Should unanticipated non-responders or viral breakthrough be 
observed despite this pre-screening process, a portion of the screening blood sample will be 
archived for phenotyping and/or genotyping of any previously unidentified clinically 
meaningful resistance variants.
Rationale for Dose Selection/Regimen/Modification
4.2.2
As this is a Phase I assessment of MK-8583 in humans, and the PK, PD and safety profiles of 
the compound are still being evaluated, modifications to the dose or dosing regimen may be 
required to achieve the scientific goals of the trial objectives and/or to ensure appropriate 
safety monitoring of the trial subjects.  Details of allowed modifications are provided in 
Section 7.1.5.5 - Trial Design/Dosing/Procedures Modifications Permitted within Protocol 
Parameters.
The doses tested in this study will evaluate the effectiveness of MK-8583 in suppressing viral
replication and will allow for assessment of potential differentiation in tolerability and
efficacy. The study is specifically designed with an emphasis on collecting single dose viral
dynamic data. Since only a single dose of MK-8583 will be administered to each subject, risk 
of resistant strain emergence is minimal.
Doses selected for this study are projected to fall within the expected clinical dose range. A 
dose that achieves a TFV-DP C168h in PBMCs of 100 nM is projected to be efficacious. 
This is approximately the Day 7 PBMC Ctrough achieved with daily dosing of TDF 300 mg 
(the therapeutic dose) for one week, which results in a 0.5 log10 reduction in VL [4]. In the 
single-rising dose study of MK-8583 in healthy subjects, a PBMC TFV-DP C168h target of 
100 nM was achieved at doses 40 mg of MK-8583.
 
 
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To maximize the chances of efficacy and minimize the impact of inter-subject PK variability, 
a 100 mg dose of MK-8583 will be administered to subjects in Panel A. This dose is 
expected to achieve PBMC TFV-DP concentrations well above that of the projected 
minimum effective dose of 40 mg (see above) while maintaining a plasma concentration of 
the TFV metabolite (the relevant correlate of toxicity) at ½ the exposure seen at the 
preclinical no-observed-adverse-effect level (NOAEL).
There will be a break between dosing of panels to allow for review of all available safety, 
PK, and viral dynamic data to inform dose selection in the following panel. It is estimated 
that this review will take approximately 30-40 days. Because plasma MK-8583, plasma TFV, 
and PBMC TFV-DP PK data from healthy subjects are expected to be similar to that of HIV-
1 infected subjects, PK data from single doses administered to healthy subjects in Protocol
001 will also be used to aid in the selection of doses for the present study to ensure that 
plasma MK-8583 levels do not exceed the exposure cap.
The specific dose selected for Panel B will depend on data from Panel A. Assuming PK data 
indicate that higher exposures maintain safety margins, a higher dose may be tested to see if 
it delivers greater efficacy. Alternatively, if 100 mg generates exposures in HIV-infected 
subjects that are higher than what was seen in healthy subjects, or if safety concerns arise, a 
lower dose may be tested. After Panel B, the Sponsor will assess the utility of testing a third 
dose in Panel C to further explore PK, PD, and the safety profile of the compound.
Additionally, safety data through at least 168 hours post-dose, including AEs, standard 
laboratory safety tests, VS, and 12-lead ECGs, physical examinations (PEs) will be reviewed 
by the Sponsor and the investigator prior to dose escalation, and the decision to proceed to a 
new dose level will be based upon acceptable safety of MK-8583 at the previous dose. The 
doses selected for Panels B and C in this study will not exceed the maximum dose of 150 mg 
previously administered to healthy subjects.
The reduction in VL for each dose level will be compared to historical placebo data from 
clinical trials previously conducted by the Sponsor. Given the overall favorable safety profile 
of MK-8583 in preclinical and clinical testing to date, a placebo control to minimize 
investigator and subject bias with respect to adverse experiences is not deemed necessary.
Starting Dose for This Trial
4.2.2.1
The proposed starting dose in Panel A is 100 mg as noted above. Prior clinical evaluation up 
to 150 mg demonstrated that MK-8583 was generally well tolerated.
The toxicity studies (summarized below) indicated that the no-observed-adverse-effect level 
(NOAEL) in the more sensitive preclinical species was 3 mg/kg/day in the dog. Previous 
studies indicate TFV PDs exhibit generally similar PK in healthy subjects and HIV-infected 
subjects [7]. Assuming the same correlation holds for MK-8583, a dose of 100 mg is 
expected to yield an AUC0-inf (approximately equivalent to AUC0-168hr) for plasma TFV 
and plasma MK-8583 of 2,380 nM*hr and 430 nM*hr, respectively. The dog NOAEL 
yielded an AUC0-168hr (calculated by multiplying the AUC0-24hr x 7 days) for TFV and 
MK-8583 of 17,850 nM*hr and 620 nM*hr, respectively. Therefore, relative to the predicted 
exposures at 100 mg, the safety data provide a 7.5-fold (for TFV) and 1.4-fold (for MK-
8583) safety margin (see Table 2).
 
 
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Table 2
Exposure predictions for the starting dose of 100 mg
Maximum Dose/Exposure for This Trial
4.2.2.2
The maximum allowable clinical exposure for this study is defined by the safety findings
from 3-month Good Laboratory Practice (GLP) oral toxicity studies in rat and canine models.
In rats, the 3-month oral toxicity study identified no test article related toxicology findings at 
the highest dose tested, 150 mg/kg/day, and this was set as the rodent no-observed-adverse-
effect level (NOAEL).
Dogs were administered MK-8583 at 3, 10, and 30 mg/kg/day in 3-month oral toxicity
studies. All animals in the 30 mg/kg/day dose group were terminated early in Study Week 7 
or 8 due to severe body weight losses, associated with decreased food consumption, 
decreased activity, and decreased heart rate. Increased incidences of emesis and salivation, 
and hematological and serum biochemical changes were also observed, including laboratory 
and histomorphologic indicators of significant kidney toxicity. In the 10 mg/kg/day dose 
group, observed test article-related clinical pathology findings included mild increases in 
creatinine associated with histomorphologic changes in the kidneys and slight increases in 
aspartate aminotransferase (AST) and alkaline phosphatase. The increases in AST and 
alkaline phosphatase were not associated with histomorphologic changes and were therefore 
not toxicologically significant. The maximum tolerated dose for the dog was therefore set at 
10 mg/kg/day.
Test article-related postmortem changes were observed in the stomachs of dogs receiving the 
3 mg/kg/day dose. Specifically, these were large vacuolated cells in the gastric mucosal 
pyloric mucosa. Although these changes were of unknown toxicological significance, the 
NOAEL for the dog was set at 3 mg/kg/day.
There are significant differences in the protein binding of MK-8583 in rat (71-82%, 
depending on concentration) vs. human and dog (93% and 95%, respectively), whereas TFV 
protein binding is minimal across all species. For these reasons, exposure to total TFV and 
exposure to unbound MK-8583 were used to select the more sensitive species for the 
NOAEL exposure margins.
Preclinical NOAEL
AUC0-168hr
(nM*hr) a  
Clinical 
Dose
Clinical AUC0-
inf (nM*hr)
Exposure 
Multiple
Plasma TFV
17,850
100 mg
2,380 b
7.5
150 mg
3,840 c
4.7
Plasma MK-8583
620
100 mg
430 b
1.4
150 mg
684 c
0.9
a AUC0-168hr (AUC0-24 x 7 days) observed at the dog NOAEL (3 mg/kg/day)
b AUC0-inf interpolated from Protocol 001, assuming dose-proportionality
c AUC0-inf calculated from Protocol 001, predicted to be similar to AUC0-168hr
 
 
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The AUC0-168hr was selected as the relevant exposure parameter, instead of Cmax, because 
the preclinical toxicity of MK-8583 was associated with chronic dosing and was similar to 
clinical toxicity observed with chronic dosing of marketed TFV prodrugs. (The mean TFV 
Cmax at the preclinical NOAEL and at the maximum clinical dose of 150 mg were 102 nM 
and 175 nM, respectively. The mean MK-8583 Cmax at the preclinical NOAEL and at the 
maximum clinical dose of 150 mg were 168 nM and 1,074 nM, respectively.)
TFV Exposure Multiple: Comparing the TFV AUC0-168hr at the dog NOAEL (17,850 
nM*hr at 3 mg/kg/day) to that of the rat (446,000 nM*hr at 150 mg/kg/day), the dog 
represents the more sensitive species. Therefore, the maximum allowable exposure is based 
on the TFV AUC0-168hr at the NOAEL of the dog, in this case 17,850 nM*hr. In healthy 
subjects, the maximum dose of 150 mg yielded a TFV AUC0-inf (approximately equal to the 
AUC0-168hr) of 3836 nM*hr; the preclinical safety data provide a 4.7-fold exposure margin 
(EM) (see Table 2).
MK-8583 Exposure Multiple: Whereas the plasma protein binding of TFV is minimal
across all species, there are significant inter-species differences in the protein binding of MK-
8583 (~70-80% in rat, ~93-95% in human and dog). The total MK-8583 AUC0-168hr at the 
dog NOAEL (620 nM*hr at 3 mg/kg/day) and at the rat NOAEL (540 nM*hr at 150 
mg/kg/day) are similar. But comparing the unbound MK-8583 AUC0-168hr at the dog 
NOAEL (29.8 nM*hr at 3 mg/kg/day) to that of the rat (96.6 nM*hr) identifies the dog as the 
more sensitive species. In healthy subjects, the maximum dose of 150 mg yielded an MK-
8583 AUC0-inf (approximately equal to the AUC0-168hr) of 684 nM*hr, which is 0.9-fold
that of the MK-8583 AUC at the dog NOAEL (620 nM*hr, see Table 2).
All changes observed in the toxicology studies were similar to those reported for other TFV 
prodrugs (TDF and TAF) at similar systemic exposures of the TFV metabolite [8] and [9].
Based on the consistency of preclinical findings with MK-8583, TDF, and TAF, no specific 
preclinical findings were attributed to the novel prodrug, MK-8583. Therefore, although the 
MK-8583 prodrug exposure at 150 mg slightly exceeds that at the preclinical NOAEL, the 
150 mg dose is an appropriate maximum for this single-dose trial because the observed 
preclinical toxicity is attributable to TFV, not to the MK-8583 prodrug, and because 150 mg 
was generally well-tolerated by healthy subjects in Protocol 001.
While plasma MK-8583, plasma TFV, and PBMC TFV-DP PK data from healthy subjects 
are expected to be similar to that of HIV-1 infected subjects, the PK and safety data from 
each panel in this study will also be reviewed and compared with data from Protocol 001 
prior to dose selection for the next panel.
Rationale for Dose Interval
4.2.2.3
MK-8583, a prodrug of tenofovir, which inhibits HIV-1 reverse transcriptase, is not 
considered a compound with a high degree of uncertainty related to the potential risk of harm 
to participants, according to the publication "Guideline on Strategies to Identify and Mitigate 
Risks for First-in-Human and Early Clinical Trials with Investigational Medicinal Products" 
(European Medicine Agency [EMA] guidance released July 2017).
The degree of 
uncertainty was determined by careful evaluation of the following: mode of action of MK-
8583, presence or absence of biomarkers, the nature of the target, the relevance of available 
animal models and/or findings in non-clinical safety studies, single dose safety/PK data in 
 
 
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healthy volunteers, and the study population. Furthermore, it acts via a well-established 
mechanism (inhibition of HIV-1 reverse transcriptase), for which multiple marketed agents 
act similarly (TDF, TAF, and others). Safety assessment toxicity studies,  ancillary 
pharmacology studies, and
the first in human data
with MK-8583
provide no 
contraindications to the initiation of clinical studies in subjects with this compound via the 
oral route. No dose-limiting toxicities were observed in 3-month rat and dog toxicity studies.
The trial design includes three sequential panels of 6 subjects each.  For each panel in each 
period, subjects that receive MK-8583 on the same day will be spaced apart by time intervals 
according to Phase I Clinical Research standards for compounds not considered to be of high 
risk. There will be a break of at least approximately 30 to 40 days between dosing of MK-
8583 in consecutive panels to allow for review of safety data and potential AEs as well as PK 
and viral dynamic data to inform dose selection. There will also be frequent, careful 
assessments of adverse events throughout the post-dose period.  This recommendation is in 
keeping with the projected safety profile and the ability of the Phase I unit to monitor each 
subject closely.
Rationale for Endpoints
4.2.3
Safety Endpoints
4.2.3.1
The safety and tolerability of MK-8583 will be monitored by standard clinical assessments, 
which will adequately assess for preclinical safety findings in the rodent and canine models.
Pharmacokinetic Endpoints
4.2.3.2
Antiviral efficacy of TFV PDs is believed to be related to the concentration of the active 
moiety (TFV-DP) in PBMCs, rather than to concentrations in plasma. Considering that this is 
a weekly compound, the C168h in PBMCs is expected to be associated with efficacy. Based 
on a combined meta-analysis of in vitro and published clinical exposure response data, the 
target PBMC TFV-DP Ctrough concentration will be 100 nM. This target is hypothesized to 
achieve a reduction in HIV viral load of ≥0.5 log10 copies, relative to historical placebo, 
which is predictive of longer term efficacy (see below and Section 4.2). This is the Ctrough 
and associated VL reduction seen with the clinical dose of TDF.
The PK of MK-8583 and its anabolites in HIV subjects will be evaluated to refine the PBMC 
TFV-DP target concentrations associated with efficacy. In addition, information regarding 
PK and safety will be evaluated by means of assessment of plasma concentrations of MK-
8583 and TFV.
Pharmacodynamic Endpoints
4.2.3.3
A PD endpoint of ≥0.5 log10 suppression of HIV-1 RNA from baseline on Day 7, relative to 
historical placebo data, will be used. This target is consistent with prior monotherapy proof-
of-concept studies of NRTIs, including TDF 300 mg daily, which has proven long-term 
efficacy both as treatment and prevention of HIV infection [4] [10]. An endpoint at 7 days
was set based on these published results with daily TDF monotherapy, but also with the 
expectation that a weekly drug will need to deliver persistent VL suppression throughout the 
duration between doses.
 
 
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A posterior probability threshold P%=80% is chosen. A favorable posterior probability 
threshold is defined when the true mean HIV-1 reduction > 0.5 log [relative to Placebo] is
>P%; there is relatively low probability of a favorable outcome when the true mean reduction
is < 0.5 log10 copies/mL (about 20% or less) and relatively high probability for favorability
when the true mean reduction is > 0.7 log10 copies/mL (about 80% or more), assuming a true 
SD = 25%.
Based on the long half-life of the active moiety TFV-DP, changes in VL may be assessed 
through 28 days for subjects who do not initiate follow-on ART. Additionally, the kinetics of 
VL reduction versus dose and exposure will also be determined.
Planned Exploratory Biomarker Research
4.2.3.4
Planned Genetic Analysis
Understanding genetic determinants of drug response and the molecular basis of disease 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 and/or disease. If genetic variation is found to predict efficacy or adverse events, 
the data might inform optimal use of therapies in the patient population. Knowledge of the 
molecular basis of disease contributes to the development of novel biomarkers and the 
identification of new drug targets. This research contributes to understanding molecular basis 
of disease and the genetic determinants of efficacy and safety associated with the treatments 
in this study.
Future Biomedical Research
4.2.3.5
The Sponsor will conduct Future Biomedical Research on specimens consented 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, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
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.
The Sponsor will also be collecting baseline stool samples for future HIV research. Analysis 
of these samples may include, but will not be limited to, measurement of host inflammatory 
markers, microbiome composition, gene expression, metabolites, and viral load dynamics.
Detailed instructions for stool sample collection are included in the Study Operations 
Manual.
 
 
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Benefit/Risk
4.3
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with HIV-1 infection who are naïve to ART between the ages of 18
and 60 years (inclusive) 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. Provide written informed consent. The subject may also provide consent for Future 
Biomedical Research. However, the subject may participate in the main trial without 
participating in Future Biomedical Research.
2. Be a male or non-pregnant and non-breast feeding female, 18 to 60 years of age at the 
pretrial (screening) visit; further:
a.
if male with female partner(s) of child-bearing potential: see Section 5.7.3.1 for 
required methods of birth control. 
b. if female with reproductive potential: subject must demonstrate a serum β -
human chorionic gonadotropin (β–hCG) level consistent with the nongravid state
at the pretrial (screening) visit and agree to use acceptable methods of birth
control beginning at the pretrial (screening) visit, throughout the trial and until 30
days following cessation of treatment. Acceptable methods of birth control are
defined in Section 5.7.3.1.
c.
if postmenopausal female: subject is without menses for at least 1 year and 
have
a
documented follicle
stimulating
hormone
(FSH)
level
in
the 
postmenopausal range at pretrial (screening),
AND/OR
 
 
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d. If surgically sterile female: subject is status post hysterectomy or oophorectomy. 
NOTE: These procedures must be confirmed with medical records. In the
absence of documentation, hysterectomy may be confirmed by pelvic exam or if
necessary by ultrasound; oophorectomy may be confirmed by hormone levels,
particularly FSH in the post-menopausal range. Information must be captured 
appropriately within the site's source documents
3. Have a Body Mass Index (BMI) ≤35 kg/m2. BMI = weight (kg)/height (m) 2.
4. Other than HIV infection, have baseline health judged to be stable based on medical 
history, physical examination, vital sign measurements, and laboratory safety tests
(see Section 7.1.3) performed at the prestudy (screening) visit and/or prior to 
administration of the initial dose of study drug.
5. Be documented HIV-1 positive as determined by a positive ELISA or QT-PCR with 
confirmation (e.g., Western Blot).
6. Be diagnosed with HIV-1 infection ≥3 months prior to screening or perform
the French 2008 HAS Algorithm to confirm chronic HIV.
7. Have a screening plasma CD4+ T-cell count of 200/mm3.
8. Have a screening plasma HIV-1 RNA ≥5,000 copies/mL within 30 days prior to the 
treatment phase of this study.
9. Be ART-naïve, which is defined as having never received any anti-retroviral agent
OR the following:
≤30 consecutive days of an investigational anti-retroviral agent, excluding an 
NRTI, 
OR
≤60 consecutive days of combination ART not including an NRTI
10. Have
no
evidence
at
screening
for
mutations
affecting
susceptibility
to
tenofovir [including K65R, K70E, M184V/I, or combinations of three or more 
thymidine analog mutations (TAMs) including M41L, L210W, T215Y, D67N, K70R, 
K219Q/E/N] as previously defined in Section 4.2.1.
11. Have the following laboratory values at screening: direct bilirubin ≤ 1.0 mg/dL, AST 
(SGOT) and ALT (SGPT) ≤ 2 x upper limit of normal.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is under the age of legal consent.
2. Is mentally or legally institutionalized / incapacitated, has significant emotional 
problems at the time of pretrial (screening) visit or expected during the conduct of the 
trial or has a history of clinically significant psychiatric disorder of the last 5 years. 
Subjects who have had situational depression may be enrolled in the trial at the 
discretion of the investigator.
 
 
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3. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological,hepatic, immunological (outside
of
HIV-1
infection),
renal,
respiratory, genitourinary or major neurological (including stroke and chronic 
seizures) abnormalities or diseases. Subjects with a history of a minor medical event 
(e.g., uncomplicated kidney stones, as defined as spontaneous passage and no 
recurrence in the last 5 years, or childhood asthma) may be enrolled in the trial at the 
discretion of the investigator.
4. Has a history of cancer (malignancy). Subjects who have a remote cancer history 
who, in the opinion of the trial Investigator, are highly unlikely to sustain a recurrence 
for the duration of the trial may be included. 
5. Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic 
allergic reaction) to prescription or non-prescription drugs or food.
6. Is positive for Hepatitis B surface antigen.
7. Subject has a history of chronic Hepatitis C unless there has been documented cure 
and/or patient with a positive serologic test for HCV has a negative HCV viral load, 
in which case may be enrolled in the trial at the discretion of the investigator.
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the pretrial (screening) visit.
9. Has participated in another investigational trial within 4 weeks or 5 half-lives,
whichever is greater, prior to the pretrial (screening) visit. The 4-week or 5-half-lives 
window will be derived from the date of the last visit in a previous trial.
10. Is unable to refrain from or anticipates the use of any medication, including 
prescription and non-prescription drugs or herbal remedies beginning approximately
2 weeks (or 5 half-lives) prior to administration of the initial dose of trial drug, 
throughout the trial, until the post-trial visit. There may be certain medications that 
are permitted, see Section 5.5.
11. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. Subjects who consume 4 glasses of alcoholic beverages 
per day may be enrolled at the discretion of the investigator.
12. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy -drinks, 
or other caffeinated beverages per day.
13. Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict 
smoking to ≤10 cigarettes per day or is unwilling to follow the smoking restrictions 
defined by the CRU.
14. Has a clinically significant abnormality on the electrocardiogram (ECG) performed at 
the prestudy (screening) visit and/or prior to administration of the initial dose of study 
drug.
15. Has QTcF interval ≥ 470 msec (for males) or ≥ 480 msec (for females).
 
 
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16. Has a positive urine drug screen (except for cannabis) at screening and/or pre-dose;
rechecks are allowed.
17. Has received any investigational agent or any anti-retroviral agent within 60 days of
study drug administration.
18. Intends to receive any ART during the treatment phase of this study.
19. Is any concern to the investigator regarding the safe participation of the subject in the 
trial or if, for any other reason; the investigator considers the subject inappropriate for 
participation in the trial (e.g. prior NRTI exposure).
20. Is unwilling to comply with additional the trial restrictions (see Section 5.7 for a 
complete summary of trial restrictions).
21. 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
The treatment to be used in this trial is outlined below in Table 3.
Table 3
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Panel
Use
MK-8583
100 mg
1
Oral
Single Dose/Panel A
Experimental
MK-8583
≤150 mg
1
Oral
Single Dose/Panel B
Experimental
MK-8583
≤150 mg
1
Oral
Single Dose/Panel C
Experimental
Trial treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
Study medication should be administered in the fasted state, with approximately 240 mL of 
water. Additional water may be offered during the capsule administration in increments of 50 
mL, as needed. On all treatment days, subjects will fast from all food and drink except water 
for at least 8 hours prior to trial drug administration. Water will be restricted from 1 hour 
prior to and after trial drug administration.
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/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
 
 
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Dose Modification (Escalation/Titration/Other)
5.2.1.2
All dose modification decisions will be made jointly by the investigator and the Sponsor.  
Each dose modification decision will occur after at least 6 subjects have completed the 
previous dose level.
Before proceeding to Panel B, PK data will be reviewed from Panel A to determine whether
or not PK from HIV-infected subjects is similar to that observed in healthy subjects from
Protocol 001.  Dose modification decisions will be based on key safety data including: vital 
signs, 12-lead ECG, laboratory safety tests, adverse events and review of viral dynamic data
from the previous dose levels up to at least 168
hours. Pharmacokinetic and 
pharmacodynamic data may be included in the dose modification decisions.  See Background 
& Rationale - Section 4.0.
If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose modification, the dose will not be modified as planned. Instead, subjects may:
●
receive the same dose level to further explore safety and tolerability at that level;
●
receive a lower dose of the trial drug;
●
receive the same or lower dose as a divided dose; or
●
receive a lower dose with or without food.
Or, dosing may be stopped. Subject discontinuation criteria are outlined in Section 5.8.
Prior to each treatment, the clinical and laboratory safety data from the previous dose level 
will be reviewed by the investigator and discussed with the Sponsor to permit a decision on 
whether to advance to the next dose level.  No dose modification will occur without the joint 
agreement of the investigator and the Sponsor.
Timing of Dose Administration
5.2.2
All doses of MK-8583 will be given at approximately the same time in the morning.
Trial Blinding 
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
Subjects will be assigned randomly according to a computer-generated allocation schedule.
A sample allocation schedule is shown below in Table 4.
 
 
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Table 4
Sample Allocation Schedule
Subjects a
Panel A
Panel B b
Panel C b
N=6 (per panel)
100 mg
≤150 mg
≤ 150 mg
a Subjects will participate in only one panel.  
b Doses may be adjusted based on viral load data and review of key safety variables (including vital 
signs, 12-lead ECGs, laboratory safety tests, and adverse events).
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
If a subject does not discontinue all prior medications within 14 days or 5 half-lives of 
starting the trial, he/she may be included in the study if the investigator can rationalize that 
the specific use of a prior medication is not clinically relevant within the context of the trial.
Concurrent use of any prescription or non-prescription medication, or concurrent vaccination,
during the course of the trial (i.e., after randomization or treatment allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult.  The subject will be allowed to continue in the trial if both the Sponsor 
and the investigator agree.
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the Sponsor.
Initiation of ART: All subjects will be encouraged to initiate ART some interval after their 
dose of MK-8583. The exact timing and regimen will be decided by the subject in 
consultation with his/her physician, but ART initiation will not occur before Day 10 (240 
hours post-dose). This timing is required to gather full efficacy data for this novel long-acting 
anti-retroviral compound and is consistent with prior anti-retroviral monotherapy proof-of-
concept trials, in which low-dose anti-retroviral monotherapy has been administered for as 
long as 28 days [10] and with European Medicines Agency (EMA) guidance [5]. If the 
physician and/or Investigator believe there is a strong indication to start ART before Day 10, 
this should be discussed with the Sponsor prior to starting, as with other concomitant 
medications (see above). 
To lessen the chance of HIV resistance mutations developing, the Sponsor recommends that 
ART initiation occurs before PBMC TFV-DP concentrations fall below 100 nM. (100 nM is 
set as the lower limit because this is the steady-state Ctrough of TDF.) In Panel A (100 mg 
dose), the PBMC TFV-DP concentration is expected to fall below 0.1 M after 4 half-lives, 
or 14 days, and therefore it is recommended that ART is initiated on or before Day 14. In 
subsequent panels, the Sponsor will provide the site with written guidance, prior to the start 
of dosing, as to the time when PBMC TFV-DP concentrations are expected to fall below the 
100 nM lower limit.
 
 
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For subjects who choose to initiate ART following the treatment phase of the study, the 
specific ART regimen selected will be a decision of the subject in consultation with the 
Investigator and/or the subject’s physician.
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.  
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.
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 and Fruit Juice Restrictions
5.7.1
Diet
5.7.1.1
Fasting requirements for trial procedures, such as but not limited to laboratory safety 
evaluations are specified in Section 7.0.
Subjects will fast from all food and drinks, except water, for at least 8 hours prior to trial 
drug administration (and laboratory safety tests).  Subjects will fast from all food and drinks 
except water between trial drug administration and the first scheduled meal.  Meals and 
snack(s) will be provided by the investigator at time points indicated in the trial flowchart.  
Subjects will fast from all food and drinks except water between meals and snacks.  The 
caloric content and composition of meals will be the same in each treatment period. After the 
24-hour post-dose procedures have been completed, subsequent meals and snacks will be 
unrestricted in caloric content, composition and timing. 
Water will be provided during trial drug administration.  Water will be restricted 1 hour prior 
to and 1 hour after trial drug administration. 
Instructions on whether to take MK-8583 with or without food and/or drink may be modified 
during the trial based on newly available data.
Fruit Juice Restrictions
5.7.1.2
Subjects will refrain from the consumption of grapefruit juice, grapefruits and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of trial 
drug, throughout the trial and until the post-trial visit.  
On the dosing day, subjects will also refrain from the consumption of all fruit juices 24 hours 
prior to and after trial drug administration.  All other days during the trial, consumption of 
fruits and fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is 
allowed. 
 
 
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Alcohol, Caffeine, Tobacco, Activity
5.7.2
Alcohol Restrictions 
5.7.2.1
Subjects will refrain from consumption of alcohol 24 hours prior to the pre- and post-trial 
visits and from 24 hours prior to and after trial drug administration. At all other times, 
alcohol consumption is limited to no more than approximately 3 alcoholic beverages or 
equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 
ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
Caffeine Restrictions 
5.7.2.2
Subjects will refrain from consumption of caffeinated beverages from 12 hours prior to the 
pre- and post-trial visits and from 12 hours prior to and after trial drug administration. At all 
other times, caffeinated beverages or xanthine-containing products will be limited to no more 
than 6 servings per day amounts (>6 servings: 1 serving=120 mg of caffeine).  
Smoking Restrictions 
5.7.2.3
Smoking should be limited to ≤ 10 cigarettes per day and follow the smoking restrictions 
defined by the CRU while on site.
Activity Restrictions
5.7.2.4
Subjects will avoid unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the pre-trial (screening) visit until the post-trial visit.
Contraception and Pregnancy Testing
5.7.3
Contraception
5.7.3.1
Women of childbearing potential can be enrolled.  However, a highly effective method of 
contraception must be used with a failure rate of < 1%. Acceptable methods of birth control
(to be used during the period as specified in Section 5.1.2) are the following:  intrauterine 
device (IUD without local hormone release), vasectomy of partner having occurred >3 
months prior to screening with a confirmatory negative sperm count.  Surgical sterilization of 
the male partner or the female subject (hysterectomy or oophorectomy) must be documented 
with medical records.
Oral contraceptives are not allowed as a method of birth control in this trial.
Subjects must be completely informed of the unknown risks of pregnancy and agree not to 
become pregnant during the time they are participating in this trial.  
If there is any question that a subject will not be reliable in the use of appropriate 
contraceptive methods, they should not be entered into the trial.
Male subjects with female partner(s) of child-bearing potential must agree to use a medically 
acceptable method of contraception during the trial and for 90 days after the last dose of trial 
drug. Males should use a condom. Female partners must additionally use one of the 
 
 
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following methods if they are not pregnant: hormonal contraception, intra-uterine device, 
diaphragm, or cervical cap. If their partner is pregnant, males must agree to use a condom 
and no additional method of contraception is required for the pregnant partner. Male subjects 
must also agree to not donate sperm during the study and for a period of 90 days after the last 
dose of study drug.
If there is any question that a subject will not be reliable in the use of appropriate 
contraceptive methods, he/she should not be entered into the trial
5.7.3.1.1 Pregnancy Testing 
Female subjects of childbearing potential will be tested for serum -human chorionic 
gonadotropin (hCG) at pretrial. Serum or urine -hCG will be tested at pre-dose and at the 
last trial visit.  In the case of a positive or borderline serum β-hCG pregnancy test at the 
pretrial visit, the subject must not enter the trial; in the case of a positive or borderline serum
or urine β-hCG pregnancy test during the trial, the pregnancy test should be repeated and 
confirmed positive.  If the pregnancy has been confirmed the subject must be discontinued 
from the trial immediately and the pregnancy must be reported the Sponsor as outlined in 
Section 7.2.2.    
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation
5.8.1
For subjects who are discontinued from treatment, all applicable discontinuation activities 
will be performed according to Section 7.1.4.1 – Withdrawal/Discontinuation, or if available, 
Protocol Clarification Letter.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Withdrawal from the Trial
5.8.2
A subject must be withdrawn from the trial if the subject withdraws consent from the trial.
If a subject withdraws from the study, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
5.9
If a subject discontinues from trial treatment or withdraws from the trial, a replacement 
subject may be enrolled if deemed appropriate by the investigator and Sponsor.  The 
replacement subject will generally receive the same treatment or treatment sequence (as 
appropriate) as the subject being replaced. The replacement subject will be assigned a unique 
treatment/randomization number. The trial site should contact the Sponsor for the 
replacement subject’s treatment/randomization number.
 
 
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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, withdraws 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator).
A trial may be paused during review of newly available preclinical/clinical safety, 
pharmacokinetic, pharmacodynamic, efficacy or biologic data or other items of interest, prior 
to a final decision on continuation or termination of the trial.  It may be necessary to keep the 
trial open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the trial.  If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated.  The overall trial end will then not be 
identified until the Sponsor has made the decision to end the trial following this review 
period.  The Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics 
Committee(s) [IRB(s)/IEC(s)] will be apprised of the maximum duration of the trial beyond 
the last subject out and the justification for keeping the trial open.
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
A primary objective of this early Phase I trial is to identify a safe and well-tolerated dose 
and/or dosing regimen that achieve pharmacokinetic, pharmacodynamic and/or biologic 
targets in humans based on preclinical or early clinical data.  Therefore, it is possible that 
trial subjects may not receive all doses specified in the protocol if this objective is achieved 
at lesser dose levels in this trial.  This would not be defined as early termination of the trial, 
but rather an earlier than anticipated achievement of the trial objective(s).  If a finding (e.g., 
pharmacokinetic, pharmacodynamic, efficacy, biologic targets, etc.) from another preclinical 
or clinical trial using the trial treatment(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this trial, results in the trial(s) or program being stopped for non-
safety reasons, this also does not meet the definition of early trial termination.
Early trial termination is defined as a permanent discontinuation of the trial due to 
unanticipated concerns of safety to the trial subjects arising from clinical or preclinical trials 
with the trial treatment(s), comparator(s), drug(s) of the same class or methodology(ies) used 
in this trial.
Enrollment of the trial will be halted in the following circumstances:
1.
One subject reports a serious adverse event with a potential causal 
relationship to the study drug or two (2) subjects per panel report severe 
adverse events with a potential causal relationship to study drug.
2.
Three (3) or more of the enrolled subjects experience the same adverse event
requiring withdrawal from the study, or the same severe adverse event 
assessed as having a potential causal relationship to study drug.
3.
Two (2) subjects experience severe but not life threatening adverse 
experiences or severe clinically significant laboratory abnormalities that are 
similar in nature.
 
 
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4.
One (1) serious adverse experience/laboratory abnormality is reported that is 
life threatening, results in persistent or significant disability/incapacity, 
results in or prolongs an existing inpatient hospitalization, or is another 
important medical event OR participant death thought to be potentially 
related to the investigational product.
5.
Two (2) or more of the enrolled subjects experience confirmed QTcF > 500 
ms or QTcF change from baseline > 60 ms in a given panel with a potential 
causal relationship to study drug.
If one of the above circumstances occurs, enrollment and dosing will be halted, and an 
internal safety review will be conducted prior to making a decision about terminating the 
study. The safety of subjects will be assessed on an ongoing basis, and while conditions that 
could warrant early trial termination are not limited to those noted above, these criteria are 
meant to pre-specify circumstances under which the trial may be terminated early. In the 
event that the trial is interrupted or safety data suggest that the benefit-to-risk assessment has 
been meaningfully altered and must be reassessed, the Regulatory Authority will be notified. 
Following the internal safety review, if the Sponsor deems it appropriate to restart enrollment 
and dosing, if required, the Sponsor will submit an amendment to the competent authority 
prior to restart. If approved, enrollment and dosing may restart at that time.
 
 
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6.0 TRIAL FLOW CHART
Panels A, B, and C
Scheduled Time
Hours Post-dose
Prestudy
Pre-dose
0 0.25 0.5 1
2
4
6 12 24 36 48 72 96 168 240
312
672/Post-
trial a
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical 
Research
X
Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X
Medical History
X
Assignment of Screening Number
X
Assignment of Randomization Number c
X
Prior/Concomitant Medication Review
X
       X------------------------------------------------------------------------------------------------------------------X
Subject domiciling in the clinical research unit
            X----------------------------------------------------X
Clinic Procedures/Assessments
Full Physical Examination (PE)
X
Xd
X
X
Height
X
Weight
X
12-Lead Electrocardiogram e
X
X
X
X
X
X
Vital Signs (heart rate, blood pressure, 
respiratory rate, body temperature) f
X
X
X
X
X
X
Orthostatic Vital Signs (heart rate, blood 
pressure) f
X
X
X
X
X
X
Standard Meals g
X-----------X
MK-8583 Administration
X
Adverse Events Monitoring
X ------------------------------------------------------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Laboratory Safety Tests (hematology, chemistry, 
urinalysis)
X
Xd
X
X
X
Urine /Serum -Human Chorionic Gonadotropin 
(β-hCG) h
X
Xd
X
Serum FSH i
X
Urine/Blood Drug Screen j
X
Xd
HIV/Hepatitis Screen 
X
Blood for Genetic Analysis b
X
 
 
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Panels A, B, and C
Scheduled Time
Hours Post-dose
Prestudy
Pre-dose
0 0.25 0.5 1
2
4
6 12 24 36 48 72 96 168 240
312
672/Post-
trial a
Stool for Future Biomedical Research o
X
Pharmacokinetic/Pharmacodynamic 
Evaluations 
Blood for Plasma MK-8583 and TFV Assay k
X
X
X
X X X X X
X
X
X
X
Blood for MK-8583 PBMC Assay l, n
X
X
X
X
X
X
X
X
X
X
X
Blood for HIV RNA, Viral Resistance m, n
X
X
X
X
X
X
X
X
X
X
X
X
CD4-positive cell count
X
 
 
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Panels A, B, and C
Scheduled Time
Hours Post-dose
Prestudy
Pre-dose
0 0.25 0.5 1
2
4
6 12 24 36 48 72 96 168 240
312
672/Post-
trial a
a.
The post-trial visit will occur approximately 28 days following administration of the study drug. Follow up for any clinical or laboratory adverse experiences should 
occur by phone or in person if the post-trial visit occurs prior to 28 days following the last dose of study drug. For confirmation of viral load return to baseline, 
additional data from viral load samples collected during routine follow-up visits may be transmitted to the sponsor for those patients who do not begin ART and who 
provide appropriate informed consent. Subjects may be asked to participate in observational monitoring beyond the 672 hour post-trial visit.
b.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at the site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the 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.  This sample, to be collected on randomized subjects only, should be 
obtained one time only, pre-dose, on Day 1.
c.
On Day 1, the randomization number is assigned after the completion of all pre-dose procedures prior to trial drug administration.
d.
The pre-dose PE, laboratory assessments, and urine/blood drug screen may be performed within 24 hours prior to dosing.
e.
Pre-dose ECGs will be obtained in triplicate, at least 1-2 minutes apart, and will be obtained within 3 hours prior to dosing of the trial drug. Pre-study and post-dose 
ECGs will be single measurements. Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to obtaining ECG. See Section 7.1.2 for 
additional details. 
f.
Pre-dose semi-recumbent HR and BP will be triplicate measurements obtained at least 1-2 minutes apart within 3 hours prior to study administration. Subjects should 
be resting in the semi-recumbent position for at least 10 minutes prior to obtaining HR and BP. Following each semi-recumbent HR and BP measurement, subjects 
assume a standing position for at least ~2 minutes and then orthostatic HR and BP will be obtained. Pre-study and post-dose vital sign measurements will be single 
measurements. See Section 7.1.2 for additional details.  
g.
Standardized meals will be provided at ~4 and ~10 hours post-dose. A snack will be offered at ~ 7 and 13 hours post-dose. After the 24 hour post-dose procedures have 
been completed, subsequent meal and snacks will be unrestricted in terms of caloric content, composition and timing.
h.
For female subjects of childbearing potential only. Urine pregnancy test may be performed instead of serum at pre-dose.
i.
For postmenopausal woman only.
j.
Additional urine drug screen tests may be performed at the discretion of the Investigator.  
k.
Leftover main study plasma will be stored for future biomedical research, if the subject consents to Future Biomedical Research consent.
l.
For all panels, PBMC samples may be collected up to the post-trial visit regardless of initiation of ART.  
m.
For all panels, blood for HIV-1 viral RNA (also called viral load, VL) and viral resistance may be collected up to and including the day of ART initiation. Subjects 
choosing to forgo follow-on ART may also be asked if they wish to continue to participate in observational monitoring of VL and viral resistance testing beyond 28 
days. 
n.
The 672 hour sample may be collected at the post-trial visit. Leftover main study PBMC will be stored for future biomedical research if the subject consents to Future 
Biomedical Research consent.
o.
Informed consent for future biomedical research samples must be obtained to collect the stool samples. Stool samples will be collected at any time before dosing, 
according to the instructions in the Study Operations Manual. But if a sample cannot be obtained prior to dosing, this subject will be omitted from stool collection, the 
dosing will still proceed as scheduled and this will not be considered a protocol deviation. 
 
 
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7.0 TRIAL PROCEDURES
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
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject prior to participating in a clinical trial or Future Biomedical Research. If there are 
changes to the subject’s status during the trial (e.g., health or age of majority requirements), 
the investigator or qualified designee must ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’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 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.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
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.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
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. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
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.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
 
 
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occurring after 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.
Trial Compliance (Medication/Diet/Activity/Other)
7.1.1.8
Administration of trial medication will be witnessed by the investigator and/or trial staff.
Clinical Procedures/Assessments
7.1.2
Physical Exam:
The physical exam assessments will be defined and conducted per the site SOP.
Body Weight and Height
Body weight and height will be obtained with the subjects shoes off, jacket or coat removed.
Body Mass Index (BMI)
BMI equals a person's weight in kilograms divided by height in meters squared. 
(BMI=kg/m2).
12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement.  Subjects may need to be shaved to ensure proper lead 
placement.  Female subjects may need to remove interfering undergarments.  
Subjects should be resting in the semi-recumbent for at least 10 minutes prior to each ECG 
measurement.  
The correction formula to be used for QTc is Fridericia.
For repeat ECGs, the clinical site will decide whether to leave the electrodes in place or mark 
the position of the electrodes for subsequent ECGs.  To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker 
pen to ensure reproducible electrode placement.
Pre-dose ECGs will be obtained in triplicate at least 1-2 minutes apart, and the pre-dose ECG 
will be obtained within 3 hours prior to dosing MK-8583.  The average of triplicate pre-dose
measurements will be used for the baseline ECG.  Pre-study screening and post-dose ECG 
measurements will be single measurements.
If a subject demonstrates an increase in QTcF interval ≥60 msec compared with mean pre-
dose baseline measurement, the ECG will be repeated twice within 5 minutes.  The average 
value of the QTcF interval from the 3 ECGs will represent the value at that time point.  If the 
average QTcF interval increase from baseline for any post-dose time point is ≥60 msec, the 
subject will continue to be monitored by repeat 12-lead ECGs every 15 minutes for at least 1 
hour or until the QTcF is within 60 msec of baseline.  If prolongation of the QTcF interval 
 
 
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≥60 msec persists, a consultation with a study cardiologist may be appropriate and the 
Sponsor should be notified.
If the QTcF interval is 500 msec (confirmed upon recheck and manual measurement), the 
Sponsor should be notified and the ECGs should be reviewed by a cardiologist. The subject 
should be telemetry-monitored (until the QTcF is <500 msec) or should be considered for 
transfer to a location where closer monitoring and definitive care (e.g., a Cardiac or Intensive 
Care Unit) is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the subject should be immediately transferred to an acute care setting for 
definitive therapy.  
If prolongation of the QTcF is noted, concomitant medications that prolong QTcF should be 
held until the QTcF is within 60 msec of baseline and the QTcF is <500 msec.
A study cardiologist should be arranged by the Principal Investigator to be available as 
needed to review ECG tracings with abnormalities.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual subject and should be the same for all subjects.
Vital Sign Measurements (Heart Rate and Blood Pressure)
Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to 
having vital sign measurements obtained.  Semi-recumbent vital signs will include heart rate 
(HR) and blood pressure (BP).  The correct size of the blood pressure cuff and the correct 
positioning on the subjects' arm is essential to increase the accuracy of blood pressure 
measurements.  The same method (e.g., manual or automated) must be used for all 
measurements for each individual subject and should be the same for all subjects.
Pre-dose HR and BP will be triplicate measurements obtained at least 1-2 minutes apart, and 
the pre-dose measurements will be obtained within 3 hours of dosing MK-8583.  The average
of these measurements will be used as the baseline.  Pre-study screening and post-dose vital 
sign measurements will be single measurements.
Orthostatic vital signs (HR and BP) will also be obtained.  Subjects should be semi-
recumbent for at least 10 minutes and then stand upright for 2 minutes prior to measurement 
of orthostatic vital signs. 
Subjects will continue to rest semi-recumbent from dosing until 4 hours post-dose except to 
stand for the measurement of orthostatic vital signs or other trial related procedure.  Pre-dose
vital signs may be obtained up to 3 hours prior to dosing.
 
 
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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 12.3.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Red blood Cell & 
white blood cell
Follicle Stimulating 
Hormone (FSH) - for 
postmenopausal 
females only*
Hemoglobin
Alkaline phosphatase Glucose
Urine/Serum β-human 
chorionic gonadotropin 
(β-hCG) – for females 
of childbearing 
potential only**
Platelet count
Alanine 
aminotransferase 
(ALT)
Protein
Hepatitis B surface 
antigen and HCV 
antibodies
WBC (total and 
differential)
including: 
Absolute neutrophils
Absolute lymphocytes 
Absolute monocytes 
Absolute eosinophils 
Absolute basophils
Aspartate 
aminotransferase 
(AST)
Specific gravity 
HIV (including HIV-
RNA, resistance 
mutations (per 
inclusion criterion 10))
CD4+ T cell count 
(screening)
Bicarbonate
Microscopic exam, 
if abnormal results 
are noted
Urine/Blood Drug 
Screen
Calcium
pH
Chloride
Creatinine
Glucose
Phosphorus
 
 
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Hematology
Chemistry
Urinalysis
Other
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin
Total protein
Urea 
*Only collected at prestudy.
**Serum pregnancy test to be performed at prestudy; serum or urine pregnancy test will be performed at
pre-dose.
Laboratory safety tests will be performed after at least an 8-hour fast.  Pre-dose laboratory 
procedures can be conducted up to 24 hours prior to dosing.
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
The decision as to which plasma and/or urine samples collected will be assayed for 
evaluation of PK/PD will be collaboratively determined by the Department of Quantitative 
Pharmacology and Pharmacometrics (QP2)
and the appropriate department within 
Translational Pharmacology, (e.g., samples at lower doses may not be assayed if samples at 
higher doses reveal undetectable drug concentrations).  If indicated, these samples may also 
be assayed and/or pooled for assay in an exploratory manner for metabolites and/or 
additional PD markers.
7.1.3.2.1 Blood Collection for Plasma TFV and MK-8583
Sample collection, storage and shipment instructions for plasma MK-8583 and TFV samples 
will be provided in a Study Operations Manual. 
7.1.3.2.2 Blood Collection for PBMC
Sample collection, processing, storage and shipment instructions for PBMC samples will be 
provided in the Study Operations Manual.
7.1.3.2.3 Blood Collection for HIV-1 Viral RNA and Viral Resistance
Sample collection, storage and shipment instructions for these blood samples will be 
provided by the site’s local laboratory.
Planned Genetic Analysis Sample Collection
7.1.3.3
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Study Operations Manual. 
 
 
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Future Biomedical Research Samples
7.1.3.4
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Stool for future research

Leftover main study PBMC stored for future research

Leftover main study plasma from MK-8583 and TFV assays stored for future 
research
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
The investigator or trial coordinator must notify the Sponsor when a subject has been 
discontinued/withdrawn from the trial.  If a subject discontinues for any reason at any time 
during the course of the trial, the subject may be asked to return to the clinic (or be 
contacted) for a post-trial visit (approximately 28 days after the last dose of trial drug is 
given) to have the applicable procedures conducted.  However, the investigator may decide 
to perform the post-trial procedures at the time of discontinuation or as soon as possible after 
discontinuation.  If the post-trial visit occurs prior to 28 days after the last dose of trial drug
is given, the investigator should perform a follow-up phone call 28 days after the last dose of 
trial drug to determine if any adverse events have occurred since the post-trial clinic visit.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  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).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (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 withdrawal cannot be processed.
 
 
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7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g. phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified statistical data handling and analysis guidelines.
Subject Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
Domiciling
7.1.4.3
Subjects will report to the clinical research unit (CRU) the evening prior to the scheduled day 
of trial drug administration in each treatment period and remain in the unit until 24 hours 
post-dose.  At the discretion of the investigator, subjects may be requested to remain in the 
CRU longer.
Calibration of Critical Equipment
7.1.4.4
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:

Vital signs, ECG and centrifuge equipment

Equipment and specified supplies necessary for PBMC sample collection and 
processing:
o
Equipment such as, but not limited to, centrifuges with refrigeration function, 
microscope, and pipettes
o
Freezers for the assay samples
 
 
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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.
Screening
7.1.5.1
Approximately 4 weeks prior to treatment allocation/randomization, potential subjects will 
be evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1.
Subjects may be rescreened after consultation with the Sponsor. Rescreening should include 
all screening procedures listed in the protocol flow chart, including consent review.   
Rescreen procedures cannot be conducted the day prior to treatment allocation/randomization 
if there are Day -1 procedures planned per protocol.
Treatment Period
7.1.5.2
7.1.5.2.1 Pre-dose Procedures (All Panels)
Prior to each treatment panel, the clinical and laboratory safety data from the previous dose 
level and previous treatment panel will be reviewed by the Investigator and the Clinical 
Team and a mutual decision on whether to advance to the next higher dose level will be 
made.  No dose modification will occur without agreement of the Investigator and the 
Sponsor.
Subjects will report to the CRU the day prior to the scheduled day of administration of the 
study drug or time specified by the investigator.  Subjects will fast from all food and drink, 
except for water, for a minimum of 8 hours prior to study drug administration and prior to 
obtaining samples for laboratory safety tests (refer to Section 7.1.3.1).
After the Day 1 pre-dose procedures have been completed, subjects will be assigned a unique 
randomization number associated with a specific treatment sequence as defined by a 
computer-generated allocation schedule.  For details on procedures, please refer to the Study 
Flow chart (Section 6.0), Procedures (Section 7.1.2) and/or corresponding appendices. 
7.1.5.2.2 Treatment Procedures (All Panels)
Procedures for study drug administration and post-dose procedures are listed in the Study 
Flow Chart, Section 6.0 of this protocol.
Subjects will be administered a single dose of MK-8583 in the morning.  The exact clock 
time of dosing should be recorded.
Post-Trial
7.1.5.3
Post-trial procedures are listed in the Study Flow Chart, Section 6.0 of this protocol.
Subjects will be required to return to clinic approximately 28 days after the last dose of trial 
drug for the post-trial visit.  If the post-trial visit occurs less than 28 days after the last dose 
of trial drug, a subsequent follow-up phone call should be made at 28 days post the last dose 
of trial drug to determine if any adverse events have occurred since the post-trial clinic visit.
 
 
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Critical Procedures Based on Trial Objectives: Timing of Procedure 
7.1.5.4
For this trial, the blood sample for viral load and the blood sample for MK-8583 PBMC are
the critical procedures. 
At any post-dose time point, the blood samples for viral load and MK-8583 PBMC need to 
be collected as close to the exact time point as possible.  All other procedures should be 
completed as close to the prescribed/scheduled time as possible. Trial procedures can be 
performed prior or after the prescribed/scheduled time.  
The order of priority can be changed during the trial with joint agreement of the investigator 
and the Sponsor Clinical Director.  
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.  
The following variance in procedure collection times will be permitted.

PK Collection as outlined in Table 6 below
Table 6
PK (Blood)/PBMC/Viral Load Collection Windows
PK/PBMC/Viral Load
collection
PK/PBMC/Viral Load
Collection Window
0 to < 1 hr
5 min
1 to < 24 hr
15 min
24 hr to < 48 hr
2 hrs
48 to 168 hr
3 hrs
168 to 240 hr
24 hrs
> 240 hr
72 hrs

Pre-dose standard safety evaluations:  vital signs
(including RR and body 
temperature) & ECG 3 hrs; laboratory safety tests (including drug screen) & physical 
exam 24 hrs prior to dosing

Post-dose standard safety evaluations (vital signs, ECG, laboratory safety tests, 
physical exam) as outlined in Table 7 below:
Table 7
Post-dose Standard Safety Evaluations Collection Windows
Scheduled Time
Data Collection 
Window
0 to < 24 hr
30 min
24 to < 48 hr
2 hrs
48 to 168 hr
3 hrs
168 to 240 hr
24 hrs
> 240 hr
72 hrs
 
 
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Trial Design/Dosing/Procedures Modifications Permitted within Protocol 
7.1.5.5
Parameters
This is a Phase I assessment of MK-8583 in humans, and the PK, PD and safety profiles of 
the compound is still being elucidated.  This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of Phase I clinical trials.  Modifications to the 
dose, dosing regimen and/or clinical or laboratory procedures currently outlined below may 
be required to achieve the scientific goals of the trial objectives and/or to ensure appropriate 
safety monitoring of the trial subjects.  
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.

Repeat of or decrease in the dose of the trial drug administered

Entire panel(s) may be omitted

Instructions to take trial drug with or without food or drink may also be modified based 
on newly available data

Modification of the PK/PD sample processing and shipping details based on newly 
available data

Decrease in the length of post-dose PK/PD sample collection
The PK/PD sampling scheme currently outlined in the protocol may be modified during the 
trial based on newly available PK or PD data (e.g., to obtain data closer to the time of peak 
plasma concentrations).  If indicated, these collected samples may also be assayed in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or PD analyses. The total 
blood volume withdrawn from any single subject will not exceed the maximum allowable 
volume during his/her participation in the entire trial (Section 12.3).
The timing of procedures for assessment of safety procedures (e.g., vital signs, ECG, safety 
laboratory tests, etc.) currently outlined in the protocol may be modified during the trial 
based on newly available safety, tolerability, pharmacokinetic or pharmacodynamic data 
(e.g., to obtain data closer to the time of peak plasma concentrations).  Additional laboratory 
safety tests may be added to blood samples previously drawn to obtain additional safety 
information (e.g., adding creatinine kinase to serum chemistry panel that was already drawn). 
These changes will not increase the number of trial procedures for a given subject during 
his/her participation in the entire trial. 
It is understood that the current trial may employ some or none of the alterations described 
above.  Any alteration made to this protocol to meet the trial objectives must be detailed by 
the Sponsor in a letter to the Trial File and forwarded to the investigator for retention.  The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
If an alteration impacts subject safety, affects the scientific value of the study results, and/or
significantly alters the execution of the trial, a notification will be submitted prior to
proceeding with the trial. If approved, enrollment and dosing may restart at that time
 
 
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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.  
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.
For randomized subjects only, all adverse events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by investigator if they 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 28 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 Electronic Data Capture (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
An overdose is defined when the subject has taken (accidentally or intentionally) any drug 
administered as part of the protocol and exceeding the dose as prescribed by the protocol. It 
is up to the investigator or the reporting physician to decide whether a dose is to be 
considered an overdose, in consultation with the Sponsor.
 
 
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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 non-serious adverse event, unless other serious 
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.
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 28 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
Serious Adverse Events
7.2.3.1
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.
 
 
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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.
●
Is a cancer (within 5 calendar days of learning of event);
●
Is associated with an overdose.
Refer to Table 8 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 28 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
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 28 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
 
 
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2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
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).
It may also be appropriate to conduct additional evaluation for an underlying etiology in 
the setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and 
alkaline phosphatase that do not meet the criteria noted above. In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this trial.
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 8. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 8 for instructions in evaluating adverse events.
 
 
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Table 8
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.  (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of 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 5 calendar days to meet certain local requirements); or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is 
reportable to the Sponsor within 24 hours to meet certain local requirements.
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 THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
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.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Statistical Methods
Primary Objective (Safety):
Incidence of adverse experiences will be descriptively
summarized. Summary statistics and plots will be generated for the change from baseline
values in the vital signs, ECG parameters, and selected laboratory safety parameters for
subjects, as deemed clinically appropriate. Depending on the safety parameter, the difference
from baseline will either be computed on the original scale (raw change from baseline) or on
the log scale and back-transformed for reporting (percent change from baseline). Summary
statistics for the raw laboratory safety tests, ECGs, and/or vital signs may also be computed,
as deemed clinically appropriate.
Primary Objective (Pharmacodynamics):
The log10 plasma HIV-RNA (copies/mL)
measurements from subjects in all panels will be pooled and analyzed based on a longitudinal
data analysis model containing fixed effects for dose level, time (pre-dose, 168 hrs post-dose)
and dose level by time interaction, and a random effect for patient. The change from baseline
for each dose level at 168 hours post-baseline will be estimated from this model. A posterior
distribution for the true mean change from baseline at 168 hours will be generated for each
dose level using flat priors under a normal likelihood assumption. Historical placebo data
from recent monotherapy studies in HIV-1 subjects (MK-0518 Protocol 004, MK-1439
Protocol 005, MK-6186 Protocol 007, and MK-1972 Protocol 003) will be separately
analyzed based on a longitudinal data analysis model containing fixed effects for study and
time (pre-dose, 168 hours post-dose), and a random effect for patient. The change from
baseline for placebo at 168 hours post-baseline will be estimated from this model, and a
posterior distribution for the true mean change from baseline at 168 hours will be generated
using flat priors under a normal likelihood assumption. Using the posterior distributions for
each dose level and placebo, the posterior distribution of the true mean difference between
each dose level and placebo will be generated, and the posterior probability that the true
mean difference in the log10 plasma HIV-1 RNA reduction from baseline between MK-8583 
and placebo is at least 0.5 log10 copies/mL will be calculated. An 80% posterior probability
for at least one dose level that also exhibits an acceptable safety and tolerability profile will
satisfy the primary PD hypothesis.
Power
If the true SD of the log10 reduction from baseline in plasma HIV-RNA at 168 hours post-
dose is 0.25(0.4) for MK-8583, there is ~80% power to yield at least 80% posterior 
probability that the true mean difference in the plasma HIV-1 RNA reduction from baseline 
 
 
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between MK-8583 and placebo is at least 0.5 log10 copies/mL, if the true mean log10 
reduction is at least 0.7 log10 (0.8 log10) with N=6 subjects in a Panel. It assumes the
historical placebo sample size of 20 with mean reduction of 0 log10 and SD = 0.25. The 
information of placebo data was from historical placebo data of recent monotherapy studies 
in HIV-1 subjects (MK-0518 Protocol 004, MK-1439 Protocol 005, MK-6186 Protocol 007, 
and MK-1972 Protocol 003). The SD of MK-8583 is estimated based on MK-8591 Protocol 
003and MK-8507 Protocol 003 studies (SD ranges from 0.24 to 0.4). 
Statistical Analysis Plan
8.2
The statistical analysis of the data obtained from this study will be conducted by, or under the
direct auspices of, the Early Clinical Development Statistics Department in collaboration
with the Quantitative Pharmacology and Pharmacometrics Department and Translational
Pharmacology Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below,
then these deviations to the plan will be listed, along with an explanation as to why they
occurred, in the Clinical Study Report.
Hypotheses
8.2.1
Primary PD Hypothesis: At a dose that is sufficiently safe and generally well tolerated, MK-
8583 has superior anti-retroviral activity compared to placebo, as measured by change from 
baseline in plasma HIV-1 RNA (log10 copies/mL) at 168 hours post-dose. That is, the true 
mean difference in the plasma HIV-1 RNA reduction from baseline between MK-8583 and 
placebo is at least 0.5 log10 copies/mL.
Secondary Pharmacokinetics Hypothesis: The true geometric mean (GM) TFV-DP PBMC
C168hr is ≥ 0.1 μM for at least one dose level that also exhibits an acceptable safety and
tolerability profile.
Analysis Endpoints
8.2.2
Primary Endpoints
Safety: Primary safety endpoints will include adverse experiences, in addition to laboratory 
safety tests, ECGs, and vital signs.
Pharmacodynamics: The primary PD variable in this study is plasma HIV-1 RNA collected 
at pre-dose and 4, 12, 24, 48, 72, 96, 168, 240, 336 and 504 hours post-dose.
Secondary Endpoints
The secondary endpoints in this study include: TFV-DP PBMC AUC0-168hr, Cmax, Tmax,
C168hr and t1/2; MK-8583 plasma AUC0-last, AUC0-inf, AUC0-168hr, Tmax, Cmax, t1/2,
CL/F and Vz/F; TFV plasma AUC0-last, AUC0-inf, Tmax, Cmax and t1/2.
Exploratory Endpoints
PBMC TFV-MP concentrations at designated time points.
 
 
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Approaches to Analyses
8.2.3
The following populations are defined for the analysis and reporting of data. All subjects will 
be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated (ASaT): The All Subjects as Treated Population consists of all 
subjects who received at least one dose of treatment. This population will be used for 
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the subset of subjects who 
comply with the protocol sufficiently to ensure that generated data will be likely to exhibit 
the effects of treatment, according to the underlying scientific model. Compliance covers 
such considerations as exposure to treatment, availability of measurements and absence of 
major protocol deviations. Major protocol deviations will be identified to the extent possible 
by individuals responsible for data collection/compliance, and its analysis and interpretation. 
Any subjects or data values excluded from analysis will be identified, along with their reason 
for exclusion, in the CSR. At the end of the study, all subjects who are compliant with the 
study procedure as aforementioned and have available data from at least one treatment will 
be included in the Per-Protocol dataset. This population will be used for the PK and PD 
analyses.
Statistical Methods
8.2.4
Primary (Safety)
Incidence of adverse experiences will be descriptively summarized. Summary statistics and
plots will be generated for the change from baseline values in the vital signs, ECG
parameters, and selected laboratory safety parameters for subjects, as deemed clinically
appropriate. Depending on the safety parameter, the difference from baseline will either be
computed on the original scale (raw change from baseline) or on the log scale and back -
transformed for reporting (percent change from baseline). Summary statistics for the raw
laboratory safety tests, ECGs, and/or vital signs may also be computed, as deemed clinically
appropriate.
Primary (Pharmacodynamics)
The log10 plasma HIV-RNA (copies/mL) measurements from subjects in all panels will be
pooled and analyzed based on a longitudinal data analysis (LDA) model containing fixed
effects for dose level, time (pre-dose, 168 hrs post-dose) and dose level by time interaction,
and a random effect for patient. The response vector consists of the baseline and 168 hours
post-baseline values. Time is treated as a categorical variable so that no restriction is imposed
on the trajectory of means over time. The change from baseline for each dose level at 168
hours post-baseline will be estimated from this model. A posterior distribution for the true
mean change from baseline at 168 hours will be generated for each dose level using flat
priors under a normal likelihood assumption. Historical placebo data from recent
monotherapy studies in HIV-1 subjects (MK-0518 Protocol 004, MK-1439 Protocol 005,
MK-6186 Protocol 007, and MK-1972 Protocol 003) will be separately analyzed based on a
longitudinal data analysis model containing fixed effects for study and time (pre-dose, 168
hrs post-dose), and a random effect for patient. The change from baseline for placebo at 168
hours post-baseline will be estimated from this model, and a posterior distribution for the true
 
 
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mean change from baseline at 168 hours will be generated using flat priors under a normal
likelihood assumption. Using the posterior distributions for each dose level and placebo, the
posterior distribution of the true mean difference between each dose level and placebo will be
generated, and the posterior probability that the true mean difference in the log10 plasma
HIV-1 RNA reduction from baseline between MK-8583 and placebo is at least 0.5 log10
copies/mL will be calculated. An 80% posterior probability for at least one dose level that
also exhibits an acceptable safety and tolerability profile will satisfy the primary PD
hypothesis. For each dose level, the posterior probability that the true mean log10 plasma 
HIV-1 RNA reduction from baseline is at least 0.5 log10 copies/mL will also be calculated. 
Similar exploratory analyses may be performed using viral load measurements at baseline 
and specified post-baseline time points.
Secondary (Pharmacokinetics)
Separately for each PK parameter, individual values of TFV-DP in PBMC PK parameters 
AUC0-168hr, Cmax, and C168hr from subjects in all panels will be pooled, natural log 
transformed and analyzed based on a linear model containing a fixed effect for dose level. 
The 95% confidence intervals for the least squares means by dose level will be constructed 
on the natural log scale and will reference the t-distribution. Exponentiating the least-squares 
means and lower and upper limits of these confidence intervals will yield estimates for the 
population geometric means and confidence intervals about the geometric means on the 
original scale. The posterior probability that the true GM C168hr PBMC TFV-DP level is ≥ 
0.1 μM will be calculated for each dose level using flat priors under a normal likelihood 
assumption. An 80% posterior probability for at least one dose level that also exhibits an 
acceptable safety and tolerability profile will satisfy the secondary PK hypothesis.
MK-8583 plasma AUC0-last, AUC0-inf, Cmax, CL/F and Vz/F, and TFV plasma AUC0-
last, AUC0-inf and Cmax will be analyzed in a similar fashion.
Descriptive Statistics
Individual values will be listed for each PK parameter by dose level, and the following (non-
model-based) descriptive statistics will be provided: N (number of subjects with non-missing 
data), arithmetic mean, standard deviation, arithmetic percent CV (calculated as 100 x 
standard deviation/arithmetic mean), median, minimum, maximum, geometric mean, and 
geometric percent CV (calculated as 100 x sqrt( exp(s2) - 1), where s2 is the observed 
variance on the natural log-scale).
The above descriptive statistics, as well as a mean plot will also be provided for VL 
reduction by dose level and all time points.
Secondary and Exploratory (Pharmacokinetic/Pharmacodynamic)
The PK-PD and dose-PD association of MK-8583 will be explored. Graphs to visualize the 
association of the reduction in log10 plasma HIV-1 RNA levels with TFV-DP in PBMC by 
parameters and dose will be generated. Exploratory linear and/or non-linear model fits may 
be considered, as appropriate. Exposure levels and doses that result in various proportions of 
the population (e.g., 80%, 90%) that have at least 0.5 log10 reduction from baseline in 
plasma HIV-1 RNA levels with high confidence may be estimated.
 
 
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The duration of anti-retroviral suppression after single dose MK-8583 will be evaluated with
individual plots across time.
For PBMC levels of TFV-MP, descriptive statistics (similar to those of secondary PK 
parameters) will be provided by dose.
General
For all analyses, data will be examined for departures from the assumptions of the statistical 
model(s) as appropriate; e.g., heteroscedasticity, nonnormality of the error terms. 
Distribution-free methods may be used if a serious departure from the assumptions of the 
models(s) is observed, or suitable data transformations may be applied.
Multiplicity
8.2.5
Since there is only one primary PD hypothesis and it is being evaluated with Bayesian 
methods, no multiplicity adjustment will be made.
Sample Size and Power
8.2.6
If the true SD of the log10 reduction from baseline in plasma HIV-RNA at 168 hours post-
dose is 0.25(0.4) for MK-8583, there is ~80% power to yield at least 80% posterior 
probability that the true mean difference in the plasma HIV-1 RNA reduction from baseline 
between MK-8583 and placebo is at least 0.5 log10 copies/mL, if the true mean log10 
reduction is at least 0.7 log10 (0.8 log10) with N=6 subjects in a Panel. It assumes the
historical placebo sample size of 20 with mean reduction of 0 log10 and SD = 0.25. The 
information of placebo data was from historical placebo data of recent monotherapy studies 
in HIV-1 subjects (MK-0518 Protocol 004, MK-1439 Protocol 005, MK-6186 Protocol 007, 
and MK-1972 Protocol 003). The SD of MK-8583 is estimated based on MK-8591 Protocol 
003and MK-8507 Protocol 003 studies (SD ranges from 0.24 to 0.4). 
A posterior probability threshold P%=80% is chosen. A favorable posterior probability 
threshold is defined when the true mean HIV-1 reduction > 0.5 log [relative to Placebo] is
>P%; there is relatively low probability of a favorable outcome when the true mean reduction
is < 0.5 log10 copies/mL (about 20% or less) and relatively high probability for favorability
when the true mean reduction is > 0.7 log10 copies/mL (about 80% or more), assuming a true 
SD = 25%.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
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 9.
 
 
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Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 9
Product Descriptions
Product Name 
& Potency
Dosage Form
Source/Additional Information
MK-8583 10 mg
Capsule
Provided centrally by the Sponsor
MK-8583 100 mg
Capsule
Provided centrally by the Sponsor
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 single doses dispensed from supplies packaged in bulk open 
label 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.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
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 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/IEC 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 Protocol/CSR 
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.
11.0 LIST OF REFERENCES
[1]
Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic 
review and meta-analysis: renal safety of tenofovir disoproxil fumarate in 
HIV-infected patients. Clin Infect Dis. 2010 Sep 1;51(5):496-505.
[2]
Horberg M, Tang B, Towner W, Silverberg M, Bersoff-Matcha S, Hurley L, 
et al. Impact of tenofovir on renal function in HIV-infected, antiretroviral-
naive patients. J Acquir Immune Defic Syndr. 2010 Jan;53(1):62-9.
[3]
Bolland MJ, Grey A, Reid IR. Skeletal health in adults with HIV infection. 
Lancet Diabetes Endocrinol. 2015 Jan;3(1):63-74.
[4]
Ruane PJ, DeJesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et 
al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of 
tenofovir alafenamide as 10-day monotherapy  in HIV-1-positive adults. J 
Acquir Immune Defic Syndr. 2013 Aug 1;63(4):449-55.
[5]
European Medicines Agency. Committee For Medicinal Products For Human 
Use(CHMP): guideline on the clinical development of medicinal products for 
the treatment of HIV infection (EMEA/CPMP/EWP/633/02), 20-Nov-2008.
[6]
Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, Carpenter CC, et 
al. Treatment for adult HIV infection: 2004 recommendations of the 
International AIDS Society-USA Panel. JAMA. 2004 Jul 14;292(2):251-65.
[7]
Hendrix CW. The clinical pharmacology of antiretrovirals for HIV 
prevention. Curr Opin HIV AIDS. 2012 Nov;7(6):498-504.
[8]
Wrzesinski C. Pharmacology review of NDA 207-561 for Genvoya 
(Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide), Gilead, 09-
Jan-2015.
[9]
Verma S. Pharmacology review of NDA 21-356 for Tenofovir Disoproxil 
Fumarate (Gilead Sciences Inc.) 16-May-2001.
[10]
Barditch-Crovo P, Deek SG, Collier A, Safrin S, Coakley DF, Miller M, et al. 
Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of 
tenofovir disoproxil fumarate in human immunodeficiency virus-infected 
adults. Antimicrob Agents Chemother 2001;45(10):2733-9.
 
 
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12.0 APPENDICES
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 consented and/or collected in this trial as outlined in Section 7.1.3.4 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
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 the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  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.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the 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.  This 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 unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (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 ask that their 
biospecimens not be used for Future Biomedical Research.  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). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (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 withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to 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 important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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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 participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies and procedures to address 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/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.3
Sample Types
Panels A, B, and C
Pre-trial
Treatment Periods
Post-trial
Total Collections
mL 
Per 
Collection
Total mL/ 
Test
Laboratory safety tests‡
1
3
1
5
10.2
51
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for TFV assays and 
MK-8583
12
12
4
48
Blood for PBMC assay
10
1
11
16
176
Blood for HIV RNA, viral 
resistance§
1
10
1
12
12
144
Total Blood Volume Per Subject†
427.5
†
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, up to 50 mL of additional blood 
may be obtained.  
‡
Blood for Serum β -Human Chorionic Gonadotropin (β-hCG), HIV/Hepatitis screen, FSH, and CD4 cell count are 
included in the Laboratory Safety blood draw volume.
§
For all panels blood for HIV-1 viral RNA and viral resistance may be collected up to the post-trial visit if subjects do 
      not start ART. 

An additional 4 mLs of blood may be drawn at 168 hours post-dose if ultra-deep sequencing is needed.
*   Sample may be urine OR serum
 
 
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Algorithm for Assessing Out-of-Range Laboratory Values
12.4
For all laboratory values obtained at prestudy (screening) visit and/or pre-dose evaluation:
A. If all protocol-specified laboratory values are normal, the subject may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the subject will be excluded 
from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The subject may be excluded from the study;
2. The subject may be included in the study if the abnormal value(s) is not clinically 
significant (NCS) (the investigator must annotate the laboratory value “NCS” on the 
laboratory safety test source document).
3. The subject may be included in the study if the abnormality is consistent with a pre-
existing medical condition which is not excluded per protocol (e.g., elevated 
eosinophil count in a subject with asthma or seasonal allergies) the medical condition 
should be annotated on the laboratory report or
4. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the subject may enter the study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential subject with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question.  If such diseases can be ruled out, and if the abnormal laboratory value 
is not clinically relevant, then the subject may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
subject will be excluded from the study.
 
 
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List of Abbreviations Used in this Document
12.5
Abbreviation
Definition
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase or All Subjects as Treated
ART
Anti-retroviral therapy
AUC
Area Under the Curve
-hCG
-human chorionic gonadotropin
BMD
Bone Marrow Density
BMI
Body Mass Index
BP
Blood Pressure (Systolic or Diastolic)
Bpm
Beats per minute
BT
Body Temperature
CBC
Complete Blood Count
CI
Coordinating Investigator
CL/F
Apparent total clearance of drug from plasma after oral administration
Cmax
Maximum Plasma Concentration
CRU
Clinical Research Unit
C12 hr
Plasma Concentration at 12 hours post-dose
CV
Cardiovascular 
DBP
Diastolic Blood Pressure
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECI
Event of Clinical Interest
EDC
Electronic data capture
EM
Exposure Margin
EMA
European Medicines Agency
ERB
Ethics Review Board
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
 
 
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Confidential
Abbreviation
Definition
GM
Geometric Mean
HIV
Human Immunodeficiency Virus
hr
Hour
HR
Heart Rate
IB
Investigator’s Brochure
ICF
Informed Consent Forms
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IUD
Intrauterine Device
LDA
Longitudinal data analysis
µM
Micromolar (10-6)
MRL
Merck Research Labs
NCS
Not Clinically Significant
NDA
New Drug Application
NOAEL
No Observed Adverse Event Level
NRTI
Nucleoside reverse transcriptase inhibitor
NNRTI
Non-nucleoside Reverse Transcriptase Inhibitor
PBMC
Peripheral blood mononuclear cell
PE
Physical exam
PK
Pharmacokinetics
PP
Per-Protocol
QP2
Department of Quantitative Pharmacology and Pharmacometrics
QRS
QRS Complex
QT
QT Interval
QTcF
Corrected QT Interval (Fridericia’s)
RNA
Ribonucleic acid
RR
Respiratory Rate
RT
Reverse Transcriptase
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
 
 
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Confidential
Abbreviation
Definition
SBP
Systolic Blood Pressure
SOP
Standard Operating Procedure
TAF
Tenofovir alafenamide fumarate
TAM
Thymidine analog mutations
TDF
Tenofovir disoproxil fumarate
TFV-DP
Tenofovir diphosphate
TFV-MP
Tenofovir monophosphate
TFV PD
Tenofovir prodrug
Tmax
Time to Maximum Concentration
t1/2
Half life
VL
Viral load
VS
Vital Signs
 
 
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13.0 SIGNATURES
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 – TRIAL PROCEDURES (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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