Clinical trial NCT03351699
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-01-18; Completion date: 2018-11-02
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The study will evaluate the safety, tolerability, pharmacokinetics, and anti-retroviral activity of MK-4250 monotherapy in anti-retroviral therapy (ART)-naïve, HIV-1 infected participants. The primary hypothesis of the study is that at a dose that is sufficiently safe and generally well tolerated, MK-4250 has superior antiretroviral activity compared to a historical placebo, as measured by change from baseline in plasma HIV-1 ribonucleic acid (RNA) (log10 copies/mL) at 168 hours postdose.

Detailed description:
The study consists of 5 panels; Panel C (MK-4250 ≤600 mg) was removed from the study with Protocol Amendment 1.

Arms: arm 1: Participants will receive MK-4250 150 mg tablet by mouth on Day 1 after an 8-hour fast. arm 2: Participants will receive MK-4250 600 mg tablet by mouth on Day 1 after an 8-hour fast. The decision to enroll Panel B and the dose selected (i.e., ≤600 mg) will be made based on evaluation of pharmacokinetics and 7-day safety and viral load data from Panel A. arm 3: Participants will receive MK-4250 900 mg tablet by mouth on Day 1 after an 8-hour fast. The decision to enroll Panel D will be made upon completion of Panels A and B and evaluation of safety and viral load data from those panels. arm 4: Participants will receive MK-4250 ≤900 mg tablet by mouth on Day 1 with a low-fat meal. The decision to enroll Panel E will be made upon completion of Panel D and evaluation of safety and viral load data from that panel. arm 5: Participants will receive MK-4250 ≤900 mg tablet by mouth on Day 1 with a moderate-fat meal. The decision to enroll Panel F will be made upon completion of Panel D and evaluation of safety and viral load data from that panel. The decision to enroll Panel F will be made based on evaluation of PK and safety data from other studies with MK-4250.
Interventions: intervention 1: MK-4250
Intervention descriptions: intervention 1: MK-4250 tablets for oral administration

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03351699
Document Date: 
13-Jul-2018
A Single-Dose Clinical Trial to Study the Safety, Tolerability, 
Pharmacokinetics, and Anti-Retroviral Activity of MK-4250 
Monotherapy in Anti-Retroviral Therapy (ART)-Naive, HIV-1 
Infected Subjects


Product:  MK-4250 
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Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Single-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Anti-
Retroviral Activity of MK-4250 Monotherapy in Anti-Retroviral Therapy (ART)-Naive,
HIV-1 Infected Subjects
EudraCT NUMBER:  2017-001784-21
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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 9
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Trial Diagram........................................................................................................ 16
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es) .............................................................. 17
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 17
3.2
Exploratory Objectives......................................................................................... 18
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
4.1
Pharmaceutical and Therapeutic Background .................................................... 18
4.1.1
Pre-clinical Studies ............................................................................................. 19
4.1.2
Completed and Ongoing Clinical Trials ............................................................. 20
4.1.3
Additional Background – Amendment 002-01............................................ 20
4.1.3.1
Rationale................................................................................................................ 22
4.2
Rationale for the Trial and Selected Subject Population .................................... 22
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 23
4.2.2
Rationale for the Use of Historical Placebo................................................. 28
4.2.2.1
Starting Dose for This Trial ......................................................................... 28
4.2.2.2
Maximum Dose/Exposure for This Trial..................................................... 28
4.2.2.3
Rationale for Dose Interval and Trial Design .............................................. 28
4.2.2.4
Rationale for Endpoints ...................................................................................... 29
4.2.3
Safety Endpoints .......................................................................................... 29
4.2.3.1
Pharmacokinetic Endpoints ......................................................................... 29
4.2.3.2
Pharmacodynamic Endpoints....................................................................... 30
4.2.3.3
Planned Exploratory Biomarker Research................................................... 30
4.2.3.4
Future Biomedical Research........................................................................ 30
4.2.3.5
Benefit/Risk ........................................................................................................... 30
4.3
 
 
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5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
5.1
Diagnosis/Condition for Entry into the Trial...................................................... 31
5.1.1
Subject Inclusion Criteria.................................................................................... 31
5.1.2
Subject Exclusion Criteria .................................................................................. 32
5.1.3
Trial Treatment(s) ................................................................................................ 34
5.2
Dose Selection/Modification .............................................................................. 35
5.2.1
Dose Selection (Preparation) ....................................................................... 35
5.2.1.1
Dose Modification ....................................................................................... 35
5.2.1.2
Timing of Dose Administration .......................................................................... 35
5.2.2
Trial Blinding...................................................................................................... 35
5.2.3
Randomization or Treatment Allocation............................................................ 36
5.3
Stratification.......................................................................................................... 36
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 36
5.5
Rescue Medications & Supportive Care............................................................. 37
5.6
Diet/Activity/Other Considerations..................................................................... 37
5.7
Diet and Fruit Juice Restrictions......................................................................... 37
5.7.1
Diet............................................................................................................... 37
5.7.1.1
Fruit Juice Restrictions ................................................................................ 39
5.7.1.2
Alcohol, Caffeine, Tobacco, Activity ................................................................. 39
5.7.2
Alcohol Restrictions..................................................................................... 39
5.7.2.1
Caffeine Restrictions.................................................................................... 39
5.7.2.2
Smoking Restrictions................................................................................... 39
5.7.2.3
Activity Restrictions .................................................................................... 39
5.7.2.4
Contraception and Pregnancy Testing ......................................................... 40
5.7.2.5
5.7.2.5.1
Contraception........................................................................................ 40
5.7.2.5.2
Pregnancy Testing................................................................................. 40
Subject Withdrawal/Discontinuation Criteria................................................... 40
5.8
Discontinuation of Treatment ............................................................................. 40
5.8.1
Withdrawal from the Trial .................................................................................. 41
5.8.2
Subject Replacement Strategy............................................................................. 41
5.9
Beginning and End of the Trial ........................................................................... 41
5.10
 
 
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Clinical Criteria for Early Trial Termination ................................................... 42
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 44
7.0
TRIAL PROCEDURES ........................................................................................... 47
Trial Procedures ................................................................................................... 47
7.1
Administrative Procedures.................................................................................. 47
7.1.1
Informed Consent......................................................................................... 47
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 47
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 47
Inclusion/Exclusion Criteria ........................................................................ 48
7.1.1.2
Subject Identification Card .......................................................................... 48
7.1.1.3
Medical History ........................................................................................... 48
7.1.1.4
Prior and Concomitant Medications Review ............................................... 48
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 48
7.1.1.5.2
Concomitant Medications..................................................................... 48
Assignment of Screening Number............................................................... 48
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 49
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other) ................................... 49
7.1.1.8
Clinical Procedures/Assessments........................................................................ 49
7.1.2
Laboratory Procedures/Assessments .................................................................. 51
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 51
7.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 53
7.1.3.2
7.1.3.2.1
Blood Collection for Plasma MK-4250................................................ 53
7.1.3.2.2
Blood Collection for HIV-1 Viral RNA and Viral Resistance ............. 53
Planned Genetic Analysis Sample Collection.............................................. 53
7.1.3.3
Future Biomedical Research Samples ......................................................... 53
7.1.3.4
Other Procedures................................................................................................. 53
7.1.4
Withdrawal/Discontinuation........................................................................ 53
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 54
7.1.4.1.2
Lost to Follow-up.................................................................................. 54
Subject Blinding/Unblinding ....................................................................... 54
7.1.4.2
Domiciling ................................................................................................... 54
7.1.4.3
 
 
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Calibration of Critical Equipment................................................................ 55
7.1.4.4
Visit Requirements.............................................................................................. 55
7.1.5
Screening...................................................................................................... 55
7.1.5.1
Treatment Period (All Panels) ..................................................................... 55
7.1.5.2
Post-Trial...................................................................................................... 55
7.1.5.3
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 56
7.1.5.4
Trial 
Design/Dosing/Procedures Modifications Permitted 
within 
7.1.5.5
Protocol Parameters ..................................................................................... 57
Assessing and Recording Adverse Events .......................................................... 58
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 59
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 59
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 59
7.2.3
Serious Adverse Events ............................................................................... 59
7.2.3.1
Events of Clinical Interest............................................................................ 60
7.2.3.2
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 61
7.2.3.3
Evaluating Adverse Events ................................................................................. 61
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 64
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 64
Statistical Analysis Plan Summary ..................................................................... 64
8.1
Statistical Analysis Plan ....................................................................................... 65
8.2
Hypotheses.......................................................................................................... 65
8.2.1
Analysis Endpoints ............................................................................................. 65
8.2.2
Approaches to Analyses...................................................................................... 65
8.2.3
Statistical Methods.............................................................................................. 66
8.2.4
Multiplicity ......................................................................................................... 68
8.2.5
Sample Size and Power....................................................................................... 68
8.2.6
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 68
Investigational Product ........................................................................................ 68
9.1
Packaging and Labeling Information ................................................................. 69
9.2
Clinical Supplies Disclosure................................................................................. 69
9.3
Storage and Handling Requirements.................................................................. 69
9.4
 
 
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Discard/Destruction/Returns and Reconciliation .............................................. 69
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 69
Confidentiality....................................................................................................... 69
10.1
Confidentiality of Data ....................................................................................... 69
10.1.1
Confidentiality of Subject Records ..................................................................... 70
10.1.2
Confidentiality of Investigator Information........................................................ 70
10.1.3
Confidentiality of IRB/IEC Information............................................................. 70
10.1.4
Compliance with Financial Disclosure Requirements....................................... 71
10.2
Compliance with Law, Audit and Debarment ................................................... 71
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 73
10.4
Quality Management System............................................................................... 73
10.5
Data Management................................................................................................. 73
10.6
Publications ........................................................................................................... 73
10.7
11.0
LIST OF REFERENCES......................................................................................... 75
12.0
APPENDICES........................................................................................................... 77
Merck Code of Conduct for Clinical Trials........................................................ 77
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 79
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.3
by Sample Types ................................................................................................... 83
13.0
SIGNATURES........................................................................................................... 84
Sponsor's Representative ..................................................................................... 84
13.1
Investigator............................................................................................................ 84
13.2
 
 
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LIST OF TABLES
    
Table 1
MK-4250 Dosing Scheme................................................................................... 17
Table 2
Preliminary Geometric Mean (% Coefficient of Variation) MK-4250 Plasma 
Pharmacokinetics Following Single Dose Administration of MK-4250 to
HIV-1 Infected Subjects (N=6 per Dose) .......................................................... 21
Table 3
Summary of Results from InSTI Short Duration Monotherapy Studies 
(Approved Dosing Regimen for these drugs is listed for reference) ................. 23
Table 4
Exposure Predictions for the Tablet Doses......................................................... 25
Table 5
Observed Geometric Mean (%Coefficient of Variation) MK-4250 Plasma 
PK and for Population Pharmacokinetic Model Predicted 50th Percentile 
MK-4250 PK for Panels E and F....................................................................... 27
Table 6
Trial Treatment ................................................................................................... 34
Table 7
Sample Allocation Schedule............................................................................... 36
Table 8
Contents of Low Fat Breakfast ........................................................................... 38
Table 9
Contents of Moderate Fat Breakfast ................................................................... 38
Table 10
Laboratory Tests ................................................................................................. 52
Table 11
Plasma PK and HIV RNA - Blood Collection Windows ................................... 56
Table 12
Postdose Scheduled Time – Data Collection Windows...................................... 56
Table 13
Evaluating Adverse Events................................................................................. 62
Table 14
Product Descriptions........................................................................................... 68
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design Diagram ......................................................................................... 16
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0; 2.0; 4.2.2; 5.2; 5.2.1.2;
5.3; 6.0
Trial Summary; Trial Design;
Rationale 
for 
Dose 
Selection/Regimen/Modification;
Trial 
Treatment;
Dose 
Modification, 
Randomization;
Trial Flow Chart
Removed Panel C (≤600 mg)
and added Panels E and F, 
resulting in an overall increase 
in 
sample 
size 
from 
a 
maximum of 24 to 30 subjects 
and an increase in duration of 
the overall trial. See Table 1
for planned treatment/doses to 
be evaluated in Panels E and F.
Variability was noted in the
emerging PK data from the 
panels 
of 
HIV-infected 
subjects. Changes are being 
made to the trial design to 
allow
further evaluation of 
doses administered in various 
fed states. Dosing with food 
will increase exposure and 
enable exploration of dose- and 
exposure-response relationship 
of MK-4250.
5.7.1.1
Diet
Added information regarding 
timing and contents of the 
dietary 
treatments 
to 
be 
evaluated in Panels E and F 
(low fat and moderate fat 
breakfast).
Provided operational details in 
order to execute amended trial 
design.
7.1.5.5
Trial Design/Dosing/Procedures 
Modifications Permitted within 
Protocol Parameters
Added flexibility to modify 
composition of the meal taken 
with the trial drug based on 
newly available data
This flexibility will support 
objective of amended study 
design as described in the 
previous rationale section. 
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.1.1
Pharmaceutical and Therapeutic 
Background
Updated 
and 
streamlined 
section by moving data from 
pre-clinical studies to Section 
4.1.2. 
These changes were made to 
organize presentation of data. 
4.1.2
Pre-clinical Studies
Provided additional pre-clinical 
data not previously available at 
the 
time 
of 
the 
original 
protocol. 
Updates were made to this 
section 
to
inform 
the 
investigator of newly available 
data.
4.1.3
Completed and Ongoing 
Clinical Trials
Updated 
clinical 
program 
status with inclusion of new 
information from completed 
clinical trials (Protocols 001 
and 003) as well as data from 
ongoing trial (Protocol 002)
These changes were made to 
provide 
the 
background 
information to support the 
amended trial design and to 
further inform the investigator 
of newly available data.
4.2.2
Rationale for Dose 
Selection/Regimen/Modification
Per PCLs #2, 4, 5, and 6: 
Clarified recommendations for 
timing of ART initiation for 
Panels A and B (10 days post 
dose for Panel A [N=6] and 
Panel 
B 
[last 
3 
subjects 
enrolled, N=3], and 8 days post 
dose for Panel B [first 3 
subjects enrolled, N=3])
For Panel A: correction of 
typographical error to align 
with Section 2.0 Trial Design
For Panel B: recommendation 
based on observed PK results 
from 
ongoing 
trial 
(as 
described in Section 4.1.3), and 
implemented to ensure full 
antiviral 
efficacy 
until 
initiation of ART
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3
Subject Exclusion Criteria
Per PCL #1, clarified criterion 
#5 to note that subjects with 
rare hereditary galactose 
intolerance, lactose deficiency 
and glucose-galactose 
malabsorption are considered 
to have a significant 
intolerability to the lactose in 
the study drug and should be 
excluded from this trial.
The study drug
contains a 
small amount of lactose.
6.0
Trial Flow Chart
Per PCL #2, clarified footnote 
l, that a portion of the blood 
collected for viral resistance 
testing will be sent to Labor 
Berlin for extraction of proviral 
DNA (sample to be frozen and 
analyzed for the presence of 
VR mutations only if standard 
Sanger sequencing cannot be 
performed because plasma VL 
is too low at this time point).
As 
there 
is 
potential 
for 
emergence of InSTI resistance 
during monotherapy with an 
InSTI, 
it 
is 
important 
to 
confirm at the end of the period 
of monotherapy that a subject 
does not have VR mutation 
which would preclude selection 
of a given long-term InSTI-
containing regimen. 
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.0
Trial Flow Chart
Per PCL #4, added footnote n:
plasma for the  MK-4250 PK 
assay will be collected at 72 hrs 
post dose (instead of the 240 
hours post dose time point) for 
the first 3 subjects enrolled in 
Panel B. 
For these 3 subjects in Panel B 
who initiated ART 8 days post 
dose, the 240 hr time point
cannot be used to characterize 
t1/2 (as MK-4250 PK may be 
altered by ART). Based on PK 
from Panel A, inclusion of a 72 
hr PK sample is considered 
important to ensure the t1/2 is 
well characterized.
7.1.2
Clinical 
Procedures/Assessments
Per 
PCL 
#3, 
under 
the 
subsection on 12-Lead ECG, 
clarified with additional text in 
parenthesis: 
“If 
the 
QTc 
interval 
is 
≥500 
msec 
(confirmed upon recheck and 
manual 
measurement),
the 
Sponsor should be notified and 
the ECGs should be reviewed 
by a cardiologist.”
Clarified the steps to be taken 
before notifying Sponsor of a 
QTc interval ≥500 msec.
7.1.3.4
Future 
Biomedical 
Research 
Samples
Added leftover plasma samples 
collected for HIV RNA and 
viral resistance assays to be 
obtained as part of Future 
Biomedical Research
Retaining these non-acidified 
samples for future biomedical 
research may further inform on 
PK 
differences 
observed 
between HIV infected and 
uninfected subjects.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
12.3
Approximate Blood/Tissue 
Volumes Drawn/Collected by 
Trial Visit and by Sample Types
Per PCL #2, ~2.7 mL of the 16 
mL 
total 
blood 
volume 
originally noted for the pre-trial 
visit for HIV RNA and viral 
resistance testing is shifted to 
the timepoint prior to the start 
of ART. This additional blood 
collected at the later timepoint 
during the Treatment Period 
will be used
for potential 
proviral DNA testing. Total 
blood volume for the study 
remains at ~ 208 mL.
The 16 mL of blood specified 
for the viral load and viral 
resistance testing at the pre-
trial visit is in excess of what is 
required. This excess blood 
volume 
will 
instead 
be 
collected at the end of study 
treatment (i.e. no later than 
study Day 11) for additional 
viral resistance testing which 
may be necessary if a subject’s 
post-study therapy viral load is 
too low for standard Sanger 
sequencing. 
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-4250 Single Dose Trial in HIV-1 Infected Subjects
Sponsor Product Identifiers
MK-4250
Trial Phase
Ib
Clinical Indication
Treatment of HIV-1 Infection
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Up to 5 panels (Panels A, B, D, E and F) of 6 subjects each will 
receive a single dose of MK-4250. Panel C has been removed per this 
amendment.
Panel A: 150 mg
Panel B: 600 mg
Panel D: 900 mg
Panel E: ≤900 mg, with low fat meal
Panel F: ≤ 900 mg, with moderate fat meal
Number of trial subjects
Approximately 30 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 10 
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 6 weeks 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of 4 weeks, each 
subject will receive a single dose of study medication.  After dosing,
each subject will be followed for 14 days.
2.0 TRIAL DESIGN
Trial Design
2.1
This is an open-label, single dose, multiple panel trial to evaluate the safety, tolerability, anti-
retroviral activity, and pharmacokinetics of MK-4250 monotherapy in antiretroviral therapy 
(ART)-naïve, HIV-1 infected subjects. The primary study endpoints are the safety and 
tolerability of MK-4250 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 5 panels of 6 subjects each (Panels A, B, D, E and F) will be enrolled. Panels A 
through D will be conducted in a sequential manner such that enrollment in Panel B will 
commence when 6 subjects have been enrolled in Panel A, and so forth. Panel E/F will 
commence after Panel D, but Panels E and F may be conducted in either order or in parallel. 
Subjects will receive a single dose of 150 mg of the MK-4250 tablet formulation in Panel A
 
 
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and 600 mg of the MK-4250 tablet formulation in Panel B. The assumption is made that PK 
in HIV-infected subjects will be comparable to that observed previously in healthy subjects
(Protocol 001). However, PK data from Panel A will be reviewed prior to Panel B to confirm 
this assumption. The dose in Panel B may be adjusted downward based on review of safety 
and viral dynamic data out to 7-days post-dose from Panel A in addition to the review of PK 
data. The exact dose of the tablet formulation of MK-4250 to be administered in subsequent 
panels will be selected following the review of the safety and viral dynamic data out to 7 
days post-dose from the preceding panels, but will not exceed 900 mg.
Based on in vitro potency of MK-4250 and modeling of clinical data from other InSTIs, it is 
anticipated that the doses tested in Panels A and B will result in similar and maximal efficacy 
(i.e., approximately -1.4 log10 copies/mL or greater). The intent of additional panels will be 
to further inform the full range of exposure/viral load reduction and safety in HIV-infected 
subjects.
For Panels A through D, there will be sufficient time between panels to allow for review of 
all available safety data and viral load data (up to 7 days post-dose) to inform dose selection 
in the following panel. In addition, there will be sufficient time between Panels A and B to 
review Panel A PK data prior to Panel B. All doses of study drug (Panels A through D) will
be administered following at least an 8-hour fast. The doses of study drug in Panel E and F 
will be administered following a breakfast. Panels E and F may be conducted in either order 
or in parallel and will not begin until all available safety data (up to 7 days post-dose) and 
viral load data (up to 10 days post-dose) have been reviewed from Panel D. In addition, prior 
to dosing Panel F at 900 mg (tablet) with a moderate fat meal, safety data (through 168 hrs 
following the first dose) will be reviewed from the first 8 subjects dosed in Protocol 005 with 
1000 mg MK-4250 or placebo (randomized in a 3:1 ratio) following a high fat meal.
Following the treatment portion of the study, subjects will be encouraged to initiate an ART 
regimen which does not contain an integrase strand transfer inhibitor (InSTI).  Follow-on 
ART should be administered for at least two weeks (14 days), which corresponds to more 
than 5 half-lives of MK-4250.  The initiation of follow-on ART is not a requirement for 
participation in the study and is ultimately a decision of the subject in consultation with the 
primary investigator (PI) and his/her physician. The exact timing of initiation of ART relative 
to MK-4250 dosing will be dependent on the dose administered in each panel, but will not 
exceed 10 days post dose. For subjects who do not initiate follow-on ART, changes in viral 
load (VL) may be assessed through the post-study visit.
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-4250 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.
.
Figure 1
Trial Design Diagram
 
 
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Table 1
MK-4250 Dosing Scheme
Panela
Treatmentb
Panel A
150 mg, 
fasted
Panel B
600 mg, fasted
Panel Dc
900 mg, fasted
Panel E
≤900 mg, with a 
low fat meal
Panel F
≤900 mg, with a 
moderate fat meal
a In each panel, 6 subjects will receive a single dose of MK-4250. Panel C was removed per this amendment.
b The decision to proceed to the next panel and selection of the dose in Panels B and D will be made 
following review of safety and viral load data out to Day 8 (i.e., 7 days post-dose) from the preceding panel;
Panel E and F may be conducted in either order or in parallel but will not begin until the available safety 
data (up to 7 days postdose) and viral load (up to 10 days postdose) have been reviewed from Panel D. PK 
data from Panel A will be reviewed prior to proceeding to Panel B to evaluate whether HIV-infected 
subjects have PK comparable to healthy subjects. In addition, prior to dosing Panel F at 900 mg (tablet) with 
a moderate fat meal, safety data (through 168 hrs following the first dose) will be reviewed from the first 8 
subjects dosed in Protocol 005 with 1000 mg MK-4250 or placebo following a high fat meal. 
c   A decision to enroll Panel D will be made upon completion of Panels A - B and review of the safety and 
viral PD data in these panels.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To evaluate the antiretroviral activity of MK-4250 in ART-naïve, HIV-1 
infected subjects relative to historical subjects receiving placebo.
Hypothesis:  At a dose that is sufficiently safe and generally well tolerated, MK-4250 
has superior antiretroviral activity compared to placebo, as measured by change from 
baseline in plasma HIV-1 RNA (log10 copies/mL) at 168 hours postdose. That is, the 
true mean difference in the plasma HIV-1 RNA reduction from baseline between 
MK-4250 and placebo is ≥1.4 log10 copies/mL. 
2) Objective: To evaluate the safety and tolerability of MK-4250 in HIV-1 infected 
subjects.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To characterize the single dose plasma PK profile of MK-4250 and to 
determine the PK parameter values (including AUC0-last, AUC0-inf, AUC0-168hr, 
Tmax, Cmax, C168hr, apparent terminal t1/2, CL/F and Vz/F) after single dose 
administration of MK-4250 to HIV-1 infected subjects.
 
 
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Hypothesis: The true geometric mean C168hr is > 1250 nM following single dose 
administration of MK-4250 for at least one dose level of MK-4250.
Exploratory Objectives
3.3
1) Objective:  To evaluate the pharmacokinetic-pharmacodynamic association of MK-
4250 with viral load reduction.
2) Objective: To evaluate the relationship between dose and antiretroviral activity of 
MK-4250. 
3) Objective: To explore the relationship between genetic variation and response to the
treatment 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) for detailed background information on MK-4250.
A list of nonclinical studies conducted with MK-4250 is presented in the IB. Results from 
additional pre-clinical studies and the clinical trial currently being conducted with MK-4250 
are summarized in the sections below.
Pharmaceutical and Therapeutic Background
4.1.1
Human immunodeficiency virus 1 (HIV-1; referred to hereafter as HIV) is a lentivirus, a 
subgroup of retroviruses, that causes HIV infection. Without treatment, average survival time 
after infection with HIV is estimated to be 9 to 11 years. HIV infects CD4+ T cells, 
macrophages, and dendritic cells, leading to destruction of these critical immune system 
cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is 
lost, and the body becomes progressively more susceptible to opportunistic infections. If left 
untreated, over time HIV infection will nearly always lead to acquired immunodeficiency 
syndrome (AIDS), a progressive failure of the immune system that is fatal.
While a number of effective and well-tolerated antiretroviral (ARV) agents are available, 
infection with HIV remains a global health challenge. Medical need for novel ARVs remains 
high. In particular, there is need for development of compounds possessing better safety and 
tolerability profiles,
better resistance profiles, and
properties that simplify drug 
administration (e.g., fixed dose combinations or extended dosing intervals).
Current HIV treatment guidelines support triple therapy administration of 2 nucleoside 
reverse transcriptase inhibitors (NRTIs) together with an anchor agent of a different class 
including InSTIs [1]. InSTIs have become the primary anchor agent of choice in combination 
HIV ART because of their high antiviral potency, rapid HIV RNA declines, favorable
tolerability and safety profiles, and absence of significant drug-drug interactions [1, 2].  
Currently approved InSTIs include raltegravir [3], elvitegravir [4] and dolutegravir [5].
Cabotegravir is in Phase 3 development as a longer acting parenteral agent [6,7]. While 
InSTIs are widely used to treat HIV-1, recent data suggest that there is some evidence of 
 
 
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resistance emergence particularly for raltegravir and elvitegravir, although as a class InSTIs 
have a high barrier to resistance [2,8]. Additionally, recent reports suggest a high rate (~16%) 
of discontinuation of dolutegravir due to intolerance [2,9]. There still exists a need for novel 
InSTIs that possess, simultaneously, an improved barrier to resistance, an improved 
tolerability profile and, ideally, simplified drug administration.
MK-4250 is a novel, potent, small molecule HIV-1 InSTI. MK-4250 exhibits a high genetic 
barrier to resistance. The retroviral enzyme integrase is required to catalyze the insertion of 
viral DNA into the genome of the host cell. Integrase assembles on the ends of the viral DNA 
and catalyzes two sequential reactions, specifically 3’ endonucleolytic processing of the viral 
DNA ends and strand transfer or joining of the viral and cellular DNAs.
MK-4250 is a low clearance compound with a ~47 hr half-life in humans (see Section 4.1.3),
supporting potential extended duration dosing intervals. It is 99.8% bound to proteins in 
human plasma. Based on in vitro metabolism data and studies in rats and dogs, elimination of 
MK-4250 in humans is anticipated to occur in part by secretion into the GI tract, potentially 
via P-glycoprotein (P-gp) and/or other transporters, and by metabolism via glucuronidation. 
Oxidation is expected to be a minor pathway. No circulating metabolites were detected in rat 
and dog. Only trace amounts of MK-4250 were detected in urine of rats and dogs. Since MK-
4250 is a substrate of P-gp and uridine 5'-diphospho-glucuronosyltransferases (UGTs), there 
is a potential for MK-4250 PK to be affected by strong UGT and/or P-gp inhibitors or 
inducers. MK-4250 is not a potent reversible inhibitor of UGT1A1 and major CYP enzymes 
or a time-dependent inhibitor of CYP3A4. It is also not a potent inhibitor of OATP1B1 or P-
gp transporters. MK-4250 has shown the potential to induce metabolic enzymes and/or 
transporters at high concentrations.
Pre-clinical Studies
4.1.2
In vitro experiments were conducted to determine binding of MK-4250 over the 
concentration range of 2 µM to 800 µM to proteins in rat, dog and human plasma. MK-4250 
was highly bound to proteins in plasma from all species. The unbound fractions in rat, dog 
and human plasma were 0.0004, 0.003, and 0.002, respectively, at 20 µM MK-4250 and were 
similar at 2 µM MK-4250. The fraction unbound increased at MK-4250 concentrations that 
are above expected clinical concentration range: approximately two fold at 200 µM, and 
more significantly at 600 µM and 800 µM.
Additional Pre-clinical Background – Amendment 002-01
MK-4250 does not pose a risk of genotoxicity in clinical use. Target organ toxicity identified 
in repeat-dose studies was limited to the liver of dogs, with transient minimal to mild biliary 
ductule hyperplasia correlating with transient increases in ALT, ALP, and/or glutamate 
dehydrogenase (GLDH). The histomorphologic liver findings were only observed after 4 
months (15 weeks) of dosing at the highest dose level tested in dogs, 400 mg/kg/day, and not 
after 9 months of dosing at the same dose level, indicating the transient nature of the 
findings. Based on the transient nature of the liver finding, it is considered non-adverse and 
the no observed adverse effect level (NOAEL) in dogs is set at 400 mg/kg/day (AUC0-168hr 
of 24710 μM•hr). The 9-month study supports that the findings from the 4-month study were 
minimal to mild and would not progress to become adverse.
 
 
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Of note, in rats, there were no liver changes, and the high dose of 1000 mg/kg/day (AUC0-
168hr of 40600 µM•hr) was the NOAEL. The changes in rats were limited to slight non-
adverse vacuolation of epithelial cells in the nonglandular mucosa and inflammation of the 
glandular mucosa of the stomach. Stomach findings were limited to rat and were not 
observed in the repeat dog toxicity studies at equivalent or greater exposures and dose levels. 
These changes did not progress in severity in the 3˗month toxicity study compared to the 
2˗week study, did not impact the general health status of the animals, and are therefore of 
low toxicological relevance and non-adverse.
There was no evidence of MK-4250˗related maternal or developmental toxicity in a 
preliminary oral embryo-fetal development study in pregnant rats given doses up to 1000 
mg/kg/day once daily from GD 6 through 20. The definitive embryo-fetal developmental 
studies have not been conducted. Inclusion of women of childbearing potential in clinical 
trials should be in accordance with the study protocol and applicable regulatory guidances 
(e.g., ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals).  
Completed and Ongoing Clinical Trials
4.1.3
Additional Background – Amendment 002-01
4.1.3.1
MK-4250 has been evaluated as an oral formulation in two clinical studies in healthy subjects 
to date: a completed single ascending dose study (Protocol 001) and a clinically complete
multiple ascending once weekly dose (up to 4 weeks) and midazolam drug drug interaction
study (Protocol 003). The effect of a high fat meal on MK-4250 PK was evaluated in 
Protocol 001, and the effects of a low fat and moderate fat meal were evaluated in Protocol 
003.  
Plasma PK data following oral administration indicate that MK-4250 is absorbed with a 
Tmax of approximately 4 hours; plasma concentrations decline with terminal half-life (t1/2) 
of about 45 hours. Pharmacokinetic parameter values increase less than dose proportionally 
as bioavailability decreases with dose. Following multiple once weekly administration, there 
was minimal accumulation and no change in t1/2. Exposures up to 4800 µM∙hr were attained 
with single dose administration (1600 mg) and 3270 µM∙hr with multiple dose administration 
(900 mg QWk x 4). A high fat meal increased the AUC0-168hr, Cmax and C168hr of MK-
4250 by 1.8-fold, 2.1-fold and 1.6-fold, respectively. A moderate fat meal increased the 
AUC0-168hr, Cmax and C168hr of MK-4250 by 1.8-fold, 1.8-fold and 1.6-fold, respectively. 
A low fat meal increased the AUC0-168hr, Cmax and C168hr of MK-4250 by 1.6-fold, 1.8-
fold and 1.5-fold, respectively. While a high fat and moderate fat meal delayed median Tmax 
by 2 hours, a low fat meal had no effect on Tmax. 
Single doses up to 1200 mg tablet and 1600 mg capsule and multiple doses up to 900 mg
tablet QW for 4 weeks of MK-4250 have been generally well tolerated. There were no 
treatment emergent serious adverse events (SAE) and other than one participant who 
discontinued due to a flu-like illness (considered not drug related), there have been no 
discontinuations due to an adverse event (AE). All AEs were mild or moderate in intensity 
(except for the participant with a flu-like illness which was severe) and generally transient in 
nature. No consistent dose-related trends in AEs, electrocardiograms (ECGs), vital signs, or 
 
 
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laboratory parameter values have been observed. Some safety data remain blinded and it is 
unknown if participants received active drug or placebo.
Protocol 001
This was a randomized, alternating panel, placebo-controlled, double-blind trial evaluating 
the safety and pharmacokinetics of single rising doses of MK-4250 in 40 healthy male 
subjects. Single oral doses of 20 to 1600 mg capsule formulation and 100 to 1200 mg tablet
formulation were administered. Food effect was also evaluated at 400 mg for both 
formulations. MK-4250 was generally well tolerated, the most common AEs (≥2 incidents) 
reported by subjects administered MK-4250 were headache, abdominal discomfort, and 
dizziness. All AEs were mild or moderate in intensity and transient in nature. There were no 
SAEs and no discontinuations due to an AE. There were no clinically meaningful changes in 
ECGs, vital signs and laboratory safety evaluations.
Protocol 002 (Panels A and B)
As of 21-Jun-2018, 12 HIV-infected male subjects have been administered (fasted) single 
oral doses of MK-4250 (6 received 150 mg in Panel A and 6 received 600 mg in Panel B). 
Panel A and B are clinically complete. Preliminary PK, viral load and safety data are 
provided. Exposure of MK-4250 in HIV-infected subjects has been, on average, lower than 
that observed in uninfected subjects (Table 2). In addition, PK variability has been higher 
with some subjects exhibiting PK comparable to uninfected subjects while others exhibit 
diminished absorption and/or shorter t1/2 resulting in lower than anticipated C168hr. 
Following the 150 mg dose, the mean (range) change from baseline in viral load was -1.56 (-
1.21 to -1.89) log10 copies/mL. Following the 600 mg dose, the mean (range) change from 
baseline in viral load at 7 days post-dose was -1.76 (-1.06, -2.27) log10 copies/mL. This 
change is comparable to the mean change observed in monotherapy studies following 7 days 
of dosing for other InSTIs (see Section 4.2.2).
Table 2
Preliminary Geometric Mean (% Coefficient of Variation) MK-4250 Plasma 
Pharmacokinetics Following Single Dose Administration of MK-4250 to HIV-1 
Infected Subjects (N=6 per Dose)
Dose
(mg)
Cmax
(µM)
Tmax1
(hr)
t½
(hr)
AUC0-∞
(µM·hr)
AUC0-last
(µM·hr)
AUC0-168
(µM·hr)
C168
(µM)
CL_F
(L/hr)
V_F
(L)
150
16.6 
(46.7)
4.00 
(1.00 - 4.00)
35.9 
(22.9)
785 
(54.6)
774
(54)
751 
(52.6)
0.558 
(117)
0.456 
(54.6)
23.6 
(45.1)
600
37.6
(26)
4.00 
(4.00 - 6.00)
38.5 
(31.9)
2120
(18.4)
2040 
(17.1)
1980 
(16.7)
2.2
(57.4)
0.676 
(18.4)
37.6
(23.5)
1Median (Min-Max)
Single doses of MK-4250 were generally well tolerated. Eight of the 12 subjects (75%) 
reported one or more AEs. There were no SAEs. The most common AEs were headache 
(n=4, 33%), diarrhea (n=4, 33%), and nasopharyngitis (n=3, 25%). All AEs were mild or 
moderate in intensity and generally transient in nature. No subjects have discontinued due to 
an AE. Three subjects reported a total of 5 AEs considered by the investigator to be drug 
 
 
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related (headache [n=2], diarrhea [n=1], nausea [n=1], and vomiting [n=1]) There has been
no evidence of dose-related abnormalities in ECGs, vital signs and laboratory safety 
evaluations.
Protocol 003
Protocol 003, is a two part, clinically complete trial. Part 1 is a randomized, placebo-
controlled, double-blind multiple ascending dose and midazolam drug interaction, 4-panel 
trial in 32 healthy adult males and females of non-childbearing potential. Subjects were 
dosed 100, 300 and 600 mg MK-4250 (or placebo) once weekly for 3 weeks and 900 mg (or 
placebo) once weekly for 4 weeks. In the 900 mg panel, midazolam was administered prior 
to the initial dose and concomitantly with the final dose of MK-4250/placebo. Part 2 is a 
randomized, 3-period food effect assessment. Nine subjects received 400 mg MK-4250 
fasted, with a low fat breakfast, and with a moderate fat breakfast.
Preliminary safety data indicate that multiple doses of MK-4250 and single doses with and 
without food have been generally well-tolerated. Thirty-two of the 41 subjects (78%) 
reported one or more treatment emergent AEs. There were no treatment associated SAEs
(one subject was in a car collision during the screening period and sustained neurological 
trauma that was an SAE; this subject was not randomized). The most common AEs were 
headache (n=16, 31%), nasopharyngitis (n=9, 22%), oropharyngeal pain (n=8, 20%), 
diarrhea (n=4, 10%), and cough (n=4, 10%).  One subject in the 600 mg panel was 
discontinued due to flu-like symptoms which were deemed not drug related. All AEs were 
generally mild or moderate in intensity and transient in nature. Twenty subjects (49%) 
reported one or more AEs considered by the investigator to be drug related. The most 
common were headache, diarrhea, gastrointestinal discomfort, abdominal cramps, and 
fatigue. It is not known whether these subjects received MK-4250 or placebo. There was no 
evidence of dose-related abnormalities in ECGs, vital signs and laboratory safety evaluations.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
The primary objective of this study is to assess the single-dose activity of MK-4250 in ART-
naïve HIV-1 infected subjects. This study will also assess the relationship between dose, 
exposure, and short-term in vivo antiretroviral activity of MK-4250.  Data from this study 
will aid dose selection in future HIV-infected subject studies in which MK-4250 will be 
administered in combination with other antiretroviral agents.  The study objectives conform 
to the EMA guideline describing appropriate clinical development for antiretroviral agents as 
monotherapy and in combination with established therapy [10]. As described in this 
Guideline, antiretroviral agents are typically administered in combination to minimize the 
risk for resistance; therefore, demonstration of antiviral activity in subjects for a new antiviral 
should be limited to treatment naïve subjects without advanced disease.  
Although resistance to InSTIs remains rare [2,8], resistance mutations to all approved InSTIs 
have been identified. Therefore, prior to enrollment, subjects will be screened for the 
presence of InSTI resistance mutations to set a baseline standard for MK-4250 sensitivity to 
 
 
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the viral variants present in each subject.  Subjects identified with an InSTI mutation (e.g., 
E92Q, N55H, Q148K, Q148R and Y143R) will be excluded from the study.  
Rationale for Dose Selection/Regimen/Modification
4.2.2
Rationale for Doses – 002-00
A single dose of MK-4250, given its long t1/2, is expected to exhibit antiviral activity for at 
least 7 to 10 days, equivalent to other short-term monotherapy studies with InSTIs 
administered daily or twice daily for up to 10 days. Evaluation of these other InSTI 
monotherapy studies suggests that a robust change in VL relative to baseline will be observed 
a week after initiating InSTI dosing [11]. Limiting monotherapy of InSTIs to ten days is 
thought to adequately minimize the risk of development of resistance. 
In order to inform on the dose selection for future HIV-infected subject studies, it is 
important that the doses selected in this study provide insight into the exposure-response 
relationship between MK-4250 and VL. That is, doses will be selected which are anticipated 
to result in maximal efficacy (at least -1.4 log10 copies/ml a week after initiating InSTI 
dosing, see Table 3) as well as those which achieve VL reduction which is close to half of the 
maximal drop (approximately -0.7 log 10 copies/ml a week after initiating InSTI dosing).  
Table 3
Summary of Results from InSTI Short Duration Monotherapy Studies (Approved 
Dosing Regimen for these drugs is listed for reference)  
Drug
N
Dose
Approved Dose
Day
Log10 Change from 
Baseline Viral Load 
(copies/mL)
Dolutegravir[14]
10
50 mg QD
50 mg QD
7
-2.0
Elvitegravir[15,16]
6
400 mg BID
150 mg QD, 
boosted*
7
-1.4
Raltegravir[13]
6
400 mg BID
400 mg BID
8
-1.6
Mean
-1.7
*Boosted dose has somewhat higher Ctrough compared to the 400 mg BID monotherapy dose [14, 15, 16,13].
Doses in this study will be selected with the intent that Panel A and B doses both 
demonstrate maximal VL reduction. These two doses are expected to bracket the doses which 
will be studied in longer duration combination therapy trials. In addition, a lower dose is 
planned which is intended to also demonstrate VL reduction, but will be selected to target a 
viral load reduction approximately half of that achieved with the top doses. This dose will 
provide important information regarding the lower bound of MK-4250 levels associated with 
antiviral efficacy. Finally, a fourth dose level is included in the event that the first three dose
levels do not sufficiently support the objective of evaluating the submaximal through 
maximal range of the exposure-response relationship and may range from lower than the 
Panel A, B and C doses to higher.
 
 
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Trough concentration (Ctrough) has been found to be the most reliable PK correlate of HIV 
VL suppression [11, 12]. Xu et al. conducted a model-based meta-analysis of viral load and 
PK data from other InSTI monotherapy studies [11]. The results of this analysis predict that a 
Ctrough of 2.15-fold above the inflection point (IP) in a proprietary in vitro assay of wild 
type antiviral potency is associated with >95% maximum viral load suppression in 
monotherapy. Approved doses of raltegravir (400 mg twice daily [BID]), dolutegravir (50 mg 
once daily [QD]) and elvitegravir (150 mg BID) achieved a Ctrough/IP close to or greater 
than this value. Raltegravir dosed at 1200 mg QD has recently been shown to be non-inferior 
to raltegravir 400 mg BID in Phase 3 with a Ctrough/IP of 1.3. For MK-4250, the lower end 
of the anticipated therapeutic range is a C168hr ≥ 1.25 uM which is 2.5 times the IP for MK-
4250. Based on the analysis of Xu et al. and the 1200 mg BID raltegravir Phase 3 results, this 
Ctrough target is anticipated to result in full efficacy in both monotherapy and in long term 
combination therapy studies.
Panel A Dose Selection
The proposed dose for Panel A is 150 mg of the tablet formulation which has an anticipated 
C168hr ≥1.25 µM. 
A single 200 mg dose of MK-4250 tablet formulation had an AUC0-168hr of ~1250 µM*hr 
in healthy subjects. This is ~9-fold below the 11620 uM*hr AUC0-168hr exposure achieved 
in the 4 month dog safety study at the NOAEL. 
Panel B Dose Selection
The planned dose to be studied in Panel B will be 600 mg of the MK-4250 tablet formulation 
and will explore safety, tolerability, pharmacokinetics, and the potential for viral 
pharmacodynamic differentiation at higher exposures to confirm that the efficacy at 7 days 
post dose (i.e. Day 8) in Panel A was indeed maximal. Based on mean VL change from 
baseline a week following initiating dosing in InSTI monotherapy studies, the maximal 
decrease in VL should be ≥1.4 log10 copies/mL (see Table 3). 
Although it is anticipated that MK-4250 PK in HIV-infected subjects will be similar to that 
in healthy subjects in Protocol 001, to confirm this assumption, the decision to proceed to 
Panel B at the 600 mg tablet dose will be made following review of PK data from Panel A. In 
addition, safety and VL data out to 7 days post dose (i.e. Day 8) from Panel A will also be 
reviewed prior to proceeding to Panel B.  
The highest dose tested in Protocol 001 was 1600 mg of the capsule formulation with AUC0-
168hr and Cmax of 4270 µM*hr and 64.9 µM, respectively. This is 2.7-fold and 1.7-fold 
below the AUC0-168hr and Cmax at the NOAEL observed in the 4-month oral toxicity study 
in dogs. Table 4 shows projected exposures for the planned doses in this study. The projected 
exposure is scaled from the 200 mg tablet dose in Protocol 001, which assumes that 
bioavailability remains constant at ~40%. Based on preclinical data, bioavailability at doses 
above 200 mg may be anticipated to either stay constant or decrease, but would not be 
expected to increase; therefore, actual PK at higher tablet doses may be lower than that 
predicted in Table 4. The 600 mg dose of tablet is projected to result in exposures slightly 
below those observed at the 1600 mg dose of capsule in Protocol 001. This dose was shown 
to be well tolerated. Furthermore, the 600 mg dose is anticipated to be 3.1-fold below the 
NOAEL. See Section 4.1.1 for further information on the NOAEL. 
 
 
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Table 4
Exposure Predictions for the Tablet Doses  
Single 
Dose 
(mg)
MK-4250
AUC0-168
Cmax
C168
Observed 
(uM·hr)a
Predicted  
(uM·hr)b
Exposure 
Marginc
Observed 
(uM)a
Predicted  
(uM)b
Observed
(uM)a
Predicted
(uM)b,d
100
967
--
--
16.3
--
1.2
--
200
1250
--
--
19.6
--
1.6
--
600
--
3800
3.1
--
60
--
4.8
900
--
5700
2.0
--
90
--
7.2
a Observed AUC0-168, Cmax, and C168 from Protocol 001  
b Predicted AUC0-168, Cmax, and C168 is based on the assumption of linear dose proportionality 
relative to the 200 mg tablet geometric mean data.
c MK-4250 exposure margin was calculated  based on MK-4250 NOAEL of  11620 μM*hr  (AUC0-
168hr)  in dogs at 20 mg/kg/day from a 4-month safety study.  
dThe MK-4250 efficacy target is a C168 of 1.25 uM or greater based on an in vitro potency assay.
Panel C Dose Selection
The dose in Panel C will be selected following review of safety and VL data from at least 7 
days post dose from the preceding panels (A and B) with the intent to achieve an average log 
reduction that is approximately half of the anticipated maximal reduction, or approximately -
0.7 log10 copies/mL seven days after dosing (i.e. Day 8). The primary reason for targeting 
the lower end of the efficacy curve is to develop a dose- or exposure-response relationship 
for MK-4250 and viral load. Based on the analysis by Xu et al. [11], the Ctrough anticipated 
to result in a half-maximal viral load drop in monotherapy is ~0.15xIP. In a monotherapy 
study of raltegravir, a 100 mg BID dose (Cmin of ~0.5xIP) resulted in maximal efficacy 
through ~10 days of dosing [13]. While the exact dose in Panel C will be based on analysis 
of the PK data from Panel A, and safety and VL data from both Panels A and B, the 
raltegravir monotherapy data [13] and the Xu et al. analysis [11] suggest that the dose in 
Panel C may be as low as 10 mg (projected Cmin of ~0.3xIP). 
Although doses lower than 100 mg of tablet were not tested in Protocol 001, bioavailability 
of both the capsule and tablet formulations are anticipated to be similar at doses ≤50 mg 
based on preclinical data. In addition, the oral bioavailability of a 50 mg dose of the capsule 
formulation was ~50%, comparable to the 100 mg dose of tablet formulation. 
While the dose for Panel C is anticipated to be close to 10 mg, if data from Panel A and B 
suggest that a higher dose be studied (e.g., VL reduction with Panel A is less than in Panel 
B), the dose will not exceed 600 mg.
Panel D Dose Selection
The dose for Panel D will be selected once safety and VL data (from at least 7 days post 
dose) obtained from Panels A, B and C are reviewed. This dose will be selected to gain 
further clarity on the exposure-VL relationship and/or to explore the safety, PK and VL 
effects at higher doses of MK-4250. The dose for Panel D will not exceed 900 mg of tablet 
formulation. The dose will not be selected until safety and PK data are available from 
Protocol 001 at a tablet dose higher than that to be administered in Panel D.  
 
 
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For All Panels
After completion of the treatment phase of this study, subjects will be encouraged to initiate a 
non-InSTI containing ART regimen according to local guidelines. The timing of ART 
initiation is contingent on the doses administered and will be communicated in an official 
memo.  Based on the results of the raltegravir monotherapy study, InSTI concentrations 
greater than ~0.5xIP would be anticipated to be associated with full antiviral efficacy out to 
10 days of dosing [13]. At the Panel A dose of 150 mg, ART should be initiated 10 days 
following dosing. Concentrations are not anticipated to drop below 0.5xIP until more than 10 
days post-dose; therefore, initiation of ART at Day 10 should minimize the risk of selection 
for resistant virus. The timing of initiation of ART for subsequent panels will be informed by
the ultimate selected dose, but will not exceed 10 days post-dose, consistent with the EMA 
Guideline for HIV drugs [10]. Viral load data will continue to be collected in all Panels until 
initiation of ART or 14 days post-dose, whichever is earlier. The duration of suppressive 
ART should be at least 14 days, which is more than 5 half-lives of MK-4250. The Sponsor 
will not provide this therapy, nor will it be mandated for participation in the study. 
Rationale for Doses – Amendment 002-01
As described in Section 4.1.3, exposure of MK-4250 in HIV-infected subjects was on 
average lower and more variable compared to healthy subjects. Although viral load reduction 
was achieved in both Panels A and B, the increased variability led to some subjects having 
C168hr well below the PK target. As viral load reduction and C168hr were generally 
correlated, a portion of subjects with lower C168hr also appeared to have sub-maximal
virologic response. The results of Panel A and B support the omission of Panel C as 
submaximal viral load response was observed in some subjects and the conduct of Panel D at 
a dose of 900 mg, fasted. In addition, the protocol is being amended to include Panel E at a 
dose up to 900 mg with a low fat meal and Panel F at a dose up to 900 mg with a moderate 
fat meal. As MK-4250 exposures increase less than dose proportionally, dosing with food 
allows for further increases in exposure to further explore the dose- and exposure-response 
relationship of MK-4250. Additional PK and safety data are available and demonstrate doses 
up to 1200 mg to be generally well-tolerated, supporting conduct of Panel D at 900 mg.
Panel E Dose Selection
The dose for Panel E will be selected once safety and VL data (from at least 7 days post 
dose) obtained from Panel D have been reviewed. This dose will be selected to gain further 
clarity on the exposure-VL relationship and/or to explore the safety, PK and VL effects at 
higher exposures of MK-4250. The selected dose for Panel E will not exceed 900 mg of 
tablet formulation. This dose will be administered with a low fat meal in order to further 
boost exposures above those achieved with 900 mg, fasted. Table 5 shows the predicted PK 
parameter values for a 900 mg dose of MK-4250 with food in an HIV-infected population. 
These projections were made using a Population PK model including healthy subject data 
from Protocols 001 and 003 and HIV-infected subject data from Protocol 002 Panels A and 
B. The effect of a low fat meal is anticipated to be similar to that observed in uninfected 
subjects in Protocol 003. The projected AUC0-168hr in Panel E does not exceed that 
obtained following a single 1200 mg, fasted dose of MK-4250 shown to be generally well 
tolerated in Protocol 001.
 
 
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Table 5
Observed Geometric Mean (%Coefficient of Variation) MK-4250 Plasma PK and 
for Population Pharmacokinetic Model Predicted 50th Percentile MK-4250 PK 
for Panels E and F
Panel F Dose Selection
The dose for Panel F will be selected once safety and VL data (from at least 7 days post 
dose) obtained from Panel D have been reviewed. As with Panel E, this dose will be selected 
to gain further clarity on the exposure-VL relationship and/or to explore the safety, PK and 
VL effects at higher exposures of MK-4250. The selected dose for Panel F will not exceed 
900 mg of tablet formulation. This dose will be administered with a moderate fat meal in 
order to further boost exposures above those achieved with 900 mg, fasted and with a low fat 
meal. As the projected AUC0-168hr in Panel F slightly exceeds that obtained following a 
single 1200 mg, fasted dose of MK-4250 in Protocol 001 (Table 5), Panel F will not be 
conducted until safety data through 168hrs post-dose are available from the first dose in the 
first 8 subjects of Protocol 005 (healthy subjects to receive 1000 mg MK-4250 or placebo 
with a high fat meal, randomized in a 3:1 ratio). If the results of Panel D or E support 
conduct of Panel F at a lower dose with or without food, Panel F may be conducted prior to 
availability of the described Protocol 005 data provided that the predicted exposures do not 
exceed those observed at the 1200 mg dose of tablet in Protocol 001.
For All Panels
After completion of the treatment phase of this study, subjects will be encouraged to initiate a 
non-InSTI containing ART regimen according to local guidelines. The timing of ART 
initiation is contingent on the doses administered and will be communicated in an official 
memo.  Based on the results of the raltegravir monotherapy study, InSTI concentrations 
greater than ~0.5xIP would be anticipated to be associated with full antiviral efficacy out to 
10 days of dosing [13]. As described in Section 4.1.3, ART was recommended to initiate at 
10 days post-dose in Panel A (N=6) and for the latter 3 subjects enrolled in Panel B (N=3); 
ART was recommended to initiate at 8 days post dose for the first 3 subjects enrolled in 
Panel B (N=3). Based on PK and virologic results in Panels A and B, ART will be initiated at 
10 days post-dose (ie, 240 hrs or Day 11) in Panels D, E and F. If a lower dose is selected for 
MK-4250 Dose and Population AUC0-168hr
(µM*hr)
Cmax
(µM)
C168hr
(µM)
1200 mg, Fasted
Healthy Subjects
(observed)
4110 
(11.2)
77.9 
(11.7)
4.7 
(30.3)
900 mg, Fasted
HIV-infected Subjects
(simulated)
2480
59
2.2
900 mg, Low Fat Meal
HIV-infected Subjects
(simulated)
3970
94
3.4
900 mg, Moderate Fat Meal
HIV-infected Subjects
(simulated)
4470
106
3.9
 
 
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Panels E and F,  the timing of initiation of ART for will be informed by the ultimate selected 
dose, but will not exceed 10 days post-dose (i.e., 240 hrs or Day 11), consistent with the 
EMA Guideline for HIV drugs [10]. Viral load data will continue to be collected in all Panels 
until initiation of ART or 14 days post-dose, whichever is earlier. 
The duration of 
suppressive ART should be at least 14 days, which is more than 5 half-lives of MK-4250. 
The Sponsor will not provide this therapy, nor will it be mandated for participation in the 
study. 
As this is a Phase I assessment of MK-4250 in humans, and the pharmacokinetic, 
pharmacodynamic 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.
Rationale for the Use of Historical Placebo
4.2.2.1
The reduction in VL for each dose level will be compared to historical placebo data from 
clinical trials previously conducted by the Sponsor. Evaluation of VL data from other HIV 
monotherapy studies has indicated that results are consistent between trials and that on 
average, subjects receiving placebo do not exhibit a change from baseline that differs from 
the anticipated within-subject variability in VL. 
Furthermore, given the overall favorable safety profile of MK-4250 in preclinical and clinical 
testing to date, the need for a placebo control to minimize investigator and patient bias with 
respect to adverse experiences was deemed not necessary. 
Starting Dose for This Trial
4.2.2.2
See Section 4.2.2 for the starting dose and related rationale.
Maximum Dose/Exposure for This Trial
4.2.2.3
See Section 4.2.2 for the maximum dose and associated rationale.
Rationale for Dose Interval and Trial Design
4.2.2.4
The trial design will consist of 5 panels. Each panel will consist of 6 subjects. Up to all 6 
subjects in a given panel may be dosed on the same day, in spaced time intervals by Phase I
Clinical Research standards for compounds not considered to be of high risk. The decision to 
escalate to the next dose panel will be made based on the viral load data, laboratory safety 
tests, vital signs and ECGs obtained up to 7 days after dosing. In addition, PK from Panel A 
will be reviewed prior to dosing of Panel B to assess whether PK in HIV-infected subjects 
are comparable to those observed in healthy subjects in Protocol 001. Dosing of consecutive 
panels will be spaced to allow for assessment of safety data and potential AEs as well as 
evaluation of PK and viral dynamic data from previous panels to inform on dose selection.
Panel E and F may occur in parallel with each other or one may be conducted prior to the 
other. Neither Panel E nor F will be initiated until safety data and virologic data from Panel 
 
 
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D have been reviewed. In addition prior to dosing Panel F at 900 mg with a moderate fat 
meal, safety data (through 168 hrs following the first dose) will be reviewed from the first 8 
subjects dosed in Protocol 005 (in which healthy subjects will receive once weekly doses of 
1000 mg MK-4250 or placebo with a high fat meal.) If the results of Panel D or E support 
conduct of Panel F at a lower dose with or without food, Panel F may be conducted prior to 
availability of the described Protocol 005 data provided that the predicted exposures do not 
exceed those observed at the 1200 mg dose of tablet in Protocol 001.
Rationale for Endpoints
4.2.3
Rationale for the safety, pharmacokinetic, and pharmacodynamics endpoints, as well as the 
planned exploratory biomarker research and future biomedical research are presented in the 
following sections.
Safety Endpoints
4.2.3.1
As described in detail in the IB, the target organ/system toxicities observed in the 4-month 
dog (more sensitive species) study at the top dose (400 mg/kg/day) was minimal to mild 
hyperplasia of biliary ductules characterized by increased biliary epithelial cells in dogs 
accompanied by elevations to serum biochemistry tests (e.g., alanine aminotransferase 
[ALT], alkaline phosphatase [ALP]). Individual animals with notable serum biochemistry 
changes correlated well with animals having the observed histological changes to liver. 
Although there were no histological findings at this same dose level at the end of the 9-month 
dog study, suggesting any liver toxicity is reversible, due to the findings in the 4-month 
study, liver tests (e.g., AST, ALT, ALP, bilirubin) will be monitored throughout the study 
and up to 14 days after the last dose of study drug. Liver function tests will be conducted 
throughout the study up until the post-study visit. To date, no elevations in liver function 
tests have been observed in Protocols 001 or 003 in which single doses up to 1200 mg of 
tablet formulation and multiple doses up to 900 mg of tablet formulation have been 
administered to healthy subjects.
Pharmacokinetic Endpoints
4.2.3.2
This study will establish if the PK target concentration can be achieved at a dose which is 
well-tolerated following a single dose of MK-4250. To provide confidence that the PK target 
has been achieved at this dose, the criteria of achieving the PK target with a 70% a posterior 
probability has been set. The antiviral efficacy of InSTIs has been associated with potency 
and Ctrough in plasma. The PK target of C168hr (i.e., Ctrough for once weekly dosing) was 
set at ≥1250 nM. This is 2.5-fold above the in vitro potency in the ViKInG assay, a margin 
above in vitro potency which has been associated with robust viral load reduction in 
monotherapy proof of concept clinical trials and with sustained viral suppression below 50 
copies/mL in long term combination therapy trials in HIV-1 infected study participants [11].
The study will also characterize plasma PK parameters of MK-4250 (AUC0-last, AUC0-inf, 
AUC0-168hr, Tmax, Cmax, C168hr, CL/F, Vz/F and apparent terminal t½) to evaluate 
relationship between PK and pharmacodynamics.
 
 
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Pharmacodynamic Endpoints
4.2.3.3
A PD endpoint of a ≥ 1.4 log10 copies/mL reduction of HIV-1 RNA from baseline 7 days post 
dose (i.e. Day 8), relative to historical placebo data will be used. This target is consistent with 
prior InSTI monotherapy studies (Table 3) and with regulatory guidance limiting InSTI 
monotherapy studies to 7-10 days in duration [10]. To provide confidence that the PD target 
has been achieved at this dose, the criteria of achieving the PD target with an 80% posterior 
probability has been set.
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.
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.
 
 
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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 male or non-pregnant and non-breast feeding female, 18 to 60 years of age, 
inclusive, at the pretrial (screening) visit; further:
a.
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 a highly effective method 
of birth control with a failure rate of <1% beginning at the pretrial (screening) 
visit until 30 days after the dose of trial drug.  Acceptable methods of birth 
control are defined in Section 5.7.2.5.
b. if postmenopausal female:  subject is without menses for at least 1 year and 
has
a documented follicle stimulating hormone (FSH) level in the 
postmenopausal range at pretrial (screening), 
AND/OR
c.
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. Be documented HIV-1 positive as determined by a positive ELISA or QT-PCR with 
confirmation (e.g., Western Blot). 
4. Have no evidence at screening for mutations (e.g., E92Q, N55H, Q148K, Q148R and 
Y143R) affecting susceptibility to InSTIs.
5. Be diagnosed with HIV-1 infection ≥ 3 months prior to screening or perform the
French 2008 HAS Algorithm to confirm chronic HIV infection.
 
 
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6. Have a screening plasma CD4+ T cell count of >200/mm3.
7. Have a screening plasma HIV-1 RNA ≥ 5,000 copies/mL within 30 days prior to the 
treatment phase of this study.       
8. Be ART-naïve, which is defined as having never received any antiretroviral agent OR 
the following:
≤30 consecutive days of an investigational antiretroviral agent which is not an 
InSTI, and no exposure to such an investigational antiretroviral agent within 60 
days (or 5 t1/2s, whichever is longer) prior to screening
OR
≤60 consecutive days of combination ART which does not include an InSTI, and 
no exposure to such ART within 60 days (or 5 t1/2s, whichever is longer) prior to 
screening.
9. Must have never received any InSTI.
10. Be willing to receive no other ART for the duration of the treatment phase of this 
study.  
11. Have a Body Mass Index (BMI) ≤35 kg/m2. BMI = weight(kg)/height (m)2.
12. 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 7.1.3.1) performed at the prestudy (screening) visit and/or prior to 
administration of the initial dose of study drug.
13. 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 within the last 5 
years. Subjects who have had situational depression may be enrolled in the trial at the 
discretion of the investigator.
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., kidney stones with no recurrence in the last 5 years, childhood asthma) may be 
enrolled in the trial at the discretion of the investigator.
4. Has a history of cancer (malignancy).  
 
 
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Exceptions: (1) Subjects with adequately treated non-melanomatous skin carcinoma 
or carcinoma in situ of the cervix may participate in the trial; (2) Subjects with other 
malignancies which have been successfully treated ≥10 years prior to the pretrial 
(screening) visit where, in the judgment of both the investigator and treating 
physician, appropriate follow-up has revealed no evidence of recurrence from the 
time of treatment through the time of the pretrial (screening) visit (except those 
cancers identified at the beginning of exclusion criterion 4); or, (3) Subjects, who, in 
the opinion of the trial investigator, are highly unlikely to sustain a recurrence for the 
duration of the trial.  
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; or has hereditary
galactose intolerance, lactose deficiency and glucose-galactose malabsorption.
6. Is positive for hepatitis B surface antigen.
7. Has a history of chronic hepatitis C infection Subjects with a documented cure and/or 
a positive serologic test for HCV with a negative HCV viral load may be included.
8. Had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the pretrial (screening) visit.
9. Participated in another investigational trial within 4 weeks (or 5 half-lives, whichever 
is longer) prior to the Day 1 dosing visit. The 4 week window will be derived from 
the date of the last trial medication and / or blood collection in a previous trial and/or 
AE related to trial drug to the Day 1 dosing visit of the current 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, whichever is longer) 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.
14. Does not agree to follow the smoking restrictions defined by the CRU.
15. 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.
 
 
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16. Has QTc interval ≥ 470 msec (for males) or ≥ 480 msec (for females).
17. Has a positive urine drug screen (except for cannabis) at screening and/or predose;
rechecks are allowed. 
18. Is any concern to the investigator regarding the safe participation of the subject in the 
trial or for any other reason the investigator considers the subject inappropriate for 
participation in the trial.
19. Is unwilling to comply with the trial restrictions (see Section 5.7 for a complete 
summary of trial restrictions).
20. 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 6
Table 6
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Panel
Use
MK-4250
tablet
150 mg, 
fasted
Single dose
Oral
Day 1/ Panel A
Experimental
MK-4250
tablet
600 mg, 
fasted
Single dose
Oral
Day 1/ Panel B
Experimental
MK-4250
tablet
900 mg, 
fasted
Single dose
Oral
Day 1/ Panel D
Experimental
MK-4250
tablet
≤900 mg, 
low fat meal
Single dose
Oral
Day 1/ Panel E
Experimental
MK-4250
tablet
≤ 900 mg, 
moderate fat 
meal
Single dose
Oral
Day 1/ Panel F
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.
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.
 
 
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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.
Dose Modification 
5.2.1.2
For Panels A – D, prior to proceeding to the next Panel, viral load data for 7 days post-dose 
(out to C168hr, Day 8) will be reviewed. In addition, key safety variables including vital 
signs, 12-lead ECGs, laboratory safety tests, and adverse events up to 7 days post-dose will 
be reviewed. 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. The dose in Panel B may be reduced based on these data.
In addition, prior to proceeding to doses above 600 mg, PK and safety data from higher doses 
of the tablet formulation being tested in Protocol 001 will be reviewed. Panels E and F may 
be conducted in either order or in parallel and will not begin until all available safety data (up 
to 7 days post-dose) and viral load data (up to 10 days post-dose) have been reviewed from 
Panel D.  Prior to proceeding to a dose of 900 mg with a moderate fat meal, safety data from 
a higher dose with food tested in Protocol 005 will be reviewed (see Section 4.2.2). 
Pharmacokinetic and pharmacodynamic data may be included in the dose escalation 
decisions.  See Background & Rationale - Section 4.0.
If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose escalation, the dose will not be increased 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.
Timing of Dose Administration
5.2.2
All doses of MK-4250 will be given in the morning at approximately the same time. Subjects 
will receive a single oral dose of MK-4250 with approximately 240 mL of water. Additional 
water (in increments of 50 mL) maybe provided for subjects receiving a dose of MK-4250 
requiring more than 2 tablets.
Trial Blinding 
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
 
 
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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 7.
Table 7
Sample Allocation Schedule
Subjects
Panel A
Panel B
Panel D
Panel E
Panel F
N=6 
(per 
panel)
150 mg, 
fasted
600 mg, 
fasted
900 
mg, 
fasted
≤900 mg, 
low 
fat 
meal
≤900 mg, 
moderate 
fat meal
With the exception of Panel A, the suggested doses may be adjusted downward. The decision to 
select the precise dose will be based on viral load data for the 7 days post-dose (out to C168hr, 
Day 8), and review of  key safety variables (including vital signs, 12-lead ECGs, laboratory 
safety tests, and adverse events) up to 7 days post-dose. 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 in Protocol 001. In addition, prior to proceeding to 
doses above 600 mg, PK and safety data from higher doses of the tablet formulation being 
tested in Protocol 001 will be reviewed. Prior to proceeding to a dose of 900 mg with a 
moderate fat meal, safety data from a higher dose with food tested in Protocol 005 will be 
reviewed (see Section 4.2.2).
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.
Ibuprofen may be used for minor ailments without prior consultation with the Sponsor.
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 PI 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.  
 
 
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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.
Panels A through D
In each panel, subjects will fast from all food and drinks, except water, for at least 8 hours 
prior to trial drug administration.
Panels E and F
Subjects 
will 
fast 
from 
all 
food 
and 
drinks 
except 
water 
for 
at 
least 
10 hours prior to the start of breakfast (when dosed with a moderate fat meal or a low fat 
meal). Water will be restricted 1 hour prior to and 1 hour after trial drug administration.
Approximately 30 minutes prior to trial drug administration, subjects will begin to consume 
specified breakfast (Panel E—low fat meal, Panel F—moderate fat meal).  The contents of 
the low fat breakfast are listed in Table 8 and moderate fat breakfast in Table 9.  Breakfast 
should be consumed in its entirety within approximately 20 minutes. The start and stop time 
of the breakfast will be recorded. Within approximately 10 minutes after consuming the 
breakfast, subjects will be administered trial drug as indicated in Section 5.2. The specific 
nutritional contents of the meals may be modified during the trial based on newly available 
data.
 
 
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Table 8 Contents of Low Fat Breakfast
2 slices brown bread (70 g)
Light cream cheese (60 g)
Semi-skim milk (150 mL)
Total fat: 8.5 g (~25% of calories)
Total carbohydrates: 38.5 g (~50% of calories)
Total protein: 18.8 g (~25% of calories)
Total calories: 312 Kcalories
The exact low fat meal contents may be substituted with agreement between sponsor and
investigator and must be documented in an administrative letter. The substituted meal should 
have a fat content of 20% to 30% and a caloric content of 300 ± 25 Kcalories.
Table 9
Contents of Moderate Fat Breakfast
2 Slices brown bread (70 g)
Butter (15 g)
Cheese (45 g)
Jam (15 g)
250 mL Whole milk
Total fat: 34.4 g (~50% of calories)
Total carbohydrates: 50.5 g (~30% of calories)
Total protein: 26.7 g (~20% of calories)
Total calories: 626 Kcalories
The exact moderate fat meal contents may be substituted with agreement between sponsor 
and investigator and must be documented in an administrative letter. The substituted meal
should have a fat content of 40% to 50% and a caloric content of 600 ± 30 Kcalories.
All Panels
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 for each panel (except for the breakfast).  After the 24-hour post-dose procedures have 
 
 
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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-4250 with or without food and/or drink or the nutritional 
content of the meal 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 trial drug administration, throughout the 
trial and until the post-trial visit.  
Subject also will 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. 
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 or xanthine-containing 
products 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 units per day (1 unit=120 mg of 
caffeine).  
Smoking Restrictions 
5.7.2.3
Smoking is restricted to ≤10 cigarettes per day, and subjects will follow the smoking 
restrictions defined by the Clinical Research Unit.
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.
 
 
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Contraception and Pregnancy Testing 
5.7.2.5
5.7.2.5.1 Contraception
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, and tubal ligation
having occurred >3 months prior to screening.  Surgical sterilization of the male partner or 
the female subject 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.  
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 
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.
5.7.2.5.2 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 predose 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 to the Sponsor as outlined in Section 7.2.2.    
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
 
 
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specified 
in 
Section 
6.0 
-
Trial 
Flow 
Chart 
and 
Section 
7.1.4.1 
–
Withdrawal/Discontinuation, or if available, Protocol Clarification Letter.
Subjects may discontinue treatment at any time for any reason or be discontinued from 
treatment at the discretion of the investigator should any untoward effect occur.  In addition, 
a subject may be discontinued from treatment by the investigator or the Sponsor if treatment
is inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
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, he/she 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 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.
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 
 
 
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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 appraised 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 the maximum 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 and further dosing 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 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) severe but not life threatening adverse experiences or severe clinically 
significant laboratory abnormalities that are similar in nature with a potential causal 
relationship to study drug.
4. One (1) serious adverse experience/laboratory abnormality which 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 or more of the above conditions are met, enrollment and further dosing will be halted 
and all available safety data will be reviewed prior to making a decision about terminating 
 
 
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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: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 a notification 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
All Panels/Periods
Scheduled Time
Study Day
1
2
3
4
6
8
9
11
13
15
Hours Postdose
Prestudy
Pre-
dose
0
0.5
1
2
4
6
8
12
24
48
72
120
168
192
240
288
336/ 
Post-
trial k
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical 
Research 
X
Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X
Medical History
X
Concomitant Medication Review
X
----
----- ----- ---- ---- ---- ---
---
----
----
---
----
---
----
----
----
---
X
Subject Domiciling in Clinical Research 
Unit (CRU)
Xa
----- ----- ---- ---- ---- ---
---
----
X
Clinic Procedures/Assessments
Full Physical Examination
X
Xm
X
Height
X
Weight
X
12-Lead Electrocardiogramc
X
X
X
X
X
X
Vital Signs (heart rate, blood pressure) d
X
X
X
X
X
X
Orthostatic Vital Signs (heart rate, blood 
pressure) d
X
X
X
X
X
Vital Signs (respiratory rate, temperature)
X
X
X
X
X
X
Dosing Breakfast (Panels E and F only)o
X
 
 
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All Panels/Periods
Scheduled Time
Study Day
1
2
3
4
6
8
9
11
13
15
Hours Postdose
Prestudy
Pre-
dose
0
0.5
1
2
4
6
8
12
24
48
72
120
168
192
240
288
336/ 
Post-
trial k
Standard Meals e
X
---
---
----
X
MK-4250 Administration
X
Adverse Events Monitoring
X
-------
----- ----- ---- ---- ---- ---
---
----
----
---
----
----
----
----
----
---
X
Laboratory Procedures/Assessments
Hematology j
X
Xm
X
X
X
Urinalysis j
X
Xm
X
X
X
Chemistry j
X
Xm
X
X
X
Serum/Urine
-Human 
Chorionic 
Gonadotropin (β-hCG) f
X
X
X
Serum Follicle Stimulating Hormone 
(FSH) - if applicable g
X
Urine Drug Screen h
X
Xm
HIV/Hepatitis Screen 
X
Blood for Genetic Analysis b
X
Pharmacokinetics Evaluations
Blood for Plasma MK-4250 assay i
X
X
X
X
X
X
X
X
X
X
Xn
X
X
X
Xn
Pharmacodynamic Evaluations
Blood for HIV RNA, viral resistance i,l
X
X
X
X
X
X
X
X
X
X
X
X
X
CD-4 cell count 
X
 
 
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a.
Subjects will be admitted to the CRU the evening before scheduled dosing.
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.
c.
ECGs are performed after the subject has remained in a semi-recumbent position for at least 10 minutes. Only the baseline ECG (pre-dose on Day1, obtained within 
3 hours prior to dosing) will be repeated 3 times with at least 1-minute intervals between ECG measurements.
d.
Only the predose semi-recumbent HR and BP (obtained within 3 hours prior to dosing) will be triplicate measurements obtained at least 1-2 minutes apart. Subjects 
should be resting in the semi-recumbent position for at least 10 minutes prior to obtaining HR and BP. Following selected measurement of the semi-recumbent HR 
and BP, subjects assume a standing position for at least 2 minutes and then orthostatic HR and BP will be obtained.
e.
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 postdose procedures 
have been completed, subsequent meals and snacks will be unrestricted in terms of caloric content, composition and timing.
f.
For female subjects of childbearing potential only. Serum pregnancy test must be performed at screening. Urine pregnancy test is an option only for the predose and 
posttrial visits. 
g.
For postmenopausal female subjects only.
h.
Screening drug screen is mandatory; any additional drug screens are conducted per site SOP and/or at the investigator’s discretion.
i.
Leftover plasma will be stored for future biomedical research if the subject consents to future biomedical research.
j.
Safety laboratory samples will be collected after at least an 8-hour fast. Screening hematology labs will include PT/INR measurements.
k.
For all subjects, the post-trial visit should occur approximately 14 days (+2 days) following administration of the study drug. 
l.
For all subjects, blood for HIV-1 viral RNA and viral resistance will be collected at timepoints up to the initiation of ART. For subjects who do not initiate follow on 
ART, blood for HIV-1 viral RNA and viral resistance will continue to be collected until the post trial visit. Ultra-deep sequencing (UDS) may be performed if viral 
resistance cannot be measured due to low viral load. At the timepoint immediately preceding initiation of ART, a portion of the blood collected for viral resistance 
testing will be sent to Labor Berlin for extraction of proviral DNA. This proviral DNA will be frozen and analyzed for the presence of viral resistance mutations only 
if standard Sanger sequencing cannot be performed because plasma viral load is too low at this timepoint.
m.
The predose PE and laboratory assessments (including drug screen) may be performed within 24 hour prior to dosing.
n.
The 72 hour post-dose PK sample will be drawn only for the first 3 subjects enrolled in Panel B; in addition, the 240 hr timepoint will not be drawn for these three 
subjects.
o.
For Panels E and F only, a dosing breakfast will be provided at approximately 30 mins pre-dose on Day 1.
 
 
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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 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.  
 
 
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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 
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.
Randomization number will be assigned just prior to dosing on Day 1.
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 position for at least 10 minutes prior to 
each ECG measurement.  
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required 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.
Predose ECGs will be obtained in triplicate at least 1-2 minutes apart within 3 hours prior to 
dosing MK-4250.  The mean of these measurements will be used as the baseline to calculate 
change from baseline for safety evaluations (and for rechecks, if needed).  Post-dose ECG 
measurements will be single measurements.  
 
 
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If a subject demonstrates an increase in QTc interval ≥60 msec compared with mean predose 
baseline measurement, the ECG will be repeated twice within 5 minutes.  The mean value of 
the QTc interval from the 3 ECGs will represent the value at that time point.  If the mean 
QTc interval increase from baseline for any postdose 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 QTc is within 60 msec of baseline.  If prolongation of the QTc interval ≥60 msec persists, 
a consultation with a study cardiologist may be appropriate and the Sponsor should be 
notified.
If the QTc 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 QTc 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 QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc 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.
Predose HR and BP will be triplicate measurements obtained at least 1-2 minutes apart 
within 3 hours of dosing MK-4250.  The mean of these measurements will be used as the 
baseline to calculate change from baseline for safety evaluations (and for rechecks, if 
needed).  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 at least 2 minutes prior to 
measurement of orthostatic vital signs. 
 
 
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Subjects will continue to rest semi-recumbent from dosing until 4 hours postdose except to 
stand for the measurement of orthostatic vital signs (if needed) or other trial related 
procedure. 
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 10.
 
 
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Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Glucose
Follicle 
Stimulating 
Hormone (FSH) – for 
postmenopausal 
females only
Hemoglobin
Alkaline phosphatase
Protein
Serum/Urine
β-human 
chorionic gonadotropin 
(β-hCG) – for females 
of 
childbearing 
potential only
Platelet count
Alanine 
aminotransferase 
(ALT)
Red blood cell
Hepatitis
B 
surface 
antigen
WBC (total and 
differential)
Including:
Aspartate aminotransferase 
(AST)
White blood cell
Hepatitis C antibodies
Absolute 
neutrophils
Bicarbonate
Microscopic exam, 
if abnormal results 
are noted
HIV (including HIV-1 
RNA, 
resistance 
mutations to InSTIs)
Absolute 
lymphocytes
Calcium
pH
Urine Drug Screen
Absolute 
monocytes
Chloride
Absolute 
eosinophils
Creatinine
Absolute 
basophils
Glucose
PT/INR 
(screening)
Phosphorus
CD4+ T-cell 
count
(screening)
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin
Total protein
Urea
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.
 
 
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Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
The decision as to which plasma samples collected will be assayed for evaluation of 
pharmacokinetics/pharmacodynamics will be collaboratively determined by the Department 
of Quantitative Pharmacology and Pharmacometrics (QP2) and Translational Pharmacology.  
If indicated, these samples may also be assayed and/or pooled for assay in an exploratory 
manner for metabolites and/or additional pharmacodynamic markers.
7.1.3.2.1 Blood Collection for Plasma MK-4250
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the Study Operations Manual. 
7.1.3.2.2 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.
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

Leftover main study plasma from MK-4250 assay stored for future research

Leftover main study plasma from HIV RNA and viral resistance assays stored for 
future use
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 14 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 14 days after the last dose of trial drug
is given, the investigator should perform a follow-up phone call 14 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 
 
 
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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.
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 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 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.
 
 
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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:

Equipment for taking VS

ECG equipment and electrodes

Equipment (including freezers) for the PK and PD samples
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, 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 if there are Day -1 
procedures planned per protocol.
Treatment Period (All Panels)
7.1.5.2
Subjects will report to the CRU the day prior to the scheduled day of dosing or at a 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.
After the Day 1 predose procedures have been completed, subjects will be assigned a unique 
allocation number associated with a specific study treatment as defined by a computer-
generated allocation schedule. All subjects in each panel will be administered a single dose 
of MK-4250 in the morning. The exact clock time of dosing should be recorded.
Post-Trial
7.1.5.3
Subjects will be required to return to the clinic at least 14 days (+2 days) after the last dose of 
trial drug for the post-trial visit. 
 
 
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Critical Procedures Based on Trial Objectives: Timing of Procedure 
7.1.5.4
For this trial, the blood samples for plasma MK-4250 and HIV-1 viral RNA data are the 
critical procedures. 
At any post-dose timepoint, the blood sample for MK-4250 and the blood sample for viral 
RNA need to be collected as close to the exact timepoint 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.

Blood collection for PK and PD as outlined in Table 11 below
Table 11
Plasma PK and HIV RNA - Blood Collection Windows
PK/PD collection
PK/PD Collection 
Window
0 to < 1 hr
5 min
1 to < 24 hr
15 min
24 to < 48 hr
2 hr
48 to 168 hr
3 hr
˃ 168 hr
24 hr

Predose standard safety evaluations:  vital signs & ECG 3 hrs; laboratory safety tests 
including drug screen & physical exam 24 hrs

Postdose standard safety evaluations (vital signs, ECG, laboratory safety tests, 
physical exam) as outlined in Table 12 below.
Table 12
Postdose Scheduled Time – Data Collection Windows
Scheduled Time
Data Collection 
Window
0 to < 24 hr
30 min
24 to <48 hr
2 hr
48 to 168 hr
3 hr
 
 
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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-4250 in humans, and the pharmacokinetic, 
pharmacodynamic 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 in any given panel

Entire panel(s) may be omitted

Addition of a study pause

Instructions to take trial drug with or without food or drink may also be modified based 
on newly available data

Composition of the meal taken with the trial drug may also be modified based on newly 
available data

Modification of the PK/PD sample processing and shipping details based on newly 
available data
The pharmacokinetic/pharmacodynamic sampling scheme currently outlined in the protocol 
may be modified during the trial based on newly available pharmacokinetic or 
pharmacodynamic data (e.g., to obtain data closer to the time of peak plasma concentrations)
but the number of samples will not increase.  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, pharmacokinetic, and/or 
pharmacodynamic 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 
 
 
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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.
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 14 days following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting timeframe 
for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
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.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
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:
 
 
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●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 13 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
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 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
 
 
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media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that 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.
Protocol-Specific Exceptions to Serious Adverse Event Reporting
7.2.3.3
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 13. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 13 for instructions in evaluating adverse events.
 
 
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Table 13
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.  (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event? The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND 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-4250 
and placebo is at least 1.4 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 pharmacodynamics hypothesis. 
Power
If the true SD of the log10 reduction from baseline in plasma HIV-RNA at 168 hours 
postdose is 0.2 (0.3), there is ~80% power to yield at least 80% posterior probability that the 
 
 
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true mean difference in the plasma HIV-1 RNA reduction from baseline between MK-4250 
and placebo is at least 1.4 log10 copies/mL, if the true mean log10 reduction is at least 1.56 
log10 (1.63 log10) with N=6 for MK-4250 in a panel and N=20 historical placebo subjects.
The SD values of 0.2 and 0.3 are chosen based on a SD of 0.26 observed for Day 8 change 
from baseline in log10 HIV RNA for 400 mg BID raltegravir.
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 Pharmacodynamics Hypothesis:  At a dose that is sufficiently safe and generally 
well tolerated, MK-4250 has superior antiretroviral activity compared to placebo, as 
measured by change from baseline in plasma HIV-1 RNA (log10 copies/mL) at 168 hours 
postdose. That is, the true mean difference in the plasma HIV-1 RNA reduction from 
baseline between MK-4250 and placebo is at least 1.4 log10 copies/mL.
Secondary Pharmacokinetic Hypothesis: The true geometric mean C168hr is > 1250 nM 
following single dose administration of MK-4250 for at least one dose level of MK-4250.
Analysis Endpoints
8.2.2
Primary Endpoints
Safety: Primary safety endpoints will include all types of adverse experiences, in addition to 
laboratory safety tests, ECGs, and vital signs. 
Pharmacodynamics: The primary pharmacodynamics variables in this study include plasma 
HIV-1 RNA pre-dose and at the time points listed in the Study Flow Chart up until the time 
at which ART is initiated. 
Secondary Endpoints 
The secondary endpoints in this study include: MK-4250 plasma AUC0-last, AUC0-inf, 
AUC0-168hr, Tmax, Cmax, C168hr, t1/2, CL/F and Vz/F.
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. 
 
 
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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 
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 
 
 
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HIV-1 RNA reduction from baseline between MK-4250 and placebo is at least 1.4 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 
pharmacodynamics hypothesis. For each dose level, the posterior probability that the true 
mean log10 plasma HIV-1 RNA reduction from baseline is at least 1.4 log10 copies/mL will 
also be calculated. Similar exploratory analyses may be performed using viral load 
measurements at baseline and specified post-baseline timepoints.
Descriptive statistics for VL reduction will be provided by dose level and time point.  Mean 
and individual plots of VL reduction over time will also be provided by dose.
Secondary (Pharmacokinetics): 
Separately for each PK parameter, individual values of MK-4250 plasma pharmacokinetic 
parameters AUC0-last, AUC0-inf, AUC0-168hr, Cmax, C168hr, CL/F and Vz/F  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 secondary hypothesis that the true geometric mean C168hr is > 1250 nM following 
single dose administration of MK-4250 for at least one dose level of MK-4250 will be tested 
using the previously-defined model. The posterior probability that the true GM C168hr is 
>1250 nM will be calculated for each dose using flat priors under an assumption of 
normality.  A 70% posterior probability that the true C168hr is > 1250 nM for at least one 
dose level will satisfy the secondary pharmacokinetic hypothesis.
Descriptive Statistics 
Individual values will be listed for each PK parameter by treatment, 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).
Exploratory (Pharmacokinetic/Pharmacodynamic)
The pharmacokinetic-pharmacodynamic and dose-pharmacodynamic association of MK-
4250 will be explored. Graphs to visualize the association of the Day 7 reduction in log10 
plasma HIV-1 RNA levels with MK-4250 C168hr plasma concentration and dose will be 
generated. Exposure levels and doses that result in various proportions of the population 
(e.g., 80%, 90%) that have at least 1.4 log10 reduction from baseline in plasma HIV-1 RNA 
levels with high confidence may be estimated.
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.  
 
 
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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 pharmacodynamic 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 
postdose is 0.2 (0.3), 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-4250 
and placebo is at least 1.4 log10 copies/mL, if the true mean log10 reduction is at least 1.56 
log10 (1.63 log10) with N=6 for MK-4250 in a panel and N=20 historical placebo subjects.
The SD values of 0.2 and 0.3 are chosen based on a SD of 0.26 observed for Day 8 change 
from baseline in log10 HIV RNA for 400 mg bid raltegravir.
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 14
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 14
Product Descriptions
Product Name & 
Potency
Dosage Form
MK-4250 1 mg
tablet
MK-4250 10 mg
tablet
MK-4250 100 mg
tablet
 
 
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Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label 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.
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.
 
 
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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.
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.
 
 
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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.
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 
 
 
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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.
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 
 
 
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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 accurac y 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
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 
 
 
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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 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
1.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use 
of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health 
and 
Human 
Services. 
Available 
at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf, Accessed 
Jun 2017.
2.
Elliot, E, Chirwa, M, Boffito, M. “How recent findings on the pharmacokinetics and 
pharmacodynamics of integrase inhibitors can inform clinical use.” Current Opinions in 
Infectious Disease. 2017 Feb; 30(1):58-73.
3.
ISENTRESS (raltegravir) [product label]. Merck Sharp & Dohme Corp; Feb 2015.
4.
VITEKTA® (elvitegravir [product label]. Gilead Sciences , Inc.; July 2015.
5.
TIVICAY® (dolutegravir) [product label]. ViiV Healthcare Company; June 2016.
6.
ViiV Healthcare. Study Evaluating the Efficacy, Safety, and Tolerability of Switching 
to Long-acting Cabotegravir Plus Long-acting Rilpivirine From Current Antiretroviral 
Regimen in Virologically Suppressed HIV-1-infected Adults. In: ClinicalTrials.gov 
[Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2017 Jan 
3]. Available at https://clinicaltrials.gov/show/NCT02951052 NLM Identifier: 
NCT02951052.
7.
ViiV Healthcare. Study to Evaluate the Efficacy, Safety, and Tolerability of Long-
acting Intramuscular Cabotegravir and Rilpivirine for Maintenance of Virologic 
Suppression Following Switch From an Integrase Inhibitor inHIV-1 Infected Therapy 
Naïve Participants. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library 
of 
Medicine 
(US). 
2000-[cited 
2017 
Jan 
3]. 
Available 
at 
https://clinicaltrials.gov/show/NCT02938520 NLM Identifier: NCT02938520.
8.
White, KL, Raffi, F, Miller, MD. “Resistance analyses of integrase strand transfer 
inhibitors within Phase 3 clincial trials of treatment-naïve patients.” Viruses (2014) 
6:2858-2879.
9.
Guido van den Berk, JO, Willem, B, Nar da van der, M, et al. “Unexpectedly high rate 
of intolerance for dolutegravir in real life setting.” Conference on Retroviruses and 
Opportunistic Infections (2016), Abstract 948, Boston, MA. Available at 
https://dl.dropboxusercontent.com/u/56658768/Flipbooks/2016/eBook/HTML/index.ht
m, Accessed Dec 2016.
10.
European Medicines Agency. Guideline on the Clinical Development of Medicinal 
Products for the Treatment of HIV Infection (EMEA/CPMP/EWP/633/02; Rev 3), 19-
Sep-2013.
11.
Xu, Y, Li, YF, Zhang, D, et al. “Characterizing Class-Specific Exposure-Viral Load 
Suppression Response of HIV Antiretrovirals Using A Model-Based Meta-Analysis” 
Clinical Translational Science (2016) 4:192-200.
12.
Rizk, M, Hang, Y, Luo, WL, et al. “Pharmacokinetics and Pharmacodynamics of Once-
Daily versus Twice-Daily Raltegravir in Treatment-Naïve HIV-Infected Patients.” 
Antimicrobial Agents and Chemotherapy (2012) 56: 3101-3106.
 
 
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13.
Markowitz, M, Morales-Ramirez, JO, Nguyen, BY, et al. “Antiretroviral Activity, 
Pharmacokinetics, and Tolerability of MK-0518, a Novel Inhibitor of HIV-1 Integrase, 
Dosed As Monotherapy for 10 Days in Treatment-Naïve HIV-1-Infected Individuals.” J 
Acquir Immune Defic Syndr 2006; 43: 509-515.
14.
Min, 
S, 
Sloan, 
L, 
DeJesus, 
E, 
et 
al.
“Antiviral 
activity, 
safety, 
and 
pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-
infected adults.” AIDS 2011, 25:1737-1745.
15.
Dejesus, E., Berger, D, Markowitz, M, et al. “Antiviral Activity, Pharmacokinetics, and 
Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-
Naïve and Treatment-Experienced Patients.” J Acquir Immune Defic Syndr 2006; 43: 
1-5.
16.
Ramanathan, S, Mathias, AA, German, P, Kearney, BP. “Clinical Pharmacokinetic and 
Pharmacodynamic Profile of the HIV Integrase Inhibitor Elvitegravir.” Clin 
Pharmacokinet 2011; 50 (4): 229-244.
 
 
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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 subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address 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, D, E, and F
Pre-trial
Treatment Periods
Post-trial
Total Collections
mL 
Per 
Collection
Total mL/ 
Test
Laboratory safety tests a
1
3
1
5
10
50
PT/INR
1
0
0
1
3
3
Blood for Planned Genetic 
Analysis 
0
1
0
1
8.5
8.5
Blood for MK-4250
0
14
0
14
4
56
Blood for HIV RNA, viral 
resistance b, c
1e
11e
1
13
16 e
208
Total Blood Volume Per Subject for Panels A, B, D, E, and F d 325.5 mL
a Blood volume includes CD4 cell count, HIV/Hepatitis Screen, β-hCG, and FSH.
b Blood volume includes proviral DNA and ultra-deep sequencing (UDS) which may be performed if viral resistance 
cannot be measured due to low viral load.
c The number of collections denoted in this row reflects the maximum quantity required if a subject does not initiate 
ART during the trial and the 14 days post trial period. 
d If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained during the trial.  
e At the Pre-trial visit only 13.3mL will be drawn. During the Treatment Period (at the final timepoint prior to initiation
of ART), an additional 2.7 mL will be drawn for proviral DNA testing. The decrease in blood volume at the pre-trial 
visit offsets the increase at the single timepoint during the Treatment Period.
 
 
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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
 
 
04Z55S