An Open-label Single Oral Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MK-0518 1200 mg (600 mg Tablet × 2) in Healthy Japanese Male Participants
Phase: PHASE4
Conditions: Human Immunodeficiency Virus (HIV) Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03667547  
Document Date: 
10-Jul-2018
An open-label single oral dose study to evaluate the safety, 
tolerability, and pharmacokinetics of MK-0518 1200 mg (600 
mg tablet × 2) in healthy Japanese male participants

Study Drug Name: MK-0518
Post-marketing Clinical Study Protocol Number-Version Number: 851-00
1
Post-marketing Clinical Study Protocol
This post-marketing clinical study (hereinafter, study) protocol and its related information are 
proprietary information, and all of them are intellectual property owned by Merck Sharp & 
Dohme Corp., a subsidiary of Merck & Co., Inc., N.J., U.S.A. (MSD), and MSD K.K.
Title:
An open-label single oral dose study to evaluate the safety, tolerability, and pharmacokinetics 
of MK-0518 1200 mg (600 mg tablet × 2) in healthy Japanese male participants
Post-marketing Clinical Study Protocol Number:
851-00
Study Drug Name:
MK-0518
Sponsor and Location:
MSD K.K. (hereinafter, Sponsor)
Refer to Appendix 7: Study Administrative Structure for the contact information for each 
role of the Sponsor.
Date of Preparation:
July 10, 2018
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Sponsor Signatory
Typed Name: 
Date
Title:
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name: 
Date
Title:
 
 
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Table of Contents
Page
List of Tables.............................................................................................................................. 7
List of Figures ............................................................................................................................ 8
1
Summary of the Study ...................................................................................................... 9
1.1
Outline................................................................................................................... 9
1.2
Schematic of Study Design................................................................................. 11
1.3
Study Schedule.................................................................................................... 12
2
Introduction..................................................................................................................... 14
2.1
Rationale for the Conduct of the Study............................................................... 14
2.2
Background......................................................................................................... 14
2.2.1
Background Related to the Drug and Treatment of Disease ................ 14
2.2.2
Clinical Study Results........................................................................... 16
2.3
Benefits/Risks ..................................................................................................... 16
3
Hypotheses, Objectives, and Endpoints.......................................................................... 17
4
Study Design................................................................................................................... 17
4.1
Study Design Outline.......................................................................................... 17
4.2
Scientific Rationale for Study Design................................................................. 17
4.2.1
Rationale for Endpoints ........................................................................ 17
4.2.1.1
Safety Endpoints .................................................................. 17
4.2.1.2
Pharmacokinetic Endpoints.................................................. 18
4.2.2
Rationale for the Use of Comparator/Placebo ...................................... 18
4.3
Justification for Dosing Regimen of the Study Drug.......................................... 18
4.3.1
Starting Dose for This Study ................................................................ 18
4.3.2
Maximum Dose/Expected Exposure for This Study ............................ 18
4.3.3
Rationale for Dose Interval and Dose Design ...................................... 19
4.4
Beginning and End-of-Study Definition............................................................. 19
4.4.1
Criteria for Early Study Termination.................................................... 19
5
Study Population............................................................................................................. 19
5.1
Inclusion Criteria ................................................................................................ 19
5.2
Exclusion criteria ................................................................................................ 20
5.3
Lifestyle Considerations ..................................................................................... 22
5.3.1
Dietary Restrictions .............................................................................. 22
5.3.1.1
Meals .................................................................................... 22
5.3.1.2
Fruit Juice............................................................................. 22
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ....................................... 22
5.3.2.1
Caffeine ................................................................................ 22
5.3.2.2
Alcohol................................................................................. 22
5.3.2.3
Tobacco ................................................................................ 23
5.3.3
Daily Living Activities ......................................................................... 23
 
 
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5.4
Screen failures..................................................................................................... 23
5.5
Criteria Related to Participant Replacement....................................................... 23
6
Intervention in the Study................................................................................................. 23
6.1
Dosage Schedule of the Study Drug ................................................................... 23
6.2
Preparation/Handling/Storage/Accountability of the Study Drug ...................... 25
6.2.1
Preparation of the Study Drug .............................................................. 25
6.2.2
Handling, Storage, and Accountability of the Study Drug................... 25
6.3
Method to Minimize Bias: Randomization and Blinding................................... 25
6.3.1
Assignment Procedure .......................................................................... 25
6.3.2
Stratification.......................................................................................... 25
6.3.3
Blinding ................................................................................................ 26
6.4
Concomitant Therapy.......................................................................................... 26
6.4.1
Rescue and Supportive Therapies......................................................... 26
6.5
Dose Modification for the Study Drug (Titration/Adjustment/Other)................ 26
6.6
Intervention After the End of the Study.............................................................. 26
6.7
Disclosure of Treatment Assignments................................................................ 26
7
Discontinuation of Study Drug Administration and Participant Withdrawal From 
the Study ......................................................................................................................... 26
7.1
Discontinuation of Study Drug Administration.................................................. 26
7.2
Participant Withdrawal From the Study ............................................................. 27
7.3
Lost to Follow-up................................................................................................ 27
8
Study Assessments and Procedures ................................................................................ 27
8.1
Study Administrative Procedures........................................................................ 28
8.1.1
Informed Consent and Information....................................................... 28
8.1.1.1
Informed Consent and Information Related to 
Participating in This Study................................................... 28
8.1.2
Inclusion/Exclusion Criteria ................................................................. 29
8.1.3
Study Identification Card...................................................................... 29
8.1.4
Medical History .................................................................................... 29
8.1.5
Prior and Concomitant Medications Review........................................ 29
8.1.5.1
Prior Medications ................................................................. 29
8.1.5.2
Concomitant Medications .................................................... 30
8.1.6
Assignment of Screening Number........................................................ 30
8.1.7
Assignment of Treatment/Randomization Number.............................. 30
8.1.8
Study Drug Administration................................................................... 30
8.1.8.1
Timing of Study Drug Administration................................. 31
8.1.9
Study Discontinuation and Withdrawal of Consent ............................. 31
8.1.10
Participant Blinding/Unblinding........................................................... 31
8.1.11
Admission............................................................................................. 31
8.1.12
Calibration of Equipment...................................................................... 32
8.2
Efficacy Assessments.......................................................................................... 32
 
 
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8.3
Safety Assessments............................................................................................. 32
8.3.1
Physical Examinations.......................................................................... 32
8.3.2
Resting Vital Signs ............................................................................... 33
8.3.3
Electrocardiograms ............................................................................... 33
8.3.4
Safety Laboratory Tests........................................................................ 33
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events.................................................................................... 34
8.4.1
Time Period and Frequency of Reporting AEs, SAEs, and Other 
Reportable Safety Events...................................................................... 34
8.4.2
Detection of AEs, SAEs, and Other Reportable Safety Events............ 35
8.4.3
Follow-up of AEs, SAEs, and other Reportable Safety Events............ 36
8.4.4
Regulatory Reporting Requirements for SAEs..................................... 36
8.4.5
Pregnancy and Exposure During Breastfeeding................................... 36
8.4.6
Disease-related Events/Disease-related Outcomes Not Qualifying 
as AEs or SAEs..................................................................................... 36
8.4.7
Events of Clinical Interest (ECIs)......................................................... 36
8.5
Treatment of Overdose........................................................................................ 37
8.6
Pharmacokinetics ................................................................................................ 37
8.6.1
Blood Collection for Plasma MK-0518 Concentrations....................... 37
8.7
Pharmacodynamics ............................................................................................. 37
8.8
Future Biomedical Research Sample Collection ................................................ 38
8.9
Planned Genetic Analysis Sample Collection..................................................... 38
8.10
Biomarkers.......................................................................................................... 38
8.11
Visit schedule...................................................................................................... 38
8.11.1
Screening .............................................................................................. 38
8.11.2
Treatment Period................................................................................... 38
8.11.3
Post-study examination......................................................................... 38
8.11.4
Critical Procedures Based on Study Objectives: Timing of 
Procedure .............................................................................................. 38
8.11.5
Study Design/Dose/Procedures Modifications Permitted Within 
the Protocol Parameters ........................................................................ 39
9
Statistical Analysis Plan.................................................................................................. 39
9.1
Statistical Analysis Plan Summary ..................................................................... 39
9.1.1
Statistical Methods................................................................................ 40
9.1.2
Statistical Power ................................................................................... 40
9.2
Statistical Analysis Plan...................................................................................... 40
9.2.1
Hypotheses/Estimation ......................................................................... 40
9.2.2
Endpoints .............................................................................................. 41
9.2.3
Analysis Populations............................................................................. 41
9.2.4
Statistical Methods................................................................................ 41
9.2.5
Multiplicity ........................................................................................... 42
9.2.6
Sample Size and Power Calculations.................................................... 42
 
 
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10
Appendices (Supporting Documentation and Operational Considerations)................... 43
10.1
Appendix 1: Procedures for the Handling of Samples for Drug 
Concentration Measurements.............................................................................. 43
10.2
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations............. 45
10.2.1
Guidelines for Clinical Study Operations............................................. 45
10.2.2
Compliance with Financial Disclosure Requirements.......................... 47
10.2.3
Protection of Data ................................................................................. 48
10.2.3.1
Confidentiality of Data......................................................... 48
10.2.3.2
Confidentiality of Participant Records................................. 48
10.2.3.3
Confidentiality of IRB/IEC Information.............................. 49
10.2.4
Publication Policy................................................................................. 49
10.2.5
Study Registration and Results Posting................................................ 49
10.2.6
Compliance with Law, Audit, and Debarments.................................... 49
10.2.7
Data Quality Assurance ........................................................................ 50
10.2.8
Source Documents ................................................................................ 51
10.2.9
Discontinuation of the Study, and Discontinuation of Study Site 
Participation.......................................................................................... 51
10.3
Appendix 3: Clinical Laboratory Tests............................................................... 52
10.4
Appendix 4: AE Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................... 53
10.4.1
Definition of AE ................................................................................... 53
10.4.2
Definition of SAE................................................................................. 54
10.4.3
Additional Events to be Reported in the Same Manner as SAE........... 55
10.4.4
Recording AE and SAE ........................................................................ 55
10.4.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ................................................................................................. 58
10.5
Appendix 5: Criteria for 12-lead ECG Abnormalities........................................ 59
10.6
Appendix 6: Algorithm for Assessing Abnormal Laboratory Values ................ 61
10.7
Appendix 7: Study Administrative Structure...................................................... 62
10.7.1
Sponsor ................................................................................................. 62
10.7.1.1
Sponsor Name and Address ................................................. 62
10.7.1.2
Sponsor Development Director............................................ 62
10.7.1.3
Medical Expertise................................................................. 62
10.7.1.4
Monitor (Representative) ..................................................... 62
10.7.2
Contract Research Organization........................................................... 62
10.7.2.1
Contract Organization for Monitoring, etc........................... 62
10.7.2.2
MSD K.K. Clinical Study Emergency Center...................... 63
10.7.3
Central Laboratory (Regarding Potential Drug-induced Liver 
Injury) ................................................................................................... 63
10.7.4
Drug Concentration Laboratory............................................................ 63
10.7.5
Principal Investigator............................................................................ 63
10.8
Appendix 8: Abbreviations................................................................................. 64
11
References....................................................................................................................... 65
 
 
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List of Tables
Page
Table 1
Study Drug ............................................................................................................ 24
Table 2
Reporting Time Periods and Time Frames for Adverse Events, Serious 
Adverse Events and Other Reportable Safety Events ........................................... 35
Table 3
Time Windows for Sample Collections for Drug Concentration 
Measurements........................................................................................................ 39
Table 4
Protocol-specified Safety Laboratory Tests .......................................................... 52
 
 
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List of Figures
Page
Figure 1
Study design .......................................................................................................... 11
 
 
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1
Summary of the Study
1.1
Outline
Title:
An open-label single oral dose study to evaluate the safety, tolerability, and pharmacokinetics 
of MK-0518 1200 mg (600 mg tablet × 2) in healthy Japanese male participants
Short Title:
ISENTRESS® Tablets 600 mg post-marketing clinical study (pharmacokinetics in Japanese 
participants)
Acronym:
Not applicable
Hypotheses, Objectives, and Endpoints:
This study will be conducted in healthy Japanese male participants.
Objectives/hypotheses
Endpoints
Primary
•
Objective: To evaluate the safety and tolerability of 
MK-0518 when administered at a single oral dose of 
1200 mg in healthy Japanese male participants
Hypothesis (H1): None
•
Physical findings
•
Vital signs (blood pressure, pulse 
rate, respiratory rate, body 
temperature [axillary])
•
Laboratory tests (hematology, 
clinical chemistry, urinalysis)
•
12-lead electrocardiograms (ECGs)
•
Adverse events (clinical 
symptoms/laboratory test values)
Secondary
•
Objective: To obtain plasma pharmacokinetic data (e.g. 
the area under the plasma concentration-time curve 
from time 0 to infinity [AUC0-∞], maximum blood 
concentration [Cmax], plasma concentration at 24 hours 
after administration [C24hr], time to reach maximum 
plasma concentration following drug administration 
[Tmax], and apparent elimination half-life [t1/2]) of 
MK-0518 1200 mg when administered as a single oral 
dose
Hypothesis (H2): To estimate the geometric mean ratio 
of plasma pharmacokinetic data (the area under the 
plasma concentration-time curve [AUC], Cmax, and 
C24hr) of a single oral dose of MK-0518 1200 mg in 
Japanese participants retrospectively compared with 
non-Japanese populations
•
Plasma MK-0518 concentrations
and pharmacokinetic parameters 
(AUC0-∞, Cmax, C24hr, Tmax, apparent 
t1/2, apparent clearance [CL/F], and 
apparent distribution volume 
[Vz/F])
 
 
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Study Design Outline:
Development phase
Phase 4 study
Primary objective
Treatment
Proposed indication
Human Immunodeficiency Virus (HIV) infection
Study population
Healthy Japanese adult male
Study type
Interventional study
Study design
Single group
This study will be conducted at a single site.
Control
No control group included
Type of blinding
Open-label
Masking
Masking is not performed.
Planned study duration
The period from the first participant’s signing informed consent to 
the last participant’s last phone call or visit will be approximately 1 
month in this study.
Target Sample Size: Approximately 12 participants (participants enrolled)
Type of Intervention Group and the Duration of Study Participation:
Type of intervention group
Use a tablet containing MK-0518 600 mg as a study drug. All 
participants will receive the study drug MK-0518 1200 mg (600 
mg tablet × 2) orally under fasted condition.
Number of intervention group
1
Duration of study 
participation
Each participant will participate in the study for approximately 1 
month from the time the participant signs informed consent to 
post-study examination (last phone call or visit).
Study Governance
Meeting Forms (Committees):
Steering Committee
Not established
Executive Oversight Committee
Not established
Data Monitoring Committee
Not established
Clinical Adjudication Committee
Not established
Study governance considerations are provided in Appendix 2.
Study Accepts Healthy Volunteers: Yes
Abbreviations are described in Appendix 8: Abbreviations.
 
 
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1.2
Schematic of Study Design
The study design is depicted in Figure 1.
Figure 1
Study design
Screening
Dosing of study drug
Post-study examination
2
Visit
1
(Admission)
(Discharge)
3
Day
−21 to −1
−1
0
2
10 to 14
 
 
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1.3
Study Schedule
Activities
Screening 
test†
Time since Study Drug Administration
Post-
study 
Examina-
tion‡
Pre-
dose
0
0.5
1
1.5
2
3
4
6
8
12
16
24
48§§
Visit Number
1
2
Admission
Dis-
charge
3
Scheduled Visits
Day −21
to Day −1
Day −1
Day
0
Day
1
Day
2
Day 10 to 
Day 14
Administrative Procedures
Informed consent to study participation
X§
Study identification card distribution
X
Inclusion/exclusion criteria review
X
X
Prior/concomitant medication review
X
X
Medical history review
X
Physical examination
X
X
X
Body weight
X
Height
X
Immunoserology
X
Urine drug screen
X
Meal¶
X
Safety Measurements
Vital signs (blood pressure, pulse rate,
and respiratory rate)#
X
X
X
X
Body temperature (axillary)#
X
X
X
Laboratory tests††
X
X║
X
12-lead ECGs#
X
X
X
Adverse events
X
X
MK-0518-related Activities
Blood sampling (MK-0518)
X
X
X
X
X
X
X
X
X
X
X
X
X
MK-0518 administration‡‡
X
 
 
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Activities
Screening 
test†
Time since Study Drug Administration
Post-
study 
Examina-
tion‡
Pre-
dose
0
0.5
1
1.5
2
3
4
6
8
12
16
24
48§§
Visit Number
1
2
Admission
Dis-
charge
3
Scheduled Visits
Day −21
to Day −1
Day −1
Day
0
Day
1
Day
2
Day 10 to 
Day 14
†
Screening test will be performed within 3 weeks prior to study drug administration.
‡
Post-study examination will be performed between Days 10 and 14 after study drug administration in each participant. However, adverse events will be examined until Day 14 study 
drug administration.
§
Written informed consent will be obtained before starting any study procedure.
║
Predose laboratory tests will be performed within 24 hours prior to study drug administration.
¶
Participants will be provided with lunch after blood sampling performed 4 hours after study drug administration. The timing and content of subsequent meals will be determined by the 
principal investigator. All participants are provided with meals of the same content.
#
Measurements will be performed after maintaining participants in a supine or semirecumbent position for at least 10 minutes.
††
Participants will be fasted for more than 8 hours before blood sampling for laboratory tests (hematology, clinical chemistry, and urinalysis).
‡‡
Participants will be fasted for more than 8 hours before study drug administration and for more than 4 hours after the administration. In addition, they are not permitted to drink water for 
1 hour before and 1 hour after the administration.
§§
An investigator will confirm the absence of any abnormalities in tests and examinations performed before 48 hours after study drug administration in individual participants to discharge 
them.
 
 
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2
Introduction
2.1
Rationale for the Conduct of the Study
MK-0518 (raltegravir potassium; hereinafter, raltegravir) is an HIV integrase inhibitor. 
The objective of this study is to evaluate the safety and pharmacokinetics of a single oral 
dose of MK-0518 in healthy Japanese male participants.
In Japan, raltegravir 400 mg tablet formulation (ISENTRESS® Tablets 400 mg) has been 
available since July 2008 with the dosing regimen of 400 mg twice daily orally. In 
anti-HIV treatment, it is preferable to reduce medication burden to patients to ensure 
better medication compliance. Accordingly, a simplified treatment regimen, i.e., the 
less-frequent dosing treatment regimen of raltegravir at a dose of 1200 mg (600 mg tablet 
× 2) once daily orally was developed. The regimen was approved in May 2018 by 
submitting an application for marketing approval as a drug with a new dose and as a drug 
with an additional dosage form using the non-Japanese application file for approval. As a 
condition for the approval, a pharmacokinetic study of raltegravir 600 mg tablet 
formulation in Japanese participants was determined to be conducted.
2.2
Background
Refer to the package insert and Pharmaceutical Interview Form of ISENTRESS® Tablets
600 mg for more details of the following background information.
•
Physical, chemical and pharmaceutical properties and formulation
•
Non-clinical pharmacology
studies (in vitro
pharmacology
studies, in vivo
pharmacology studies, and supplementary safety pharmacology studies)
•
Animal pharmacokinetics and metabolism
•
Toxicity and toxicokinetics
•
Clinical efficacy
2.2.1
Background Related to the Drug and Treatment of Disease
According to the statistics from Joint United Nations Programme on HIV and AIDS 
(UNAIDS) in 2016, the number of patients with HIV infection and acquired 
immunodeficiency syndrome (AIDS) are estimated as 36.7 million in the world. In the 
same year, the number of new patients with HIV infection was 1.8 million. The number 
of new patients with HIV infection in the world was reduced by 11% compared with 2010, 
and the spread of HIV infection has been calming down mainly in advanced countries. 
Meanwhile, the number of new patients with HIV infection has still been increasing in the 
Eastern Europe and Central Asia.
According to the survey by the Committee of AIDS Trends, the Ministry of Health, 
Labour and Welfare, the number of new patients with HIV infection (nonprogressor at the 
time of diagnosis) in Japan was 1011 in 2016, which has been reported as more than 1000 
in a year constantly since 2007 and as 18920 in total. In comparison of the number of new 
patients with HIV infection in Japan per 0.1 million population between populations by 
 
 
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age, it has been the largest in the populations in their 20’s and 30’s, followed by the 
population in their 40’s, showing a high proportion of infections in the younger 
generation. On the other hand, the number of new patients with AIDS (those diagnosed 
with AIDS at the time of initial reporting) in Japan was 437 in 2016, which has been 
reported as more than 400 in a year constantly since 2006 and as 8523 in total.
As described above, although the number of new patients with HIV infection has been in 
decreasing trend mainly in advanced countries, the number of new patients with HIV 
infection and those with AIDS have remained unchanged in Japan. In these diseases, 
early diagnoses and management of treatment remain to be important.
The stages of HIV infection can be divided into 3 main stages: acute infection, 
asymptomatic, and AIDS stages. HIV infection causes acute infection symptoms such as 
pyrexia, rash, and lymph node swelling (acute infection stage). Emergence of 
immunological reactions specific to HIV reduces the volume of viruses in blood, not 
eliminating them completely. It is then followed by the long-term antagonism between 
the patient’s immune mechanism and HIV for a long period of time (asymptomatic stage). 
Unless anti-HIV treatment is started during this stage, HIV continues proliferating, 
thereby reduces the patient’s immune strength gradually, and eventually leads to 
vulnerability to concomitant opportunistic disease (AIDS stage). The time from the initial 
infection to an AIDS stage varies with patients. With no anti-HIV treatment, the time 
from the onset of AIDS to death is considered as approximately 2 years.
With HIV infection, the volume of viruses in blood (HIV ribonucleic acid [RNA]) and the 
number of CD4 lymphocytes are critical to understand the severity and course of the 
patient’s condition. Although the level of HIV RNA is maintained at an almost constant 
level approximately at 6 months after HIV infection, the speed of disease progression 
increases with the elevated level of HIV RNA, which can therefore be used as a measure 
to predict progression of HIV infection. With regard to the number of CD4 lymphocytes, 
which is 700–1300 /mm3 in healthy adults, a level less than 200 /mm3 causes 
immunodeficiency with vulnerability to various types of opportunistic diseases. The 
number of CD4 lymphocytes indicates the remaining level of immunoresponsiveness in 
the host destroyed by HIV, providing an important measure along with the level of HIV 
RNA when starting anti-HIV treatment is considered .
As of March 2017, 8 types of nucleoside reverse transcriptase inhibitors, 4 types of
nonnucleoside reverse transcriptase inhibitors, 8 types of protease inhibitors, and 1 type 
of entry inhibitor have been approved in Japan. Among these anti-HIV drugs, selecting 3 
to 4 types of drugs with stronger inhibition of HIV (key drugs) and supplementary drugs 
that have a role of enhancing antiviral effects (backbone) as antiretroviral therapy is a 
standard treatment. The development of these antiretroviral therapies has changed HIV 
infection, previously regarded as an incurable disease, to a controllable chronic disease. 
Meanwhile, it is practically impossible to eliminate HIV completely out of the carrier’s 
body even with these therapies, and once anti-HIV therapy is started in a patient with HIV 
infection, the level of HIV RNA in blood needs to be sustained continuously at less than 
detection limits. This forces HIV-infected patients to continue therapy using anti-HIV 
drugs throughout their lifetime, and medication adherence needs to be maintained high 
 
 
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during this therapy to prevent treatment failure and the development of resistance. 
Meanwhile, multiple drugs other than anti-HIV drugs are also often used for the treatment 
of disease not related to HIV. For this reason, improvement of medication adherence with 
a simplified antiretroviral therapy (e.g., reduced medication burden and eased dietary 
restriction) is considered to increase the possibility of treatment success, and is also 
recommended by international guidelines.
MK-0518 (raltegravir; ISENTRESS® Tablets) is an HIV integrase inhibitor developed by 
Merck & Co., Inc., Whitehouse Station, N.J., U.S.A., and approved in September 2007 
for the first time in the world. Integrase is one of the three enzymes required for the 
replication of HIV, which acts on the process of incorporating deoxypentose nucleic acid 
(DNA) of HIV in the gene of the host cells. A series of the sequential reactions include 
the composition of integrase in stable complex with virus DNA, endonuclease processing 
of virus DNA, and transfer and ligation of DNA strands to DNA of virus and the host. 
The integration is required for efficient viral gene expression, as well as for stable 
maintenance of viral genome. The results of clinical studies demonstrated that MK-0518 
is an effective integrase inhibitor with strong efficacy and safety profile. In addition, the 
results of non-clinical and clinical studies suggested that MK-0518 was less likely to be 
associated with clinically significant drug interactions. Further multiple studies evaluating 
efficacy, safety, and pharmacokinetics have demonstrated the properties of MK-0518.
2.2.2
Clinical Study Results
In the non-Japanese phase 3 clinical study in HIV treatment-naive patients (ONCEMRK), 
a randomized, double-blind, parallel-controlled study of raltegravir 400 mg twice daily + 
emtricitabine (FTC) + tenofovir disoproxil fumarate (TDF) was conducted to examine the 
safety and efficacy of raltegravir 1200 mg (600 mg tablet × 2) once daily + FTC + TDF. 
The results demonstrated the noninferiority of raltegravir 1200 mg once daily to 
raltegravir 400 mg twice daily.
2.3
Benefits/Risks
The study is planned for the purpose of collecting information related to the safety and 
efficacy of the study drug. Therefore, it cannot be guaranteed that the study participants 
will obtain benefits directly from the treatment during the study period.
Since this study is conducted in healthy participants, the administration of MK-0518 is 
not likely to bring benefits to their health.
Refer to the package insert and Pharmaceutical Interview Form of ISENTRESS® Tablets
600 mg for the benefits and risks of participating in this study.
 
 
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3
Hypotheses, Objectives, and Endpoints
This study will be conducted in healthy Japanese male participants.
Objectives/hypotheses
Endpoints
Primary
•
Objective: To evaluate the safety and tolerability of 
MK-0518 when administered at a single oral dose of 
1200 mg in healthy Japanese male participants
Hypothesis (H1): None
•
Physical findings
•
Vital signs (blood pressure, pulse 
rate, respiratory rate, body 
temperature [axillary])
•
Laboratory tests (hematology, 
clinical chemistry, urinalysis)
•
12-lead ECGs
•
Adverse events (clinical 
symptoms/laboratory test values)
Secondary
•
Objective: To obtain plasma pharmacokinetic data (e.g. 
AUC0-∞, Cmax, C24hr, Tmax, and apparent t1/2) of 
MK-0518 1200 mg when administered as a single oral 
dose
Hypothesis (H2): To estimate the geometric mean ratio 
of plasma pharmacokinetic data (AUC, Cmax, and C24hr)
of a single oral dose of MK-0518 1200 mg in Japanese 
participants retrospectively compared with 
non-Japanese populations
•
Plasma MK-0518 concentrations
and pharmacokinetic parameters 
(AUC0-∞, Cmax, C24hr, Tmax, apparent 
t1/2, CL/F, and Vz/F)
4
Study Design
4.1
Study Design Outline
This is an open-label single oral dose study in healthy Japanese male participants
comprising a single panel. A total of 12 participants will receive 1200 mg of MK-0518 
under fasting conditions.
Study procedures including visit frequency during the study period and the acceptable 
range of visits are outlined in “1.3 Study Schedule.” Details of each procedure are 
provided in Section 8.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
The primary objective of this study is to evaluate the safety and tolerability of MK-0518 
by giving a single oral dose of MK-0518 1200 mg in healthy Japanese male participants.
The safety and tolerability of MK-0518 will be evaluated with vital signs, clinical 
assessments such as
physical examination, 12-lead ECGs, and laboratory tests 
 
 
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(hematology, clinical chemistry and urinalysis). Adverse events will be evaluated, 
recorded, followed up, and reported in accordance with Section 8.4 and Appendix 4.
4.2.1.2
Pharmacokinetic Endpoints
The secondary objective of this study is to obtain plasma pharmacokinetic parameters 
(AUC0-∞, Cmax, C24hr, Tmax, apparent t1/2, CL/F, and Vz/F) of a single oral dose of 
MK-0518 1200 mg in healthy Japanese male participants.
Samples for drug concentration measurements will be collected at points shown in “1.3
Study Schedule.” Pharmacokinetic parameters (AUC0-∞, Cmax, C24hr, Tmax, apparent t1/2, 
CL/F, and Vz/F) will be calculated using MK-0518 concentrations in plasma obtained at 
each collection point.
4.2.2
Rationale for the Use of Comparator/Placebo
No comparator/placebo is used in this study.
4.3
Justification for Dosing Regimen of the Study Drug
4.3.1
Starting Dose for This Study
Following the non-Japanese phase 1 clinical study that had demonstrated an improvement 
in the bioavailability of newly formulated raltegravir 600 mg tablets, a non-Japanese
phase 3 clinical study in HIV treatment-naive patients (ONCEMRK) demonstrated the 
noninferiority of raltegravir 1200 mg (600 mg tablet × 2) once daily to raltegravir 400 mg 
twice daily. On the basis of these study results and data from 3 drug interaction studies, 
the dosage and administration of raltegravir 1200 mg (600 mg tablet × 2) once daily was 
approved in Japan. The approved dose of 1200 mg (600 mg tablet × 2) was selected as the 
dose for this study.
4.3.2
Maximum Dose/Expected Exposure for This Study
A single dose of raltegravir 1200 mg (600 mg tablet × 2) in fasted healthy non-Japanese 
adult participants showed an AUC0-∞(mean) of 50.1 μM•hr, a Cmax (mean) of 15.7 μM, a 
C24hr (mean) of 41.6 nM, a Tmax (median) of 1.50 hours, and an apparent t1/2 (mean) of 
8.95 hours. Population pharmacokinetics showed no clinically meaningful effect of the 
differences in race on the pharmacokinetics of raltegravir 1200 mg (600 mg tablet × 2) 
repeatedly administered once daily. In addition, the pharmacokinetics of a single oral 
dose of raltegravir 400 mg in fasted healthy Japanese adult male participants were similar 
to those in non-Japanese. The exposures for this study are expected to be almost the same 
as those of a single dose of raltegravir 1200 mg (600 mg tablet × 2) in fasted healthy 
non-Japanese adults.
 
 
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4.3.3
Rationale for Dose Interval and Dose Design
Exposure-response analysis related to the efficacy of raltegravir has revealed that plasma
trough concentrations (Ctrough) are important for demonstrating the efficacy of raltegravir. 
Repeated once-daily dosing with raltegravir 1200 mg (600 mg tablet × 2) for 5 days in 
healthy non-Japanese adults showed no plasma raltegravir accumulation. Therefore, since 
the efficacy and exposures of repeat dosing can be fully predicted from the 
pharmacokinetic profile for a single dosing, the safety, tolerability, and pharmacokinetics 
of a single oral dose of ISENTRESS® Tablets 600 mg in healthy Japanese male 
participants was planned to be evaluated in the same design as that for the studies 
normally conducted as post-marketing clinical studies of an anti-HIV drug.
4.4
Beginning and End-of-Study Definition
This study begins when the first participant signs the Informed Consent Form (ICF). The 
study ends when the last participant completes the last follow-up (the last study-related 
telephone-call or visit), withdraws from the study, or is lost to follow-up (i.e., the 
participant is unable to be contacted by an investigator).
Prior to a final decision on continuation or termination of the study, a study may be 
paused during review of newly available preclinical/clinical safety, pharmacokinetic, 
pharmacodynamic, efficacy, or biologic data or other data of interest. It may also be 
necessary to keep the study open for gathering and reviewing of additional supportive 
data to complete the objectives of the study. If necessary, appropriate amendment(s) to 
the protocol or appropriate communication(s) will be generated. The study end will then 
not be identified until the Sponsor has made the decision to end the study following the 
completion of this review. The relevant regulatory authority(ies) and Institutional Review 
Board(s) (IRB[s])/Independent Ethics Committee(s) (IEC[s]) will be apprised of the
maximum duration of the study beyond the last participant completion and the 
justification for keeping the study open.
4.4.1
Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
Study Population
Healthy Japanese male participants between the ages of 20 and 45 will be enrolled in this 
study.
Prospective approval of protocol deviations related to inclusion criteria (e.g., waivers or 
exemptions) is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
 
 
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Type of participant/target disease
1)
Is a Japanese male between the ages of 20 and 45 at the time of signing informed 
consent.
Participant Demographics
2)
Has a Body Mass Index (BMI)† between 18.5 kg/m2 and 32.0 kg/m2 at the time 
of screening test.
† BMI = weight (kg)/height (m)2
Note: BMI values will be rounded to one decimal place.
Informed Consent
3)
Has understood the methodology of the study and voluntarily signed written 
informed consent to study participation.
Others
4)
Is considered to be in good health by an investigator based on the medical 
history, physical findings, vital signs, and the results of 12-lead ECG noted at the 
screening test and before study drug administration. Refer to Appendix 5 for
criteria for ECG abnormalities.
5)
Is considered to be in good health based on the results of laboratory tests 
performed at the screening test and before study drug administration. A list of 
laboratory tests performed for this study is attached in Appendix 3. Refer to 
Appendix 6: Algorithm for Assessing Abnormal Laboratory Values
for 
algorithm related to the assessment of abnormal laboratory values.
6)
Has been a nonsmoker and has not used nicotine-containing products for over 3 
months at the time of screening test.
7)
Is willing to comply with the study restrictions (refer to Section 5.3 for a 
summary of study restrictions).
5.2
Exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
Medical History
1)
Have a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or 
neurological (including cerebrovascular stroke and epilepsy) abnormalities or 
diseases.
2)
Has significant emotional problem at the time of screening test or suspected to 
occur during the conduct of the study, or has a history of clinically significant 
psychiatric disorder within the last 5 years.
3)
Has a history of malignancy.
4)
Has a history of clinically significant allergies to multiple antigens or severe 
allergies (e.g., food, drug, and latex [natural rubber] allergies), or has had an 
 
 
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anaphylactic reaction or significant intolerability (e.g., systemic allergic 
reaction) to prescription or non-prescription drugs or food.
5)
Is positive for hepatitis B virus surface antigen, hepatitis C virus antibodies, 
syphilis, or HIV antigen or antibody on the screening test.
6)
Had surgery, donated or lost blood within 4 weeks prior to the screening test.
Prior and Concomitant Medications
7)
Requires the use or anticipates the required use of prescription or 
non-prescription drugs or herbal products beginning 14 days prior to study drug 
administration through the post-study examination (or cytochrome P450 [CYP], 
uridine diphosphate [UDP] glucuronic acid transferase, and/or P-glycoprotein 
[P-gp] inducers including St. John's wort beginning 28 days prior to study drug 
administration through the post-study examination). There may be certain 
medications that are permitted (see Section 6.4).
Prior Study (Clinical Trial) Experience
8)
Has participated in another study (clinical trial) within 4 months prior to the 
screening test. The interval between studies (clinical trials) will be derived from 
the last procedure (e.g., post-study examination, follow-up of adverse events) for 
the last study (clinical trial) to the screening test for this study.
Diagnostic Assessments
9)
Has a systolic blood pressure < 90 mmHg or > 140 mmHg, or a diastolic blood 
pressure < 50 mmHg or > 90 mmHg on the screening test or predose blood 
pressure measurement. Blood pressure measurements will be performed after 
maintaining a supine or semirecumbent position for at least 10 minutes.
Others
10) Consumes greater than 3 glasses of alcoholic beverages (definition of 1 glass: 
354 mL for beer, 118 mL for wine, 29.5 mL for distilled spirits) per day.
11) Consumes greater than 6 servings (definition of 1 serving: equivalent to 120 mg 
of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per 
day.
12) Is a regular user of cannabis, any illicit drugs, or has a history of drug or alcohol 
abuse within 2 years at the time of the screening test. Participants must have a 
negative predose urine drug screen.
13) Is unable to consent to refrain from the consumption of citrus beverages and 
foods (e.g., grapefruits) beginning 2 weeks prior to administration of the study 
drug until the end of post-study examination, and the consumption of all fruit 
beverages and foods for 24 hours predose and postdose.
14) Is or has an immediate family member (e.g., spouse, parent/legal guardian, 
sibling, or child) who is study site or Sponsor staff directly involved with this 
study.
 
 
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5.3
Lifestyle Considerations
5.3.1
Dietary Restrictions
5.3.1.1
Meals
Fasting requirements for study procedures, such as laboratory tests are specified in 
Section 8.
Participants will fast from all food and drinks, except water, for at least 8 hours prior to 
study drug administration. Participants will fast from all food and drinks except water 
between study drug administration and the first scheduled meal. Meals will be provided at 
time points specified in the study schedule. Between these meals, participants will fast 
from all food and drinks except water. After the 24-hour postdose tests and observations
have been completed, subsequent meals and snacks will be unrestricted in caloric content, 
composition and timing.
Water will be provided at the time of study drug administration. Water will be restricted 1 
hour prior to and 1 hour after study drug administration.
The study drug will be taken with approximately 240 mL (± approximately 10 mL) of 
water.
5.3.1.2
Fruit Juice
Participants will refrain from the consumption of citrus beverages and foods (e.g.,
grapefruits) beginning approximately 2 weeks until the post-study examination.
Participants will also refrain from the consumption of all fruit beverages and food 
beginning 24 hours prior to study drug administration until 24 hours after the 
administration. At all other times, the consumption of fruits beverages and foods 
(excluding citrus [e.g., grapefruits] beverages and foods) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine
Participants will refrain from the consumption of caffeinated beverages and 
xanthine-containing products for 12 hours prior to the screening test and 12 hours prior to 
post-study examination, and beginning 12 hours prior to study drug administration until 
12 hours after the administration. At all other times, caffeinated beverages and 
xanthine-containing products will be limited to no more than 6 units per day (definition of 
1 unit: equivalent to 120 mg of caffeine).
5.3.2.2
Alcohol
Participants will refrain from the consumption of alcohol beginning 24 hours prior to 
study drug administration until 24 hours after the administration. Participants will also 
 
 
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refrain from the consumption of alcohol for 24 hours prior to the screening test and 24 
hours prior to post-study examination. At all other times, alcohol beverages are allowed 
but limited to no more than 3 glasses per day (definition of 1 glass: 354 mL for beer, 118 
mL for wine, 29.5 mL for distilled spirits).
5.3.2.3
Tobacco
Smoking (and the use of nicotine and nicotine-containing products) is not permitted from 
the screening test through the post-study examination.
5.3.3
Daily Living Activities
Participants are instructed to avoid strenuous physical activities (e.g., excessive weight 
lifting, running, bicycling) from the screening test through the post-study examination.
5.4
Screen failures
Screen failures are defined as participants who have consent to participate in this study 
but are not subsequently enrolled in the study. A minimal set of information will be 
collected on screen failures as well. Minimal information includes the following 
information specified in the “Data Handling Guidelines”: participant demography, details 
of the reasons for screen failures, inclusion/exclusion criteria, and adverse events/serious 
adverse events meeting reporting requirements.
5.5
Criteria Related to Participant Replacement
If a participant withdraws from the study, a new participant (reserve participant) can 
participate in the study if deemed appropriate by an investigator and Sponsor. The new 
participant will be assigned a unique treatment/randomization number. The study site will 
contact the Sponsor for the new participant’s treatment/randomization number.
6
Intervention in the Study
An intervention in the study is defined as the use of any study drug, marketed product or 
medical device in accordance with the protocol.
6.1
Dosage Schedule of the Study Drug
Table 1 shows the study drug for this study.
 
 
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Table 1
Study Drug
Treatment 
Group
Type of Group
Drug Name
Type
Dosage 
Form
Strength
Dose
Route
Regimen
Use
IMP/
NIMP
Supply
Investigational 
product
ISENTRESS®
Tablets 600 mg
Drug
Tablet
600 mg
2 tablets 
(1200 mg) once
Oral
Single-
dosing
Investigational 
product
NIMP
Marketed 
product
The definitions of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) will be in accordance with the guidance 
issued by the European Commission.
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As study drug shown in Table 1, the marketed product (ISENTRESS® Tablets 600 mg) 
will be purchased by the study site and used for the study.
Refer to Section 8.1.8 for the details of study drug administration.
6.2
Preparation/Handling/Storage/Accountability of the Study Drug
6.2.1
Preparation of the Study Drug
There are no specific calculations or evaluations required to be performed in order to 
determine the dose to each participant for this study. The rationale for selection of the 
dose of the study drug is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability of the Study Drug
Refer to the package insert and Pharmaceutical Interview Form of ISENTRESS® Tablets
600 mg for the handling/storage/accountability of the study drug.
Only authorized site staff may administer the study drug. Only participants enrolled in the 
study will receive study drug administration. All study drugs will be stored in a secure, 
manually or automatically monitored and controlled area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff.
The study drug storage manager will be responsible for study drug accountability, 
reconciliation, and record keeping (i.e., receipt, reconciliation, and final disposition 
records).
Where study drug disposition at the site is appropriate, the study drug storage manager 
will ensure that disposition procedure is documented.
For the marketed products purchased for this study by the study site, the study site will 
record the lot numbers, the manufacturers, and expiry dates in accordance with local 
guidelines unless otherwise instructed by the Sponsor.
The study drug storage manager is responsible for appropriate recording, appropriate 
supply, storage, handling, distribution, and use of the study drug in accordance with the 
protocol and applicable laws and regulations, and will take all measures required.
6.3
Method to Minimize Bias: Randomization and Blinding
6.3.1
Assignment Procedure
Participants will be allocated to the treatment group by nonrandom assignment in this 
study.
6.3.2
Stratification
No stratification based on age, gender, or other factors will be performed.
 
 
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6.3.3
Blinding
This is an open-label study; therefore, the treatment detail is open to the investigator, 
participants, and the Sponsor.
6.4
Concomitant Therapy
Even if a participant does not discontinue prior medications for 14 days prior to study 
drug administration (or CYP, UDP glucuronic acid transferase, and/or P-gp inducers 
including St. John's wort for 28 days prior to study drug administration), he may be 
included in the study if the investigator can rationalize that the use of the prior 
medication(s) has no clinically significant effect on the study.
Concurrent use of any medication prescribed or obtained during the study period, or 
concurrent vaccination must be discussed between the investigator and Sponsor prior to 
administration, unless treatment needs to be started before their discussion. The 
participant will be allowed to continue in the study if both the Sponsor and the 
investigator agree.
6.4.1
Rescue and Supportive Therapies
No rescue or supportive therapies are specified for this study.
6.5
Dose Modification for the Study Drug (Titration/Adjustment/Other)
No dose modification is specified for this study.
6.6
Intervention After the End of the Study
There is no intervention specified to be performed after the end of this study.
6.7
Disclosure of Treatment Assignments
This is an open-label study; therefore, the participants, the study site personnel, the 
Sponsor, or its delegate are not blinded. The drug information (name, strength, or 
potency) is included in the package insert, and no emergency key containing treatment 
assignments will be provided.
7
Discontinuation of Study Drug Administration and Participant 
Withdrawal From the Study
7.1
Discontinuation of Study Drug Administration
Participants may discontinue study drug administration at any time for any reason or be 
discontinued from the administration at the discretion of the investigator should any 
untoward event occurs. In addition, a participant may be discontinued from study drug 
 
 
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administration by the investigator or the Sponsor if study drug administration is 
inappropriate, the protocol is violated, or for administrative or other safety reasons. 
Specific procedures to be performed at the time of discontinuation of study drug 
administration are provided in Section 8.1.9.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or his legally acceptable 
representative withdraws consent.
If a participant withdraws from the study, they will no longer receive study drug 
administration or be followed at protocol-specified visits.
Specific procedures to be performed at the time of withdrawal from the study are 
provided in Section 8.1.9. The procedures to be performed should a participant repeatedly 
fail to return for protocol-specified visits and/or if the study site is unable to contact the 
participant are specified in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the study site for a specified study visit or if the site is 
unable to contact the participant, the following procedures will be performed.
•
The site must attempt to contact the participant and reschedule the missed visit. 
If the participant is contacted, the participant will be explained about the 
importance of maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (e.g., telephone calls and/or a certified letter to 
the participant’s last known mailing address or equivalent methods). These 
contact attempts will be documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled 
visit for the individual participant. The missing data for the participant will be 
handled in accordance with the prespecified statistical data handling and analysis 
guidelines.
8
Study Assessments and Procedures
•
Study procedures and their timing are outlined in “1.3 Study Schedule.”
•
Adherence to the protocol-specified requirements, including those specified in 
“1.3 Study Schedule,” is essential and required for study conduct.
•
The principal investigator is responsible for ensuring that the study procedures 
are conducted by appropriately qualified or trained staff. Delegation of study site 
personnel responsibilities will be documented and stored in the Investigator 
Study File Binder (or equivalent).
•
Study-related medical (or dental) decisions will be made by an investigator who 
is a qualified physician (or dentist only when appropriate).
 
 
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•
The investigator must perform and evaluate all screening items to confirm that 
potential participants meet all inclusion criteria. The investigator will record the 
details of all participants screened, and manage the records of confirming their 
eligibility or reasons for screening failures, as applicable.
•
Procedures conducted as part of the participant’s routine clinical care (e.g., 
hematology) before signing informed consent may be utilized for screening or 
baseline evaluations provided the procedure met the protocol-specified criteria 
and were performed within the time frame specified in “1.3 Study Schedule.”
•
Additional evaluations/testing may be deemed necessary by the investigator 
and/or the Sponsor for reasons related to participant safety. In some cases, such 
evaluations/testing may be potentially sensitive in nature (e.g., HIV infection, 
hepatitis C), and thus local laws and/or regulations may require that additional 
informed consent be obtained from the participant. In these cases, such 
additional evaluations/testing will be performed in accordance with those local 
laws and/or regulations.
The amount of blood collected from each participant over the duration of the study will 
amount to approximately 73 mL.
Repeat or unscheduled blood samples may be taken for safety reasons or for technical 
issues with the samples.
Sample
Blood collected per 
time (mL)
Number of blood 
collections
Total amount of blood 
collected (mL)
Laboratory tests
7
3
21
Samples for the measurement 
of MK-0518 concentrations
4
13
52
Total amount of blood 
collected per participant
73 mL
8.1
Study Administrative Procedures
8.1.1
Informed Consent and Information
The investigator will obtain written consent from each participant or his legally 
acceptable representative prior to participating in the study. If there are changes to the 
participant’s status during the study period (e.g., health condition or age category), the 
investigator will ensure the appropriate consent has been obtained.
8.1.1.1
Informed Consent and Information Related to Participating in This 
Study
Consent to participation in the study must be documented by the participant’s dated 
signature or by his legally acceptable representative’s dated signature on a consent form 
along with the dated signature of the person conducting the consent discussion.
 
 
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A copy of the signed and dated consent form will be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval in advance of use. The participant or his 
legally acceptable representative will be informed immediately if new information 
becomes available that may affect the participant’s willingness to continue participation 
in the study. The communication of the new information will be provided via a revised 
ICF or an addendum to the original consent form that captures the participant’s dated 
signature or his legally acceptable representative’s dated signature.
Information about the study and the study population will be added to the ICF template at 
the protocol level.
The ICF will fulfill IRB/IEC requirements, applicable laws and regulations, and the 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator to ensure that the 
participant qualifies for study participation.
8.1.3
Study Identification Card
All participants will be given a study identification card identifying them as a participant
in the study. The card will contain study site contact information (including telephone 
numbers) that can be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a study identification card immediately after the 
participant provides written consent to study participation. At the time of the provision of 
the participant’s treatment/randomization number, the number will be added to his study 
identification card.
The study identification card also contains contact information for the MSD K.K. Clinical 
Study Emergency Center so that a health care provider can obtain information about the 
participant’s study drug in emergency situations where the investigator is not available.
8.1.4
Medical History
Medical history will be reviewed by the investigator.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
There are no planned medications other than the study drug in this study. Participants are 
not permitted to use prescription or non-prescription drugs or herbal products beginning 
14 days prior to study drug administration through the end of post-study examination. 
 
 
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Participants are not permitted to use CYP, UDP glucuronic acid transferase, or P-gp 
inducers including St. John's wort beginning 28 days prior to study drug administration 
through the post-study examination.
The investigator will review the presence or absence of prior medication use, including 
any protocol-specified washout requirement, and record prior medications used by the 
participant within 14 days prior to study drug administration.
8.1.5.2
Concomitant Medications
There are no planned medications other than the study drug in this study.
The use of all medications other than the study drug will be discussed with the Sponsor 
prior to administration, unless emergency treatment is necessary.
The investigator will record medication used by participants during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures performed prior to the allocation to treatment 
group. Each participant will be assigned only 1 screening number. One screening number
must not be assigned to different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Refer to Section 8.11.1 for specific details on the 
screening-related requirements (screening/re-screening).
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated to the treatment group without randomization. 
The allocated participants will receive a treatment/randomization number each. The 
treatment/randomization numbers will be used to identify the individual participants for 
all procedures performed after treatment allocation. The screening number assigned to a
participant 
will 
be 
used 
as 
his 
treatment/randomization 
number. 
Once 
a 
treatment/randomization number is assigned to a participant, it can never be re-assigned 
to another participant.
A single participant will be assigned 1 treatment/randomization number.
8.1.8
Study Drug Administration
Participants will be given 2 tablets of MK-0518 600 mg with approximately 240 mL (±
approximately 10 mL) of water in the morning under fasting conditions. The exact time 
of administration will be recorded.
Study drug administration will be witnessed by the investigator or designee.
 
 
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Study drug administration will be performed on the day of the allocation to the treatment 
group.
8.1.8.1
Timing of Study Drug Administration
Tests and observations will be performed in accordance with “1.3 Study Schedule”(for 
further details, refer to “4.2.1.2 Pharmacokinetic Endpoints” and “4.2.1.1 Safety 
Endpoints”). At a point where multiple tests and blood collections are scheduled (e.g., 24 
hours after study drug administration), the collection of samples for the measurement of 
MK-0518 concentrations will be adjusted to a point as close as possible to the specified 
point.
8.1.9
Study Discontinuation and Withdrawal of Consent
If a participant withdraws his consent, all appropriate procedures among those specified 
for the post-study examination will be performed at the time of discontinuation. Adverse 
events occurring at the time of consent withdrawal will be followed up in accordance with 
the safety requirements specified in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; therefore, there is no blinding for this study.
8.1.11
Admission
Participants will visit the study site on the day before scheduled study drug administration 
and be admitted to the site until 48 hours after study drug administration. The absence of 
protocol violations in terms of health condition after the screening test and compliance 
related to the requirements for medications, meals, activities, etc. will be confirmed.
The investigator will review the participant’s eligibility in terms of all criteria including 
his health condition before study drug administration. Refer to “1.3 Study Schedule” for 
specific activities to be performed before study drug administration.
After admission, participants are not permitted to go out of the study site unless permitted 
by the investigator. The investigator will discharge each participant after confirming the 
absence of any abnormalities on tests and observations performed before 48 hours after 
study drug administration. The duration of admission may be extended at the discretion of 
the investigator.
If a participant develops an adverse event(s) during admission, the investigator will 
investigate whether the event requires admission. Stay at the study site beyond the 
protocol-specified admission period (see “1.3 Study Schedule”), though admission is not 
required, will be handled as “extended stay.” Conditions requiring admission will be 
treated as “serious adverse events” that will follow the reporting procedures specified in 
“8.4.4 Regulatory Reporting Requirements for SAEs.”
 
 
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8.1.12
Calibration of Equipment
The investigator or designee has the responsibility to ensure that any equipment used for a 
clinical evaluation/test during the study (device or instrument that provides information 
about inclusion/exclusion criteria or safety or efficacy parameters) is suitably calibrated 
and maintained, and that the data obtained is reliable and reproducible. Documentation of 
equipment calibration will be retained as source documentation at the study site.
8.2
Efficacy Assessments
There are no direct efficacy assessment parameters specified in this study.
8.3
Safety Assessments
Specific procedures and assessments related to laboratory tests to be performed in this 
study are provided below. The total amount of blood to be collected over the course of the 
study, including blood volumes collected by visit and by sample per participant, is shown 
in Section 8.
Planned time points for individual safety assessments are provided in “1.3 Study 
Schedule.”
8.3.1
Physical Examinations
Whole-body examination findings will be evaluated by the investigator as per 
institutional standard procedures. Height and weight will also be measured and recorded
at the time of the screening test.
Physical findings will be evaluated per institutional standard procedures.
The investigator will pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index (BMI):
BMI equals a person’s weight (kg) divided by height (m) squared (BMI = kg/m2). 
Document the BMI to one decimal place.
Measure the participant’s weight after an overnight fast, after voiding, without a jacket or 
coat, without shoes, on an accurate scale. Document the measured weight (kg) to one 
decimal place.
Measure the participant’s height on an accurate stadiometer, without shoes. Document the 
measured height (m) to the nearest 0.01 meter (1 cm).
 
 
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8.3.2
Resting Vital Signs
Vital Sign Measurements (Blood Pressure, Pulse Rate, and Respiratory Rate):
Participants will be kept supine or semirecumbent (head elevated at an angle of 45°) for at 
least 10 minutes prior to having vital sign measurements obtained. Supine or 
semirecumbent vital signs will include blood pressure, pulse rate, and respiratory rate. 
Blood pressure shall be measured using a correct size of blood pressure cuff on a correct 
position on the participants' arm to obtain accurate measurements.
A measurement before study drug administration will be used as the baseline to calculate 
the change for safety evaluations (and for rechecks, if needed). Postdose vital sign 
measurements will be single measurements.
Participants will be instructed to rest seated or semi-recumbent until 4 hours postdose 
except for the time of study-related procedures.
Body Temperature:
Body temperature will be measured. The same method shall be used for all measurements 
for all participants.
8.3.3
Electrocardiograms
A 12-lead electrocardiogram (ECG) (single measurement) will be obtained by the 
investigator or medically qualified designee as specified in “1.3 Study Schedule” using an 
ECG machine that automatically measures heart rate, PR, QRS, and QT and QTc 
intervals.
Qualified personnel will place each lead to a proper position. Skin will be clean and dry 
prior to lead placement. Participants will be shaved as needed to ensure proper lead 
placement. Participants may also need to remove garments interfering lead placement.
Participants will be kept supine or semirecumbent for at least 10 minutes prior to each 
ECG measurement.
The correction formula to be used for QTc interval is Fridericia.
8.3.4
Safety Laboratory Tests
•
Refer to Appendix 3 for the list of clinical laboratory tests to be performed for 
this study, and to “1.3 Study Schedule” for the timing and frequency of tests.
•
The investigator will review laboratory reports, document this review, and record 
any clinically meaningful changes occurring during the study in the adverse 
event form in the case report form (CRF). Laboratory reports will be filed with 
the source documents. Clinically significant abnormal laboratory findings are 
abnormal findings which are not associated with the participant’s underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.
 
 
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•
If laboratory results
from non-protocol-specified laboratory assessments 
performed at the study site require a change in study participant management or 
are considered clinically significant by the investigator (e.g., serious adverse 
event, adverse event, or dose modification of the study drug), the results will be 
recorded in the appropriate CRF (e.g., SLAB).
•
For any clinically significant abnormal laboratory findings during the study or 
within 14 days after study drug administration, every attempt will be made to 
perform repeat assessments until the values return to normal or baseline, or until
a new baseline is established as determined by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for preparing and transmitting AE, 
SAE, and other reportable safety event reports are shown in Appendix 4.
AEs, SAEs, and other reportable safety events will be reported by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator will detect, document, and report events that meet the definition of an 
AE or SAE as well as other reportable safety events. The investigator will also continue 
to follow up AEs, SAEs, and other reportable safety events for outcome according to 
Section 8.4.3.
The investigator will assess events that meet the definition of an AE or SAE as well as 
other reportable safety events with respect to seriousness, intensity/Grade and causality 
with the study drug.
8.4.1
Time Period and Frequency of Reporting AEs, SAEs, and Other 
Reportable Safety Events
All AEs, SAEs, and other reportable safety events that fall under any of the following 
criteria occurring after the consent form is signed but before treatment allocation will be 
reported by the investigator for only participants assigned to treatment: the event led to 
study withdrawal; and the event is the result of a protocol-specified medical intervention
(e.g., washout or discontinuation of usual therapy, diet, or a procedure).
From the time of treatment allocation through 14 days after study drug administration, all 
AEs, SAEs and other reportable safety events occurring will be reported by the 
investigator.
Additionally, any SAE brought to the attention of the investigator any time outside of the 
time period specified in the previous paragraph will also be reported immediately to the 
Sponsor if the event is considered “related” to the study drug.
 
 
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The investigator is not obligated to actively seek AE or SAE or other reportable safety 
events in former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
he/she considers the causality between the event and the study drug (or study 
participation) to be a reasonable possibility (related), the investigator must promptly 
report to the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded 
and reported to the Sponsor or designee within the time frames as indicated in Table 2.
Table 2
Reporting Time Periods and Time Frames for Adverse Events, Serious 
Adverse Events and Other Reportable Safety Events
Type of Event
Time Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
the Sponsor:
Consent to Allocation
Allocation through 
Protocol-Specified 
Follow-up Period
After the 
Protocol-Specified 
Follow-up Period
Non-Serious 
Adverse Event
Report if:
–
Due to 
protocol-specified 
medical intervention
–
Led to study 
withdrawal
Report all
Reporting not required
See the data 
handling 
guidelines
Serious Adverse 
Event including 
Cancer and 
Overdose
Report if:
–
Due to protocol-
specified medical 
intervention
–
Led to study
withdrawal
Report all
Report if:
–
considered “related” 
to the study drug
Follow-up ongoing 
events for outcome
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
–
Due to medical 
intervention
–
Led to study
withdrawal
Report all
Follow-up all reported 
pregnancies until 
completion/termination 
and report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (ECI)
(Require 
regulatory 
reporting)
Report if:
–
Due to medical 
intervention
–
Led to study
withdrawal
Report if:
–
Potential drug-induced 
liver injury (DILI)
–
Require regulatory 
reporting
Reporting not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (ECI)
(Do not require 
regulatory 
reporting)
Report if:
–
Due to medical 
intervention
–
Led to study
withdrawal
Report if:
–
Non- DILI ECIs not 
requiring regulatory 
reporting
Reporting not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Detection of AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE, SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
 
 
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8.4.3
Follow-up of AEs, SAEs, and other Reportable Safety Events
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety 
events (including ECIs, cancer, and overdose) will be followed until resolution or
stabilization, until the event is otherwise explained, or the participant is lost to follow-up 
(see Section 7.3). In addition, the investigator will make every attempt to follow all 
non-serious AEs that occur in participants assigned treatment for outcome. Detailed 
follow-up procedures are given in Appendix 4.
8.4.4
Regulatory Reporting Requirements for SAEs
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safe use of the study drug are met.
The Sponsor has a legal responsibility to notify local regulatory authorities about the 
safety information on the study drug. All AEs will be reported to regulatory authorities, 
IRB/IECs, and the principal investigator, etc. in accordance with all applicable global 
laws and regulations “the Ministerial Ordinance on Good Clinical Practice (GCP) for 
Drugs,” “the Ministerial Ordinance on Good Post-marketing Study Practice (GPSP) for 
Drugs,” and the “Ministerial Ordinance on Good Vigilance Practice for Drugs, 
Quasi-drugs, Cosmetics, and Medical Devices (GVP).”
Investigator safety reports will be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to the principal investigator, etc. as appropriate.
The principal investigator, etc. who receives an investigator safety report describing an 
SAE or other significant safety information (e.g., summary or listing of SAEs) from the 
Sponsor will file it along with the investigator’s brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since information on the pregnancy of 
participants’ female partners is not required for this study.
8.4.6
Disease-related Events/Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable.
8.4.7
Events of Clinical Interest (ECIs)
Non-serious AEs and SAEs specified as ECIs will be reported to the Sponsor.
 
 
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The following events are specified as ECIs for this study:
1)
An overdose of Sponsor's product, as defined in Section 8.5, that is not 
associated with clinical symptoms or abnormal laboratory results.
2)
An elevated aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) lab value that is greater than or equal to 3× the upper limit of normal and
an elevated total bilirubin lab value that is greater than or equal to 2× the upper 
limit of normal and, at the same time, an alkaline phosphatase (ALP) lab value 
that is less than 2× the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.†
† Note: These criteria are based upon U.S. regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. Refer to the 
Investigator Study File Binder (or equivalent) for the guidance for the 
assessment and follow up of participants meeting these criteria.
It may also be appropriate to conduct additional evaluation for an underlying etiology 
even in the setting of laboratory tests that do not meet the criteria for the reference 
specified above (AST, ALT, bilirubin, and ALP). In these cases, the decision to proceed 
with additional evaluation will be made by the investigator through a consultation with 
the Sponsor. However, abnormalities of liver blood tests that do not meet the criteria 
noted above are not ECIs for this study.
8.5
Treatment of Overdose
If a participant has taken, whether accidentally or intentionally, any drug as part of the 
study that exceeds the protocol-specified dose, the investigator will decide whether a dose 
is to be considered an overdose in consultation with the Sponsor.
8.6
Pharmacokinetics
Samples for the measurement of drug concentrations will be collected at time points 
specified in “1.3 Study Schedule.” Pharmacokinetic parameters will be calculated using 
the plasma MK-0518 concentrations measured.
8.6.1
Blood Collection for Plasma MK-0518 Concentrations
Refer to Appendix 1 for the procedures of plasma sample collection, processing, storage, 
and shipment.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
 
 
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8.8
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.9
Planned Genetic Analysis Sample Collection
No genetic analysis is planned in this study.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.11
Visit schedule
Visit schedule is specified in Section 1.3. Refer to Section 8 for specific procedures.
8.11.1
Screening
Within 3 weeks before study drug administration, the screening test will be performed, 
and potential participants will be evaluated to determine that they fulfill the inclusion 
criteria as set forth in Section 5. Screening procedures may be repeated as a result of 
consultation with the Sponsor.
Participants may be rescreened after consultation with the Sponsor. Rescreening will 
include all screening procedures specified in the study schedule, including a consent 
discussion.
8.11.2
Treatment Period
Participants will visit the study site on the day before the scheduled study drug 
administration and be admitted to the site until 48 hours after the administration.
8.11.3
Post-study examination
Participants will be required to return to the site 10 to 14 days after study drug 
administration for a post-study examination. If the post-study examination occurs less 
than 14 days after study drug administration, a subsequent follow-up telephone call will 
be made at 14 days after the administration or later to determine if any AEs have occurred 
since the post-study examination.
8.11.4
Critical Procedures Based on Study Objectives: Timing of Procedure
Secondary endpoints for this study will be evaluated using blood MK-0518 
concentrations.
At any post-dose time point, blood samples for the measurement of MK-0518 
concentrations need to be collected as the most exactly close to the specified time point as 
 
 
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possible. All other procedures will be completed as close to the specified time point as 
possible. Study procedures can be performed before or after the specified time points.
The order of priority for the procedures can be changed with joint agreement of the 
investigator and the Sponsor.
Any nonscheduled tests required for urgent evaluation of safety concerns take precedence 
over all prespecified procedures and items.
Variances from the specified times for the study procedures and sample collections will 
be permitted as follows:
•
Table 3 shows the time windows for sample collections for drug concentration 
measurements.
Table 3
Time Windows for Sample Collections for Drug Concentration Measurements
Sample Collection Time
Time Window
Before study drug administration
3 hours before to immediately 
before administration
0.5–12 hours after study drug administration
± 5 minutes
16–24 hours after study drug administration
± 15 minutes
48 hours after study drug administration
± 30 minutes
•
Pre-dose safety evaluations: vital signs and ECG at 3 hours before study drug 
administration; laboratory tests and physical examination at 24 hours before 
study drug administration
•
Post-dose safety evaluations (vital signs and laboratory tests)
1.
5 hours after study drug administration: within 15 minutes of the specified 
time
2.
4 hours after study drug administration: within 1 hours of the specified time 
(urine sample will be collected within 3 hours of the specified time)
8.11.5
Study Design/Dose/Procedures Modifications Permitted Within the 
Protocol Parameters
This study may employ some or none of the modifications described above. Any 
modifications meeting the study objectives will be described in a document by the 
Sponsor and agreed by the principal investigator. This document will be forwarded to the 
IRB/IEC at the discretion of the investigator.
9
Statistical Analysis Plan
9.1
Statistical Analysis Plan Summary
This section includes a statistical analysis plan summary for the study. The specific plan 
is provided in Section 9.2 of this study protocol.
 
 
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9.1.1
Statistical Methods
Safety
Summary statistics of the measured values and their changes from baseline will be 
provided for laboratory test results, 12-lead ECGs, and vital signs together with a graph as 
appropriate. The changes from baseline will be shown, calculated with the scales of 
measurements (actual changes from baseline), or calculated on the natural log scale and 
back transformed (percent changes from baseline), depending on safety variables.
Pharmacokinetics
Summary of Pharmacokinetic Parameters
Individual values will be listed for each pharmacokinetic parameter, for which the 
number of participants (the number of participants with no missing measurements), 
arithmetic mean, standard deviation, percent coefficient variation (CV) (100 × standard 
deviation/arithmetic mean), median, minimum, maximum, geometric mean, and 
geometric percent CV (100 × sqrt (exp (s2) – 1) will be calculated. The s2 here denotes an 
estimate of variance on the natural log scale. AUC0-∞, Cmax, and C24hr will be natural log 
transformed, and mean 95% confidence intervals will be calculated based on the t 
distribution. The confidence interval of geometric means will be provided with the scale 
of measurement by taking the lower and upper 95% confidence limits.
9.1.2
Statistical Power
The precision of the estimates of AUC0-∞and C24hr will be assessed by calculating the 
half-width of the 95% confidence intervals expected for the given sample size and 
assumed variability. Assuming a true standard deviation of 0.367 log-[μM•hr] and 0.590 
log-[nM] for natural log-AUC0-∞and C24hr between subjects as obtained from Study 812, 
then the half-width of the 95% confidence interval for the true mean AUC0-∞and C24hr on 
the natural log scale will be 0.233 log-[μM•hr] and 0.375 log-[nM]. The lower and upper 
95% confidence limits for the true geometric mean AUC0-∞and C24hr will be given by 
OBS/1.263 and OBS × 1.263, OBS/1.455 and OBS × 1.455, where OBS is the observed 
geometric mean. Thus, for example, if the observed geometric mean AUC0-∞was 50.1 
[μM•hr] and C24hr was 41.6 [nM], the 95% confidence interval would be 39.7 to 63.3 
[μM•hr] and 28.6 to 60.5 [nM], respectively.
9.2
Statistical Analysis Plan
Statistical analysis of data obtained in this study will be performed or supervised by the 
biostatistics department under cooperation of the translational pharmacology department. 
Once the study is initiated, any changes to the statistical analysis plan described below 
will be documented in the clinical study report along with the reasons for the changes.
9.2.1
Hypotheses/Estimation
See “3. Hypotheses, Objectives, and Endpoints.”
 
 
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9.2.2
Endpoints
Primary endpoints are all AEs, laboratory test results, 12-lead ECGs, and vital signs.
Secondary endpoints are plasma MK-0518
concentrations and pharmacokinetic
parameters (AUC0-∞, Cmax, C24hr, Tmax, apparent t1/2, CL/F, and Vz/F).
9.2.3
Analysis Populations
This section defines analysis populations. Data for all participants will be analyzed based 
on the treatment group in which individual participants have received administration.
All Subjects as Treated (AST): The set of all participants who have received at least 1 
dose of the study drug, to be used for safety and tolerability evaluations.
Per-Protocol (PP): A subset of participants meeting the protocol criteria likely to provide 
data that sufficiently reflect efficacy under the scientific model. Protocol adherence will 
be determined by measures such as the exposure to study drug, the availability of 
measurements, and the absence of significant protocol deviations. Significant protocol 
deviations will be identified by the personnel involved in the collection, analysis, and 
interpretation of data. The data of all participants excluded from analysis will be 
identified and documented in the clinical study report along with the reasons for 
exclusion. This set of participants will be included in the pharmacokinetic analysis.
9.2.4
Statistical Methods
Safety
Summary statistics of the measured values and their changes from baseline will be 
provided for laboratory test results, 12-lead ECGs, and vital signs together with a graph as 
appropriate. The changes from baseline will be shown, calculated with the scales of 
measurements (actual changes from baseline), or calculated on the natural log scale and 
back transformed (percent changes from baseline), depending on safety variables.
Summary Statistics
Pharmacokinetic parameters for each participant will be listed, for which the number of 
participants (the number of participants with no missing measurements), arithmetic mean, 
standard deviation, percent CV (100 × standard deviation/arithmetic mean), median, 
minimum, maximum, geometric mean, and geometric percent CV (100 × sqrt (exp (s2) –
1) will be calculated. The s2 here denotes an estimate of variance on the natural log scale. 
AUC0-∞, Cmax, and C24hr will be natural log transformed, and mean 95% confidence 
intervals will be calculated based on the t distribution. The confidence interval of 
geometric means will be provided with the scale of measurement by taking the lower and 
upper 95% confidence limits.
 
 
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Analysis of the pharmacokinetic similarity between Japanese and non-Japanese 
populations
For the analysis of pharmacokinetic similarity between Japanese and non-Japanese 
populations, pharmacokinetic parameters for a single dose of MK-0518 in Japanese and 
non-Japanese participants (Studies 812 and 824) will be compared in an exploratory 
manner. Pharmacokinetic parameters including AUC0-∞, Cmax and Tmax will be provided 
in graphs by race. AUC0-∞, C24hr and Cmax will be natural log transformed, for which 
geometric mean ratios and 90% confidence intervals will also be calculated based on the t 
distribution with a linear model having ethnicity (Japanese/non-Japanese) as a term.
9.2.5
Multiplicity
No multiplicity adjustments will be performed, since this study defines no hypotheses for 
testing.
9.2.6
Sample Size and Power Calculations
Precision of Pharmacokinetic Parameters
The precision of the estimates of AUC0-∞and C24hr will be assessed by calculating the 
half-width of the 95% confidence intervals expected for the given sample size and 
assumed variability. Assuming a true standard deviation of 0.367 log-[μM•hr] and 0.590 
log-[nM] for natural log- AUC0-∞and C24hr between subjects as obtained from Study 812 
in 12 subjects receiving raltegravir, then the half-width of the 95% confidence interval for 
the true mean AUC0-∞and C24hr on the natural log scale will be 0.233 log-[μM•hr] and 
0.375 log-[nM]. The lower and upper 95% confidence limits for the true geometric mean 
values will be given by OBS/1.263 and OBS × 1.263, OBS/1.455 and OBS × 1.455, 
where OBS is the observed geometric mean. Thus, for example, if the observed geometric 
mean AUC0-∞was 50.1 [μM•hr] and C24hr was 41.6 [nM], the 95% confidence interval 
would be 39.7 to 63.3 [μM•hr] and 28.6 to 60.5 [nM], respectively.
 
 
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10
Appendices (Supporting Documentation and Operational 
Considerations)
10.1
Appendix 1: Procedures for the Handling of Samples for Drug 
Concentration Measurements
Tools to be prepared
1)
Plastic vacuum blood collection tubes with EDTA-2K that can contain 4 mL of 
whole blood each (BD Vacutainer blood collection tube, brochure No. 367862; 
or Fischer blood collection tube, brochure No. 02-683-99C)
2)
3.6 mL cryotubes manufactured by NUNC (NUNC brochure No. 366524)
Note: No other tube than the one specified above (3.6 mL cryotubes by NUNC) 
should be used.
3)
Pipettes
Eppendorf Reference®
pipettes
1,000 µL (single channel) (International 
Eppendorf brochure No. 4900 000.524, North America article brochure No. 
022471651) or equivalents
4)
Pipette Tips
epTIPS Reloads 50–1250 µL containing 10
×
96 tips (brochure No. 
0030073487) or equivalents (made of polypropylene)
5)
Centrifuge
A centrifuge that can ensure a relative centrifugal force (RCF) of 1000 to 1500
(× g) for 10 minutes at 4°C to 10°C. The RCF depends on the radius of 
centrifuge rotor. The formula for calculating RCF from spin speed and the radius 
of centrifuge rotor is: RCF = 11.2 × r × (rpm/1000)2. The r here denotes the 
radius (cm) of rotor, and rpm the number of spins per minute set on the 
centrifuge. For example, a Beckman refrigerated centrifuge with a GH-3.8 rotor 
has a speed of 2500 rpm and a force of 1150 RCF.
6)
Freezer capable of ≤−20°C to −30°C operation
Blood collections
Blood collections will be performed at specified time points in accordance with the 
protocol study schedule.
Labeling on Samples
1)
Whole blood samples
Vacuum blood collection tubes will be properly labeled.
2)
Plasma samples
NUNC tubes will have a Sponsor-supplied barcode label attached. The label 
displays a treatment/randomization number, the date of sample collection, and 
blood collection point (time since administration). The label on the NUNC tube 
will be attached to the point 30% below the top to display the volume of split 
plasma. Only 1 sheet of label will be attached to each tube to ensure the 
appropriate functioning of autosampler.
 
 
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4 4
Pr oce d ure
1)
C ollect a p pr o xi matel y 4 mL of w h ole bl o o d usi n g a plastic vac u u m bl o o d 
c ollecti o n t u be wit h E D T A - 2 K, a n d mi x it b y  in verti n g 8 t o 1 0 ti mes. Attac h a n 
a p pr o priate la bel t o t he vac u u m bl o o d c ollecti o n t u be as descri be d a b o ve.
2)
C o ol t he t u be i n ice i m me diatel y after bl o o d c ollecti o n. Ce ntrif u ge it f or 1 0 
mi n utes at 4° C t o 1 0° C at a f orce of 1 0 0 0 t o 1 3 0 0 R C F
( × g). W he n a n 
i m me diate ce ntrif u ge is n ot p ossi ble, c o ol it i n ice a n d ce ntrif u ge it wit hi n 3 0 
mi n utes after bl o o d c ollecti o n.
3)
I m me diatel y after ce ntrif u gi n g w h ole bl o o d, ta ke w h ole v ol u me of plas ma usi n g 
a plastic pi pette a n d caref ull y ali q u ote it i nt o 3. 6 m L cr yot u bes b y  N U N C ( wit h a 
barc o de la bel attac he d). Plas ma sa m ples will be ke pt wit h dr y  ice at −2 0° C t o 
−3 0° C u ntil t he y  are s hi p pe d t o t he meas ure me nt site.
N ote: A pre vi o usl y  un use d plastic pi pette w ill be use d f or eac h sa m ple. W he n 
t he i m me diatel y processi n g of w h ole bl o o d sa m ples is n ot p ossi ble, c o ol t he m i n 
ice. Plas ma sa m ples will be freeze d wit hi n 6 0 mi n utes after bl o o d c ollecti o n.
S hi p me nt of sa m ples
T he pers o n nel i n v ol ve d i n t he pr ocessi n g, pac ki n g, a n d s hi p me nt of sa m ples will be 
i nstr ucte d b y  the pri nci pal i n vesti gat or t o perf or m o perati o ns i n acc or da nce wit h t he 
da n ger o us g o o ds re g ulati o ns esta blis he d b y  Inter nati o nal Air Tra ns p ort Ass ociati o n 
(I A T A).
1)
Sa m ple st ora ge b o xes will c o ntai n at least 1 0 k g of dr y  ice a n d ha ve a la bel 
stati n g “H U M A N S A M P L E S: N O NI N F E C TI O U S ” attac he d.
2)
Eac h batc h of sa m ple s hi p me nt will ha ve sa m ple i n ve nt or y attac he d.
3)
Sa m ples will be s hi p pe d at i nter vals pre vi o usl y c o nfir me d bet wee n t he S p o ns or 
a n d t he pri nci pal i n vesti gat or. Sa m ples will be s hi p pe d o n M o n da y  or T ues da y  
(Ja pa n ti me) t o reac h t he dr u g c o nce ntrati o n meas ure me nt site (S y ne os Healt h ) 
b y  Fri da y (l ocal ti me).
N ote: O n t he d a y  of s hi p me nt, S y ne o us Healt h
 will be 
i nf or me d of t he s hi p me nt ( S p o ns or na me, pr ot oc ol n u m ber, s hi p pi n g c o m pa n y, 
air bill n u m ber, s hi p per na me, tele p h o ne n u m ber, s hi p me nt date, t he n u m ber of 
pac ki n g b o xes s hi p pe d, t he t ype of sa m ples, t he n u m ber of sa m ples, a n d 
preca uti o ns f or t he ha n dli n g of sa m ples) via F A X
 or
E- mail
cc,
).
4)
Sa m ples will be s hi p pe d t o t he f oll o wi n g a d dress:
S y ne os Healt h
2 5 0 0 Ei nstei n
Q ue bec ( Q ué bec), G 1 P A 2, Ca na da
T E L :
N ote: Sa m ples will be ke pt at −2 0° C t o −3 0° C.
 
 
P P D
0 5 0 8 Z B
P P D
P P D
P P D
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10.2
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations
10.2.1
Guidelines for Clinical Study Operations
I.
Introduction
A.
Purpose
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., N.J., U.S.A. (MSD)
(including its subsidiaries) conducts clinical studies worldwide to evaluate the safety and 
effectiveness of its own products. MSD is committed to designing, implementing, 
conducting, analyzing and reporting these studies in compliance with the highest ethical 
and scientific standards. Protection of participants in clinical studies is the overriding 
concern in the design of clinical studies. In all cases, MSD clinical studies will be 
conducted in compliance with local laws and regulations (e.g., International Council for 
Harmonisation Good Clinical Practice [ICH-GCP]) and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki.
B.
Scope
Highest ethical and scientific standards must be endorsed for all clinical studies sponsored 
by MSD irrespective of the external party (parties) employed for their execution (e.g., 
contract research organizations, collaborative research institutes). This Guideline is not 
intended to apply to studies that are observational or retrospective. Further, this Guideline
does not apply to investigator-initiated clinical studies, which are not under the full 
control of MSD.
II.
Scientific Issues
A.
Study Conduct
1.
Study Design
Except for pilot or estimation trials, study protocols will be hypothesis-driven to assess 
safety, efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or 
comparator products. MSD may conduct outcome studies, studies to assess or validate 
various endpoints (outcome measures), or studies to determine participant preferences, etc. 
The design (e.g., participant population, duration, statistical power) must be adequate to 
address the specific purpose of the study. Participants must meet protocol-specified 
inclusion criteria to be enrolled in the study.
2.
Site Selection
MSD selects study sites based on medical expertise, access to appropriate participants, 
adequacy of facilities and relevant staff, previous performance in clinical studies, as well 
as financial considerations. Prior to study initiation, study sites are evaluated by MSD 
personnel to assess the ability to appropriately conduct the study.
3.
Site Monitoring/Scientific Integrity
Study sites are examined to assess compliance with the study protocol and general 
principles of Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
 
 
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completeness, and consistency by verifying them versus source documentation according 
to standard operating procedures. Per MSD policies and procedures, if fraud, 
scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues are 
investigated. When necessary, the study at the relevant site will be discontinued, and the 
responsible regulatory authorities and ethics review committees will be notified.
B.
Publication and Authorship
Regardless of study outcome, MSD commits to publish (e.g., submit a paper or give a 
presentation at a scientific meeting) primary and secondary results of the studies
registered to clinical trial registries for marketed products, according to the prespecified 
analysis plans. To the extent scientifically appropriate, MSD seeks to publish the results 
of other analyses that are important to patients, physicians, and payers. Some early phase 
or pilot studies are intended to be hypothesis-generating rather than hypothesis testing. In 
such cases, publication of results may not be appropriate since the study may be 
underpowered and/or due to the analyses complicated by statistical issues such as 
multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors. In summary, authorship should 
reflect significant contribution to the design and conduct of the study, performance or 
interpretation of the analysis, and writing of the manuscript. All named authors must be 
able to defend the study results and conclusions. MSD funding for the study will be 
acknowledged in publications.
III. Participant Protection
A.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Review
All clinical studies will be reviewed and approved by an IRB/IEC before being initiated at 
each study site. Significant changes or revisions to the protocol will be approved by the 
ethics committee prior to implementation, except changes required urgently to protect 
participant safety that may be enacted in anticipation of ethics committee approval. For 
each site, the ethics committee and the Sponsor (personnel specified in the procedures) 
will approve the ICF for participants.
B.
Safety
The guiding principle in decision-making in clinical studies is that participant protection 
is of primary importance. Potential participants will be informed of the risks and benefits 
of study participation as well as alternative courses of treatment, when enrolled in the 
study. At a minimum, study designs will take into account the local standard of care.
All participation in MSD clinical studies is voluntary. Participants enter the study only 
after informed consent is obtained. Participants may withdraw from an MSD study at any 
time, without any influence on medical care that may otherwise be available to them.
 
 
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C.
Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible. Unless required by law, only investigators, study collaborators, Sponsor (or 
representative), ethics committee, and/or regulatory authorities will have access to 
medical records that might identify the participant by name.
D.
Genetic Research
Genetic research will only be conducted in accordance with a protocol and informed 
consent form approved by an ethics committee.
IV. Financial Considerations
A.
Payments to Study Sites
Clinical studies are time- and labor-intensive. It is MSD’s policy to compensate study 
sites by fair procedures for the work performed in support of MSD trials. MSD does not 
pay any incentives to enroll participants in its studies. However, when enrollment is 
particularly challenging, additional payments will be discussed to compensate for 
recruiting efforts for that extra time was spent.
MSD does not pay for participant referrals. However, MSD may compensate physicians 
for time spent on chart review to identify potentially eligible participants.
B.
Clinical Research Funding
Informed consent forms will disclose that the study is sponsored by MSD and that the 
study site is being funded for performing the study. However, the ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial 
practices at the relevant institution. As noted above, all publications resulting from MSD 
studies will indicate MSD as the Sponsor.
C.
Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings) will be consistent with local guidelines and practices.
V.
Principal Investigator Commitment
Principal investigators will be expected to review and understand MSD’s Guidelines for 
Clinical Study Operations attached to the study protocol, and in signing the protocol, 
agree to support ethical and scientific standards provided in the guidelines.
10.2.2
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is investigators’ responsibility to comply 
with any such request.
 
 
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Investigators agree, if requested for disclosure of financial details by the Sponsor in 
accordance with the above regulations, to provide the Sponsor with accurate and 
complete information. Investigators further agree to provide this information on a 
Certification/Disclosure Form (commonly known as a financial disclosure form) provided 
by the Sponsor. Investigators 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 and regions that do not have laws protecting personal data.
10.2.3
Protection of Data
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be 
transferred.
Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to participants.
Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
IRB/IEC members, and by inspectors from regulatory authorities.
10.2.3.1
Confidentiality of Data
By signing this protocol, the principal investigator affirms to the Sponsor that information 
furnished to the principal investigator by the Sponsor will be maintained in confidence, 
and such information will be divulged to the IRB, IEC, or expert committee, affiliated 
institutions including the study site and employees, only under an appropriate 
agreement/understanding on confidentiality with such board or committee, affiliated 
institutions and employees. Data generated by this study will be considered confidential, 
except to the extent that it is included in a publication as provided in the Publication
section of this protocol.
10.2.3.2
Confidentiality of Participant Records
By signing this protocol, the principal investigator agrees that the Sponsor (or Sponsor 
representative), IRB/IEC, or regulatory authority representatives may consult study 
documents (hereinafter, direct access) and/or copy them to verify worksheet/CRF report 
form data. By signing the consent form, participants agree to these direct access and copy. 
If study documents will be photocopied during the process of verifying worksheet/CRF 
information, participants will be identified by individual unique codes only; full names
will be masked prior to transmission to the Sponsor.
By signing this protocol, the principal investigator agrees to treat participant data used 
and disclosed in connection with this study in accordance with all applicable privacy 
protection laws, regulations and rules.
 
 
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10.2.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and affiliation of each IRB/IEC that reviews 
and approves this study. The Sponsor is also required to document that each IRB/IEC 
meets regulatory and GCP requirements by obtaining 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.
10.2.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The 
Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practices, the Sponsor will support publication of 
multicenter studies only in their entirety and not as individual site data. In a multicenter 
study, coordinating investigators will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, investigators agree to provide all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to 
protect proprietary information and to provide comments.
Authorship eligibility will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.2.5
Study Registration and Results Posting
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 study is solely responsible for determining whether the study and its 
results are subject to the requirements for submission to http://www.clinicaltrials.gov,
www.clinicaltrialsregister.eu or other local registries. MSD will review the protocol, and 
register and update necessary information in accordance with applicable requirements. 
Registration and updates are not limited to FDAAA or the EMA clinical trial directive 
mandated studies. The information registered will allow participants to identify 
potentially appropriate studies for their disease conditions and obtain information on
appropriate study site locations and contact information by calling study contact center, 
etc.
By signing this protocol, the principal investigator acknowledges that the statutory 
obligations under FDAAA, the EMA clinical trials directive or other locally mandated 
registries are the obligations of the Sponsor and agrees not to submit any information 
about this study to those registries.
10.2.6
Compliance with Law, Audit, and Debarments
By signing this protocol, the principal investigator agrees to conduct the study in 
conformance with this protocol, GCP, and other applicable laws and regulations relating 
to the conduct of the study.
 
 
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The Guidelines for Clinical Study Operations, a collection of guides and considerations 
that govern the ethical and scientific conduct of clinical studies sponsored by MSD, is 
provided in this appendix.
The principal investigator agrees not to seek reimbursement from participants, their 
insurance providers, or from government programs related to medical benefit for 
procedures included as part of the study reimbursed by the Sponsor.
The principal investigator will promptly inform the Sponsor of any regulatory authority 
investigation and inspection conducted for this study.
The principal investigator agrees to provide the Sponsor with relevant information from 
investigation/inspection observations and findings to allow the Sponsor to assist in 
responding to any citations resulting from regulatory authority investigation/inspection,
and will provide the Sponsor with a copy of the proposed response for consultation before 
submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies legally or by a 
regulatory authority will not be allowed to conduct this study or participating in the study 
operations in any circumstances. The principal investigator will immediately notify the 
Sponsor in writing if any person who is involved in conducting the study is “debarred” or 
if any proceeding for debarment is pending or, to the best of the principal investigator’s 
knowledge, threatened.
10.2.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
principal investigator will verify that data records are accurate by physically or 
electronically signing the CRF.
Detailed information regarding Data Management procedures for this study will be 
provided separately.
The principal investigator must maintain accurate documentation (source data) that 
supports the information recorded in the CRF.
The principal investigator will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency investigations and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the principal 
investigator upon request and also shall be made available at the study site upon request 
for inspection, copying, review, and audit at reasonable times by representatives of the 
Sponsor or any regulatory authorities. For deficiencies detected in the study 
documentation and worksheets/CRFs, the principal investigator agrees to promptly take 
any appropriate measures that are requested by the Sponsor or any regulatory authorities 
as a result of an audit or investigation.
 
 
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The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that
data recorded in the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulations.
Records and documents, including signed ICF, pertaining to the conduct of this study will
be retained by the principal investigator for 15 years after study completion unless local 
regulatory requirements or institutional provisions require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.2.8
Source Documents
Source documents provide evidence for the existence of participants and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or eCRF that are transcribed from source documents must be 
consistent with the source documents, and reasons for any discrepancies must be 
explained. The principal investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be available.
10.2.9
Discontinuation of the Study, and Discontinuation of Study Site 
Participation
The Sponsor or its delegate may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons according to applicable 
regulations, rules and GCP. In the event the Sponsor prematurely terminates a particular 
study site, the Sponsor will promptly notify the study site’s IRB/IEC of that.
 
 
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10.3
Appendix 3: Clinical Laboratory Tests
The laboratory tests shown in Table 4 will be performed at the study site at each 
assessment point. However, blood sampling for laboratory tests (screening test, 24 hours 
before and after study drug administration) will be performed after confirming the elapse 
of at least 8 hours after a meal.
Table 4
Protocol-specified Safety Laboratory Tests
Laboratory Test 
Category
Parameters
Hematology
Platelet count
WBC count and differential: Neutrophils, 
lymphocytes, monocytes, eosinophils, basophils
RBC count
Hemoglobin
Hematocrit
Clinical 
Chemistry
Blood urea 
nitrogen
Potassium
AST
Total bilirubin (and direct 
bilirubin, if total bilirubin 
is elevated above the 
upper limit of normal)
Albumin
Chloride
Fasting blood glucose
Creatinine
Sodium
ALT
Total protein
Creatine kinase
Urinalysis
•
Specific gravity
•
Urinalysis for pH, glucose, protein and occult blood
•
Microscopy (if urine occult blood or protein is abnormal)
Other Tests
•
Serology: hepatitis B surface antigen, hepatitis C virus antibody, syphilis and 
HIV antigen and antibody (CRF completion not required)
•
Drug screen: benzodiazepines, barbiturates, tricyclic antidepressants, 
phencyclidines, stimulants, cannabis, cocaine, morphine (CRF completion 
not required)
The investigator must review each clinical laboratory result and document the results of 
review.
 
 
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10.4
Appendix 4: AE Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting
10.4.1
Definition of AE
AE Definition
•
An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of a study drug, whether or not 
considered related to the study drug.
•
Note: In other words, an AE denotes any unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a study drug.
•
Note: For purposes of AE definition, the use of a study drug (also referred to as 
Sponsor’s product in this Appendix) includes the use of any pharmaceutical 
product, biological product, vaccine, medical device, diagnostic agent, or 
protocol-specified procedure whether investigational (including placebo or 
active comparator product) or marketed, manufactured by, licensed by, provided 
by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test (hematology, clinical chemistry, or urinalysis) 
results or other abnormal safety assessments (e.g., ECG, imaging assessments, 
vital sign measurements), including those that worsen from baseline, or those
considered clinically significant in the medical and scientific judgment of the 
investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including an 
increase in frequency and/or intensity of the condition.
•
A new condition detected or diagnosed after the initiation of study drug 
administration whether or not it may have been present before the start of the 
study.
•
Signs, symptoms, or sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or sequelae of a suspected overdose of either study drug or a 
concomitant medication.
•
For any reports of overdose (whether accidental or intentional) with an 
associated AE, the AE term should reflect the relevant clinical symptom or 
abnormal test result. An overdose without any associated clinical symptoms or 
abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect” or “intentional overdose without 
adverse effect.”
•
Any new cancer or progression of pre-existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (e.g., endoscopy, appendectomy): a condition that 
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
 
 
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•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study, or such a present or detected 
disease(s) or condition(s) that does not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that 
has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.4.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions defined below are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
•
A “life-threatening” occurrence in the definition of “serious” refers to an event in 
which a participant was at risk of death at the time of its onset. It does not refer 
to an event, which hypothetically might have caused death, if it were more 
severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of the length of 
stay, including admission as a precautionary measure for observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing illness that has 
not worsened during the study is not an SAE. A clinical condition that is 
detected prior to the use of an MSD product is documented in the participant’s 
medical history.)
d.
Results in permanent or significant disability/incapacity
•
The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions.
•
This definition is not intended to include events of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In the offspring of a participant taking the study drug regardless of the time of 
diagnosis.
f.
Other medically important events
•
Medical or scientific judgment will be exercised in deciding whether SAE 
reporting is appropriate in the situations described below. Important medical 
events that, even if they are not immediately life-threatening or they do not result 
in hospitalization or death, may jeopardize the participant or may require 
medical or surgical intervention to prevent serious conditions listed in the above 
definition are usually considered serious.
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
 
 
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dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.4.3
Additional Events to be Reported in the Same Manner as SAE
Additional events that should be reported in the same manner as SAE
•
Events listed below, although not included in SAEs specified in ICH, are 
reportable to the Sponsor in the same timeframe as SAEs to meet certain local 
requirements. Therefore, these events are regarded as serious.
•
A new cancer (that is not a condition of the study)
•
An AE associated with an overdose
10.4.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital clinical records, laboratory reports, diagnostic 
reports) related to the event.
•
The investigator will enter all relevant AE/SAE information on the AE form on 
the CRF and worksheets.
•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of recording on the AE form of the CRF.
•
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers (with the 
exception of the participant number assigned for this study), will be blinded on 
the copies of the medical records before submission to the Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
“Severe” intensity of an AE is not a definition of an SAE. An event is classed as 
“serious” when it meets at least 1 of the conditions prespecified in the definition 
of an SAE.
•
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories:
•
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, but not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
•
Moderate: An event causing severe discomfort that interferes with normal 
everyday activities (for pediatric studies, definitely acting like something is 
wrong).
•
Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
 
 
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used for rating the intensity of an event; and both AE and SAE can be assessed 
as severe (for pediatric studies, extremely distressed or unable to do usual 
activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE 
will be provided by the investigator. A signature (autograph, seal, and initials are 
also acceptable)/date will be provided by the investigator on the source 
document or worksheet that supports the causality noted on the AE form, 
ensuring that a medically qualified assessment of causality was done. The 
document with a signature (autograph, seal, and initials are also acceptable) must 
be retained for the time frame specified in regulatory requirements. The 
assessment criteria below are intended as reference guidelines to assist the 
investigator in assessing the likelihood of a relationship between an AE and the 
Sponsor’s product based upon the available information.
•
The following conditions are to be used for causality assessment; the greater the 
correlation with these conditions and their respective criteria (the number of 
applicable items or intensity), the more likely the Sponsor’s product caused the 
AE:
•
Exposure to the Sponsor’s product: The presence or absence of evidence that the 
participant was actually exposed to the Sponsor’s product such as; a reliable 
dosing record, a reliable record of compliance assessment (pill count, participant 
diary, etc.), a record of the presence or absence of expected drug effect, or a 
record related to the measurement of drug/metabolite in the body
•
Temporal relationship: 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 an effect induced by the Sponsor’s product?
•
Likely cause: Is it unable to explain the AE reasonably by other cause than the 
Sponsor’s product (underlying disease, other drug(s)/vaccine(s), medical history 
or other participant or environmental factors)?
•
Dechallenge: Was the Sponsor’s product discontinued or its dose reduced?
•
Did the AE resolve or improve by discontinuation or dose reduction?
•
If “yes,” this is a positive dechallenge.
•
If “no,” this is a negative dechallenge.
Note: The dechallenge criterion is not applicable if:
(1) the outcome of the AE resulted in death or permanent disability
(2) the AE resolved/improved despite continuation of the study
product
(3) the study is a single-dose study
(4) Sponsor’s product(s) is/are used only 1 time
•
Rechallenge: Was the participant re-exposed to the Sponsor’s product?
•
Did the AE recur or worsen by re-exposure?
•
If “yes,” this is a positive rechallenge.
•
If “no,” this is a negative rechallenge.
Note: The rechallenge criterion is not applicable if:
 
 
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(1) the outcome of the AE resulted in death or permanent disability
(2) the study is a single-dose study
(3) Sponsor’s product(s) is/are used only 1 time
Note: If a rechallenge is planned for an AE that was serious and suspected to be 
relate to the Sponsor’s product, or if re-exposure to the Sponsor’s product poses 
additional potential significant risk to the participant, then the rechallenge must be 
approved in advance by the Sponsor development director/medical expertise, and if 
required, the IRB/IEC.
•
Consistency with study drug profile: Is the onset of the AE consistent with 
previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
•
The assessment of relationship will be documented on the CRFs/worksheets by 
an investigator according to his/her best clinical judgment, including 
consideration of the above elements.
•
Use the following criteria as guidance (not all criteria need to be met to be 
indicative of a relationship with the Sponsor’s product).
•
Related: There is a reasonable possibility of a relationship with the Sponsor’s 
product.
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 cause of the AE is more likely explained by the Sponsor’s 
product than by other factors (other drugs, underlying disease, medical history, 
or other participant or environmental factors).
•
Not related: There is not a reasonable possibility of a relationship with the 
Sponsor’s product.
The participant did not receive the Sponsor’s product, the temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is not 
reasonable, or the cause of the AE is more likely explained by another cause than 
the Sponsor’s product. (An overdose without an associated AE is also considered 
as “not related.”)
•
For each AE/SAE, the investigator must document in the medical records that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, 
even in such cases, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the SAE 
data to the Sponsor.
•
The investigator may change his/her opinion on causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements.
 
 
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Follow-up of AE and SAE
•
The investigator is obligated to arrange for the conduct of supplemental 
measurements and/or evaluations or perform them as medically indicated or as 
requested by Sponsor to elucidate the nature and/or causality of the AE or SAE 
as fully as possible. This may include additional laboratory tests or assessments, 
histopathological examinations, or consultation with other health care 
professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any additional information on SAE to the Sponsor 
within 24 hours of receipt of the information.
10.4.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor
SAE Reporting to the Sponsor via Paper CRF
•
If an electronic data collection tool is not operational at the study site, facsimile 
or secure e-mail transmission of a paper CRF (SAE report form) is the preferred 
method to report an SAE to the Sponsor.
•
In exceptional circumstances (e.g., in the absence of facsimile equipment), 
notification by telephone is acceptable with a copy of the paper CRF (SAE
report form) sent by overnight mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the paper CRF (SAE report form) within the specified 
reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can 
be found in the Investigator Study File Binder (or equivalent).
 
 
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10.5
Appendix 5: Criteria for 12-lead ECG Abnormalities
Criteria for 12-lead ECG Abnormalities
Drop-out of screening
Clinically meaningful finding after 
randomization
(criteria for the need of a measure)
Rhythm
Sinus tachycardia
> 110 bpm
Heart rate > 110 bpm and increased by 
≥25 bpm from baseline
Sinus bradycardia
< 40 bpm
Heart rate < 40 bpm and decreased by 
≥5 bpm from baseline
Sinus arrest/cardiac arrest
> 2.0 seconds
> 2.0 seconds
Atrial extrasystole
> 1 beat
≥3 beats
Ventricular extrasystole
All
≥3 beats
Ectopic atrial rhythm
Make an assessment along with other 
findings
Make an assessment along with other 
findings
Junctional rhythm
Junctional rhythm present and heart rate 
< 40 bpm
Junctional rhythm present and heart rate 
< 40 bpm
Idioventricular rhythm
All
All
Atrial fibrillation
All
All
Atrial flutter
All
All
Supraventricular tachycardia
All
All
Ventricular tachycardia
All
All
Axis
Left axis deviation
Right bundle branch block and left 
anterior fascicular hemiblock
New left anterior fascicular hemiblock
Right axis deviation
Right bundle branch block and left 
posterior fascicular hemiblock
New left posterior fascicular hemiblock
Conducting system
First degree AV block
PR interval ≥230 msec
PR interval ≥230 msec and prolonged 
by > 15 msec, or PR interval prolonged 
by > 25%
Second degree AV block
Mobitz II
Mobitz II
Third degree AV block
All
All
Left bundle branch block
All
All
Right bundle branch block
Right bundle branch block and left 
anterior fascicular hemiblock, or right 
bundle branch block and left posterior 
fascicular hemiblock
New right bundle branch block
(not including intermittent, associated 
with heart rate)
Incomplete right bundle branch 
block (ORS interval < 120 msec)
Not excluded
Not regarded as a clinically meaningful 
finding
Short PR interval/preexcitation 
syndrome
Delta wave present and PR interval 
< 120 msec
Delta wave present and PR interval 
< 120 msec
Other intraventricular delay
QRS ≥130 msec
QRS ≥130 msec and prolonged by 
≥10 msec
QTcB or QTcF interval
Male
QTc interval ≥ 470 msec
QTc interval ≥500 msec or prolonged by 
≥60 msec from baseline
Hypertrophy
Atrial abnormality
Definitive evidence of mitral P wave or 
P wave pulmonale
Definitive evidence of mitral P wave or 
P wave pulmonale
Ventricular abnormality
Strain pattern present in addition to the 
voltage criteria for left ventricular 
hypertrophy
Strain pattern present in addition to the 
voltage criteria for left ventricular 
hypertrophy
 
 
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Study Drug Name: MK-0518
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60
Criteria for 12-lead ECG Abnormalities
Drop-out of screening
Clinically meaningful finding after 
randomization
(criteria for the need of a measure)
Myocardial infarction
Acute or recent
All
All
Old
All
All
ST-T wave
ST-segment elevation suggestive 
of myocardiopathy
≥2 contiguous leads
≥2 contiguous leads
ST-segment reduction suggestive 
of myocardial ischemia
≥2 contiguous leads
≥2 contiguous leads
T-wave inversion suggestive of 
myocardial ischemia
≥2 contiguous leads
≥2 contiguous leads
Nonspecific ST-T change
(≥ 2 leads)
Not excluded
≥2 contiguous leads
Pacemaker
All
All
Baseline is defined as a measurement prior to study drug administration during the treatment period.
 
 
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61
10.6
Appendix 6: Algorithm for Assessing Abnormal Laboratory Values
Laboratory values obtained at the screening test and predose will be evaluated as follows.
a)
If all protocol-specified laboratory values are normal, the participant may enter the 
study.
b)
If a protocol-specified laboratory value does not meet the inclusion criteria or meets 
the exclusion criteria (including a repeat value if obtained), the participant will be 
excluded from the study.
c)
If a laboratory value not specified in the inclusion/exclusion criteria is outside the 
normal range, the following choices are available:
1.
The participant may be excluded from the study.
2.
The participant may be included in the study if the abnormal value(s) is not 
clinically significant (NCS) (the investigator must annotate the laboratory value 
“NCS” on the laboratory test source document).
3.
The participant may enter the study if the abnormality is due to a co-existing 
medical condition which is not excluded per protocol (e.g., elevated eosinophil 
count due to asthma or seasonal allergies) (the co-existing medical condition will 
be annotated as a cause on the laboratory test source document).
4.
The abnormal test may be repeated (with the following choices).
(a) If the repeat test value is within the normal range, the participant may enter 
the study.
(b) If the repeat test value is still abnormal, the investigator will evaluate the 
participant eligibility for enrollment with a complete history and physical 
examination, etc., looking especially for diseases that could result in the 
abnormal laboratory value in question. If such diseases can be ruled out, and 
if the abnormal laboratory value is not clinically relevant, then the 
participant may enter the study.
d)
If there is any clinical uncertainty regarding the reason for the abnormal value, the 
participant will be excluded from the study.
 
 
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St u d y D r u g N a me: M K - 0 5 1 8
P ost -mar keti n g C li nical St u d y P r ot oc ol Nu m ber -Versi o n N u m ber : 8 5 1- 0 0
6 2
1 0. 7
A p p e n d i x 7: St u d y A d mi ni str ati v e Str u ct ur e
1 0. 7. 1
S p o n s or
1 0. 7. 1. 1
S p o n s or N a m e a n d A d dr e s s
M S D K. K.
Kita n o mar u S q uare, 1 - 1 3-1 2, K u da n -kita, C hi y o da -k u, T o k y o 1 0 2- 8 6 6 7
1 0. 7. 1. 2
S p o n s or D e v el o p m e nt Dir e ct or
P ost -mar keti n g S ur ve y  Ma na ger
 Cli nical P har mac ol o g y  De vel o p me nt, Gl o bal Researc h a n d 
De vel o p me nt Di visi o n, M S D K. K.
Kita n o mar u S q uare, 1 - 1 3-1 2, K u da n -kita, C hi y o da -k u, T o k y o 1 0 2- 8 6 6 7
P h o ne:
  F A X : 
R ole of t he S p o ns or De vel o p me nt Direct or
T o lea d cli nical o perati o ns as t he S p o ns or de vel o p me nt direct or.
1 0. 7. 1. 3
M e di c al E x p erti s e
A ki n ori Urae ( p hys icia n), C hair ma n a n d C hief E xec uti ve Officer, Me discie nce Pla n n ni n g 
I nc.
1- 1 1- 4 4 A kasa ka, Mi nat o -k u, T o k y o 1 0 7- 0 0 5 2
P h o ne:
  FA X : 
1 0. 7. 1. 4
M o nit or ( R e pr e s e nt ati v e)
Pri mar y  Care Area,
St u d y  Operati o n De part me nt, Cli nical O perati o n Area , Gl o bal 
Researc h a n d De vel o p me nt Di visi o n, M S D K. K.
P h o ne: 
  F A X : 
C o li nical P har mac ol o g y De vel o p me nt De part me nt, Me discie nce Pla n n ni n g Inc.
P h o ne:
  F A X: 
1 0. 7. 2
C o ntr a ct R e s e ar c h Or g a ni z ati o n
1 0. 7. 2. 1
C o ntr a ct Or g a ni z ati o n f or M o nit ori n g, et c.
Cli nical P har mac ol o g y  De vel o p me nt De part me nt, Me discie nce Pla n n ni n g I nc.
1- 1 1- 4 4 A kasa k a, Mi nat o-k u, T o k y o 1 0 7- 0 0 5 2
P h o ne:
  F A X : 
 
 
P P D
0 5 0 8 Z B
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

St u d y D r u g N a me: M K - 0 5 1 8
P ost -mar keti n g C li nical St u d y P r ot oc ol Nu m ber -Versi o n N u m ber : 8 5 1- 0 0
6 3
R ole of t he C o ntract Or ga nizati o n f or M o nit ori n g, etc.
T o pre pare a pr ot oc ol ( draft) f or p ost -mar keti n g cli nical trials; pre pare a n I CF ( draft); 
pre pare a sa m ple C R F ( draft); perf or m m o nit ori n g, perf or m data ma na ge me nt; perf or m 
statistical a nal yses; pre pare a cli nical st u d y re p ort ( draft); a n d perf or m m o nit ori n g i n 
acc or da nce wit h G C P a n d G P S P as well as t he S p o ns or’s sta n dar d o perati n g pr oce d ures.
1 0. 7. 2. 2
M S D K. K. Cli ni c al St u d y E m er g e n c y C e nt er
BI Me dical, I nc.
B u n k y o Gree n C o urt Ce nter Office 1 0t h Fl o or, 2 - 2 8- 8 H o n k o ma g o me, B u n k y o -k u, 
T o k y o 1 1 3- 0 0 2 1
P h o ne:
R ole of M S D K. K. Cli nical St u d y  E mer ge nc y Ce nter
1)
C o ntact d uri n g o ut of office h o urs ( M o n da y to Fri da y : 1 8: 0 0 t o 9: 0 0 ne xt d a y . 
H oli da y s a n d M S D n o n-b usi ness da y s: 2 4 h o urs. )
1 0. 7. 3
C e ntr al L a b or at or y ( R e g ar di n g P ot e nti al Dr u g- i n d u c e d Li v er I nj ur y)
P P D Gl o bal Ce ntral L a bs
2 Tesse neer Dri ve, Hi g hla n d Hei g hts, K Y 4 1 0 7 6, U S A
P h o ne: 
R ole of Ce ntral La b orat or y  ( Re gar di n g P ote ntial Dr u g-i n d uce d Li ver I nj ur y )
1)
T o mea s ure part or all of t he Sta ge 1 a n d Sta ge 2 test para meters i n partici pa nts 
meeti n g t he criteria f or p ote ntial dr u g- i n d uce d li ver i nj ur y
2)
T o re p ort test data t o t he i n vesti gat or a n d t he S p o ns or
1 0. 7. 4
Dr u g C o n c e ntr ati o n L a b or at or y
S y ne os Healt h
2 5 0 0 r ue Ei nstei n, Q ué bec ( Q ué bec), Ca na da G 1 P 0 A 2
P h o ne: 
F A X : 
1 0. 7. 5
Pri n ci p al I n v e sti g at or
I nter nal Me dici ne, Se ki n o Cli nical P har mac ol o g y Cli nic
3 - 2 8-3 I ke b u k ur o, T os hi ma -k u, T o k y o
P h o ne:
 
 
P P D
0 5 0 8 Z B
P P D
P P D
P P D
P P D
P P D

Study Drug Name: MK-0518
Post-marketing Clinical Study Protocol Number-Version Number: 851-00
64
10.8
Appendix 8: Abbreviations
Abbreviation
Definition
AIDS
Acquired immune Deficiency Syndrome
AUC
Area Under the Plasma Concentration-Time Curve
BMI
Body Mass Index
C24hr
Plasma Concentration at 24 hours after Administration
CL/F
Apparent Total Clearance of the Drug from Plasma after Oral Administration
Cmax
Maximum Plasma Drug Concentration
CV
Coefficient of Variation
CYP
Cytochrome P450
DILI
Drug-Induced Liver Injury
DNA
Deoxyribonucleic Acid
ECI
Event of Clinical Interest
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FTC
Emtricitabine
GCP
Good Clinical Practice
GPSP
Good Post-Marketing Study Practice
HIV
Human Immunodeficiency Virus
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
NCS
Not Clinically Significant
OBS
Observed Geometric Mean
ONCEMRK
Evaluation of the Safety and Efficacy of Reformulated Raltegravir
(MK-0518) 1200 mg Once Daily in Combination With TRUVADA™ in
Human Immunodeficiency Virus (HIV)-1 Infected, Treatment-Naive 
Participants (MK-0518-292) (onceMRK)
P-gp
P-glycoprotein
RCF
Relative Centrifugal Force
RNA
Ribonucleic Acid
t1/2
Elimination half-life
TDF
Tenofovir Disoproxil Fumarate
Tmax
Time to Reach Maximum (peak) Plasma Concentration following Drug 
Administration
UDP
Uridine Diphosphate
Vz/F
Apparent Volume of Distribution during Terminal Phase after Non-Intravenous 
Administration
 
 
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11
References
Not Applicable
 
 
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6 6
[ C o ntact Inf or mati o n]
Cli nical P har mac ol o g y  De vel o p me nt, Cli nical Researc h Area ,
Gl o bal Researc h a n d De vel o p me nt Di visi o n, M S D K. K.
Kita n o mar u S q uare
1- 1 3- 1 2, K u da n -kita, C hi y o da -k u, T o k y o 1 0 2 -8 6 6 7
P h o ne: 
  F A X : 
Cli nical P har mac ol o g y  De vel o p me nt De part me nt,
Me discie nce Pla n n ni n g I nc.
P h o ne: 
  F A X : 
[O ut of Office H o urs E mer ge nc y  C o ntact I nf or mati o n]
M o n da y  t o Fri da y: 1 8: 0 0 t o 9: 0 0 ne xt da y .
H oli da y s a n d M S D n o n-b usi ness da y s: 2 4 h o urs.
M S D
Cli nical St u d y  E mer ge nc y Ce nter ( BI Me dical, I nc.)
P h o ne: 
 
 
P P D
0 5 0 8 Z B
P P D
P P D
P P D
P P D