Clinical trial NCT04995484
Conditions: Moderate Hepatic Impairment
Sponsor: Merck Sharp & Dohme LLC
Start date: 2022-06-24; Completion date: 2024-01-03
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to compare the plasma pharmacokinetics (PK) of belzutifan (MK-6482) following a single oral 80 mg dose of belzutifan in participants with moderate hepatic impairment to that of healthy matched control participants. This study will also evaluate the safety and tolerability of a single oral 80 mg dose of belzutifan in participants with moderate hepatic impairment.

Detailed description:

Arms: arm 1: Participants with moderate hepatic impairment will receive a single oral 80 mg dose of belzutifan on Day 1. arm 2: Participants with normal hepatic function will receive a single oral 80 mg dose of belzutifan on Day 1.
Interventions: intervention 1: Belzutifan
Intervention descriptions: intervention 1: Two 40 mg tablets given as a single oral 80 mg dose.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
An Open-Label, Single-Dose Study to
Investigate the Influence of Hepatic
Impairment on the Pharmacokinetics of MK-
6482
24-Nov-2022
NCT04995484


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Title Page 
 
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD). 
Protocol Title: An Open-Label, Single-Dose Study to Investigate the Influence of Hepatic 
Impairment on the Pharmacokinetics of MK-6482 
Protocol Number: 020-02 
Compound Number: MK-6482 
Sponsor Name: 
Merck Sharp & Dohme LLC 
(hereafter called the Sponsor or MSD) 
 
Legal Registered Address: 
126 East Lincoln Avenue 
PO Box 2000 
Rahway, New Jersey, 07065, USA 
Regulatory Agency Identifying Number(s): 
IND 
 
132,120 
 
 
Approval Date: 24 Nov 2022 
 
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Sponsor Signatory 
 
 
Typed Name: 
Title: 
 
Date 
 
 
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: 
Title: 
 
 
Date 
 
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DOCUMENT HISTORY 
 
Document 
Date of Issue 
Overall Rationale 
Amendment 02 
24-Nov-2022 
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address. 
Updates were also made to the statistical analysis language. 
Amendment 01 
23-Nov-2021 
Protocol amended per regulatory agency request to reduce 
the dose of MK-6482 to be administered from 120 mg to 
80 mg for all participants and to add the exclusion of 
UGT2B17 and CYP2C19 dual poor metabolizers. 
Original Protocol-Final 
26-MAY-2021 
Not applicable 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 02 
Overall Rationale for the Amendment:  
Sponsor underwent an entity name change and update to the address. Minor edits in the statistical analysis language were also made. 
Related sections within the protocol were updated to reflect these changes, as noted in chronological order below. 
Summary of Changes Table: 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
10.1.1 Code of Conduct 
for Clinical Trials 
Sponsor entity name and address change. 
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name 
change and update to the address. 
9.6.2 PK Statistical 
Analysis 
Minor corrections were made in the statistical 
analysis of PK. 
from: Separately for each PK parameter, 
individual values of MK-6482 AUC0-inf, 
AUC0-24, and Cmax will be natural log-
transformed and evaluated with a linear fixed 
effects model containing a fixed effect for 
population (hepatic impairment group and normal 
hepatic function group). 
Changes were made to correct details in the 
statistical analysis language. 
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Section # and Name 
Description of Change 
Brief Rationale 
to: Separately for each PK parameter, individual 
values of MK-6482 AUC0-inf, AUC0-24, and 
Cmax will be natural log-transformed and 
evaluated with a linear mixed effects model 
containing a fixed effect for population (hepatic 
impairment group and normal hepatic function 
group). 
 
from: Sample SAS code is given below: 
 
proc mixed data=data;  
 
class population;  
 
model lnpk = population /ddfm=kr;  
 
repeated/ group= population;  
 
lsmeans population /cl alpha=0.1; 
 
run;  
to: Sample SAS code is given below: 
 
proc mixed data=data;  
 
class population;  
 
model lnpk = population /ddfm=kr;  
 
repeated/ group= population type=UN;  
 
lsmeans population /cl alpha=0.1; 
 
run;  
 
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Section # and Name 
Description of Change 
Brief Rationale 
from: To compare participants with hepatic 
impairment to participants with normal hepatic 
function, a two sided 90% CI for the difference in 
means (hepatic impairment – normal hepatic 
function) will be calculated for each PK parameter 
using the mean square error from the model and 
referencing a t-distribution. 
to: To compare participants with hepatic 
impairment to participants with normal hepatic 
function, a two sided 90% CI for the difference in 
least-squares means (hepatic impairment – normal 
hepatic function) will be calculated for each PK 
parameter using the aforementioned model. 
 
 
 
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Amendment: 01 
Overall Rationale for the Amendment:  
To minimize the possibility of exposing participants to unanticipated higher exposures, the dose of MK-6482 in the study is being 
reduced to 80 mg and UGT2B17 and CYP2C19 dual poor metabolizers will be excluded from participation. 
Related sections within the protocol were updated to reflect these changes, as noted in chronological order below. 
Summary of Changes Table: 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Dose to be administered changed from MK-6482 
120 mg to 80 mg. 
Dose reduced to minimize the possibility of 
exposing participants with moderate hepatic 
impairment to unanticipated higher exposures. 
1.1 Synopsis 
3 Hypotheses, 
Objectives, and 
Endpoints 
The endpoints for the Secondary Objective revised 
from: AEs, clinical safety laboratory tests, ECGs, 
pulse oximetry, vital signs, and physical 
examinations 
to: AEs and discontinuation from study due to AEs 
Change made to align with the Sponsor’s 
anticipated disclosure of results on 
ClinicalTrials.gov. The full list of safety 
assessments for the study remain unchanged (see 
Sec. 4.2.1.2). 
1.3 Schedule of 
Activities 
Addition of blood collection for CYP2C19 
genotyping at Screening. 
CYP2C19 genotyping added for eligibility 
assessment. 
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Section # and Name 
Description of Change 
Brief Rationale 
2 Introduction 
Description of MK-6482 updated  
from: MK-6482 is a potent oral small molecule 
inhibitor of HIF-2α, and is currently being 
evaluated as a treatment option for patients with 
advanced renal cell carcinoma and von Hippel-
Lindau disease-associated renal cell carcinoma. 
to: MK-6482 (belzutifan) is a potent oral small 
molecule inhibitor of HIF-2α, that is indicated for 
the treatment of adult patients with VHL-RCC, 
CNS hemangioblastomas, or pancreatic 
neuroendocrine tumors not requiring immediate 
surgery. MK-6482 is also being evaluated as a 
treatment option for patients with solid tumor and 
patients with advanced RCC. 
Information updated to be more current. 
2.2.1 Pharmaceutical and 
Therapeutic Background 
Updated description of the results of preclinical 
study in mouse VHL-deficient tumor xenograft 
models. 
Information updated for consistency with the 
most recent Investigator’s Brochure (Edition 9). 
2.2.2.3 Clinical Studies 
2.2.3 Ongoing Clinical 
Studies 
Updated information on MK-6482 exposures and 
completed/ongoing studies. 
Added information on a case of multiple organ 
dysfunction syndrome reported in MK-6482-005. 
Information updated to be more current and to 
align with the most recent Investigator’s 
Brochure (Edition 9). 
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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall Design 
5 Study Population 
5.1.1 Inclusion Criteria 
for Participants With 
Healthy Hepatic 
Function 
5.1.2 Inclusion Criteria 
for Participants With 
Moderate Hepatic 
Impairment 
• Added the potential for male participants to have 
been surgically sterilized.  
• For male participants, the requirement for 
abstinence or contraception extended to at least 
7 days after study drug administration. 
• Flexibility added to allow for inclusion of male 
participants who have been surgically 
sterilized, but not vasectomized. 
• Timeframe for required abstinence or 
contraception revised to align with time needed 
for MK-6482 to be eliminated. 
5.2.1 Exclusion Criteria 
for Participants With 
Healthy Hepatic 
Function 
5.2.2 Exclusion Criteria 
for Participants With 
Moderate Hepatic 
Impairment 
Added the exclusion of participants with a 
UGT2B17 and CYP2C19 genotype consistent with 
a dual poor metabolizer phenotype. 
Exclusion criterion added to avoid unintended 
high MK-6482 exposure in study participants. 
4.1 Overall Design 
5 Study Population 
Added additional guidance in the case that a 
UGT2B17 PM moderate hepatic impairment 
participant is  enrolled in the study but a UGT2B17 
PM healthy matched control participant is not 
enrolled.  
Additional guidance added to provide clarity for 
the investigator. 
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Section # and Name 
Description of Change 
Brief Rationale 
4.3 Justification for Dose Added rationale for MK-6482 80 mg dose. 
Provided rationale for reduction of dose in the 
study to MK-6482 80 mg. 
8 Study Assessments and 
Procedures 
Revised maximum amount of blood collected from 
each participant over the duration of the study. 
Change due to addition of CYP2C19 genotyping 
assessment. 
8.1.3 Genotyping of 
UGT2B17 and 
CYP2C19 
Section added for the genotyping to be done at 
Screening. 
Addition of previously missed section. 
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
• Added the CYP2C19 genotyping to be done at 
screening.   
• Added erythropoietin test which was 
inadvertently missed in Table 7. 
• CYP2C19 genotyping added for eligibility 
assessment. 
• Addition of previously missed test in Table 7. 
10.8 Appendix 8: Blood 
Volume Table 
Added blood collection for CYP2C19 genotyping 
and updated total blood volume per participant. 
Change due to addition of CYP2C19 genotyping 
assessment. 
10.10 Appendix 10: 
Abbreviations 
Added the abbreviations “CNS”, “RCC” and 
“VHL-RCC.” 
Abbreviations added for completeness. 
11 References 
Removal of the reference “Kranidiotis GP, 
Voidonikola PT, Dimopoulos MK, Anastasiou-
Nana MI. Stauffer's syndrome as a prominent 
manifestation of renal cancer: a case report. Cases. 
J. 2009;2(1):49. Published 2009 Jan 13. 
doi:10.1186/1757-1626-2-49.” 
Reference removed as it is not cited in the 
protocol. 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Removal of gender-specific pronouns (eg, he/she, 
his/her). 
Adoption of gender neutral language. 
Throughout the protocol 
Minor editorial revisions. 
Correction of typos and other minor changes for 
clarity and/or to align with Sponsor protocol 
template changes. 
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Table of Contents 
DOCUMENT HISTORY .................................................................................................. 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................ 4 
1 
PROTOCOL SUMMARY ...................................................................................... 19 
1.1 
Synopsis ......................................................................................................... 19 
1.2 
Schema ........................................................................................................... 23 
1.3 
Schedule of Activities ..................................................................................... 24 
2 
INTRODUCTION ................................................................................................... 27 
2.1 
Study Rationale .............................................................................................. 27 
2.2 
Background.................................................................................................... 28 
2.2.1 
Pharmaceutical and Therapeutic Background .......................................... 28 
2.2.2 
Preclinical and Clinical Studies ............................................................... 28 
2.2.2.1 
Preclinical Pharmacokinetics and Metabolism ................................ 28 
2.2.2.2 
Preclinical Toxicology .................................................................. 29 
2.2.2.3 
Clinical Studies ............................................................................. 30 
2.2.3 
Ongoing Clinical Studies ........................................................................ 30 
2.3 
Benefit/Risk Assessment ................................................................................ 31 
3 
HYPOTHESES, OBJECTIVES, AND ENDPOINTS ............................................. 32 
4 
STUDY DESIGN ..................................................................................................... 33 
4.1 
Overall Design................................................................................................ 33 
4.2 
Scientific Rationale for Study Design ............................................................ 35 
4.2.1 
Rationale for Endpoints .......................................................................... 37 
4.2.1.1 
Pharmacokinetic Endpoints ........................................................... 37 
4.2.1.2 
Safety Endpoints ........................................................................... 37 
4.2.1.3 
Pharmacodynamic Endpoints ........................................................ 37 
4.2.1.4 
Planned Exploratory Biomarker Research ...................................... 37 
4.2.1.4.1 
Planned Genetic Analysis .................................................... 37 
4.2.1.5 
Future Biomedical Research .......................................................... 38 
4.3 
Justification for Dose ..................................................................................... 38 
4.4 
Beginning and End-of-Study Definition ........................................................ 39 
4.4.1 
Clinical Criteria for Early Study Termination .......................................... 39 
5 
STUDY POPULATION .......................................................................................... 39 
5.1 
Inclusion Criteria ........................................................................................... 40 
5.1.1 
Inclusion Criteria for Participants With Healthy Hepatic Function ........... 40 
5.1.2 
Inclusion Criteria for Participants With Moderate Hepatic Impairment ..... 41 
5.2 
Exclusion Criteria .......................................................................................... 43 
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5.2.1 
Exclusion Criteria for Participants with Healthy Hepatic Function ........... 43 
5.2.2 
Exclusion Criteria for Participants With Moderate Hepatic Impairment.... 45 
5.3 
Lifestyle Considerations ................................................................................ 48 
5.3.1 
Meals and Dietary Restrictions ............................................................... 48 
5.3.1.1 
Diet Restrictions ........................................................................... 48 
5.3.1.2 
Fruit Juice Restrictions .................................................................. 48 
5.3.2 
Caffeine, Alcohol, and Tobacco Restrictions ........................................... 48 
5.3.2.1 
Caffeine Restrictions ..................................................................... 48 
5.3.2.2 
Alcohol Restrictions ...................................................................... 49 
5.3.2.3 
Tobacco Restrictions ..................................................................... 49 
5.3.3 
Activity Restrictions ............................................................................... 49 
5.4 
Screen Failures .............................................................................................. 49 
5.5 
Participant Replacement Strategy ................................................................. 49 
6 
STUDY INTERVENTION ...................................................................................... 49 
6.1 
Study Intervention(s) Administered .............................................................. 50 
6.2 
Preparation/Handling/Storage/Accountability .............................................. 52 
6.2.1 
Dose Preparation .................................................................................... 52 
6.2.2 
Handling, Storage, and Accountability .................................................... 52 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................... 53 
6.3.1 
Intervention Assignment ......................................................................... 53 
6.3.2 
Stratification .......................................................................................... 53 
6.3.3 
Blinding ................................................................................................. 53 
6.4 
Study Intervention Compliance ..................................................................... 53 
6.5 
Concomitant Therapy .................................................................................... 53 
6.5.1 
Rescue Medications and Supportive Care ................................................ 55 
6.6 
Dose Modification (Escalation/Titration/Other) ............................................ 55 
6.7 
Intervention After the End of the Study ........................................................ 55 
6.8 
Clinical Supplies Disclosure ........................................................................... 55 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL ..................................................................................................... 55 
7.1 
Discontinuation of Study Intervention........................................................... 55 
7.2 
Participant Withdrawal From the Study ....................................................... 55 
7.3 
Lost to Follow-up ........................................................................................... 56 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 56 
8.1 
Administrative and General Procedures ....................................................... 57 
8.1.1 
Informed Consent ................................................................................... 57 
8.1.1.1 
General Informed Consent............................................................. 57 
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8.1.1.2 
Consent and Collection of Specimens for Future Biomedical 
Research ....................................................................................... 58 
8.1.2 
Inclusion/Exclusion Criteria ................................................................... 58 
8.1.3 
Genotyping of UGT2B17 and CYP2C19................................................. 58 
8.1.4 
Participant Identification Card ................................................................ 58 
8.1.5 
Medical History ..................................................................................... 58 
8.1.6 
Prior and Concomitant Medications Review ............................................ 58 
8.1.6.1 
Prior Medications .......................................................................... 58 
8.1.6.2 
Concomitant Medications .............................................................. 58 
8.1.7 
Assignment of Screening Number ........................................................... 58 
8.1.8 
Assignment of Treatment/Allocation Number ......................................... 59 
8.1.9 
Study Intervention Administration .......................................................... 59 
8.1.9.1 
Timing of Dose Administration ..................................................... 59 
8.1.10 
Discontinuation and Withdrawal ............................................................. 59 
8.1.10.1 
Withdrawal From Future Biomedical Research .............................. 60 
8.1.11 
Participant Blinding/Unblinding ............................................................. 60 
8.1.12 
Domiciling ............................................................................................. 60 
8.1.13 
Calibration of Equipment........................................................................ 60 
8.2 
Efficacy/Immunogenicity Assessments .......................................................... 61 
8.3 
Safety Assessments ......................................................................................... 61 
8.3.1 
Physical Examinations ............................................................................ 61 
8.3.2 
Vital Signs ............................................................................................. 61 
8.3.3 
Electrocardiograms................................................................................. 62 
8.3.4 
Pulse Oximetry ...................................................................................... 63 
8.3.5 
Clinical Safety Laboratory Assessments .................................................. 63 
8.3.6 
Photograph of Rash ................................................................................ 63 
8.4 
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events............................................................................................................. 63 
8.4.1 
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ...................................................... 64 
8.4.2 
Method of Detecting AEs, SAEs, and Other Reportable Safety Events ..... 66 
8.4.3 
Follow-up of AE, SAE, and Other Reportable Safety Event Information .. 66 
8.4.4 
Regulatory Reporting Requirements for SAE .......................................... 67 
8.4.5 
Pregnancy and Exposure During Breastfeeding ....................................... 67 
8.4.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs ...................................................................................... 67 
8.4.7 
Events of Clinical Interest ....................................................................... 68 
8.5 
Treatment of Overdose .................................................................................. 68 
8.6 
Pharmacokinetics ........................................................................................... 68 
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8.6.1 
Blood Collection for Plasma MK-6482 and PT3317 ................................ 69 
8.7 
Pharmacodynamics ........................................................................................ 69 
8.8 
Biomarkers .................................................................................................... 69 
8.8.1 
Planned Genetic Analysis Sample Collection .......................................... 69 
8.9 
Future Biomedical Research Sample Collection ............................................ 69 
8.10 
Health Economics Medical Resource Utilization and Health Economics ...... 69 
8.11 
Visit Requirements ........................................................................................ 70 
8.11.1 
Screening ............................................................................................... 70 
8.11.2 
Treatment Period .................................................................................... 70 
8.11.3 
Discontinued Participants Continuing to be Monitored in the Study ......... 70 
8.11.4 
Poststudy (Follow-up) ............................................................................ 70 
8.11.5 
Critical Procedures Based on Study Objectives: Timing of Procedure ...... 70 
8.11.6 
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters ................................................................................ 71 
9 
STATISTICAL ANALYSIS PLAN ........................................................................ 72 
9.1 
Statistical Analysis Plan Summary ................................................................ 72 
9.2 
Responsibility for Analyses ............................................................................ 72 
9.3 
Hypotheses/Estimation .................................................................................. 73 
9.4 
Analysis Endpoints ........................................................................................ 73 
9.5 
Analysis Populations ...................................................................................... 73 
9.6 
Statistical Methods ......................................................................................... 73 
9.6.1 
PK Descriptive Statistics ........................................................................ 73 
9.6.2 
PK Statistical Analysis ........................................................................... 74 
9.6.3 
Safety Analysis ...................................................................................... 75 
9.7 
Pharmacodynamics Analysis ......................................................................... 75 
9.8 
Interim Analyses ............................................................................................ 75 
9.9 
Multiplicity .................................................................................................... 75 
9.10 
Sample Size and Power Calculations ............................................................. 76 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS............................................................................................... 77 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....... 77 
10.1.1 
Code of Conduct for Clinical Trials ........................................................ 77 
10.1.2 
Financial Disclosure ............................................................................... 79 
10.1.3 
Data Protection....................................................................................... 80 
10.1.3.1 
Confidentiality of Data .................................................................. 80 
10.1.3.2 
Confidentiality of Participant Records ........................................... 80 
10.1.3.3 
Confidentiality of IRB/IEC Information ......................................... 81 
10.1.4 
Publication Policy .................................................................................. 81 
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10.1.5 
Compliance with Study Registration and Results Posting Requirements ... 81 
10.1.6 
Compliance with Law, Audit, and Debarment ......................................... 81 
10.1.7 
Data Quality Assurance .......................................................................... 82 
10.1.8 
Source Documents ................................................................................. 83 
10.1.9 
Study and Site Closure ........................................................................... 83 
10.2 
Appendix 2: Clinical Laboratory Tests ......................................................... 84 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting........................................................... 86 
10.3.1 
Definition of AE..................................................................................... 86 
10.3.2 
Definition of SAE .................................................................................. 87 
10.3.3 
Additional Events Reported .................................................................... 88 
10.3.4 
Recording AE and SAE .......................................................................... 88 
10.3.5 
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor .................................................................................................. 91 
10.4 
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ....................................................................................................... 93 
10.5 
Appendix 5: Contraceptive Guidance............................................................ 94 
10.5.1 
Definitions ............................................................................................. 94 
10.6 
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research ...................................................................................... 95 
10.7 
Appendix 7: Country-specific Requirements................................................. 99 
10.8 
Appendix 8: Blood Volume Table ................................................................ 100 
10.9 
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .... 101 
10.10 Appendix 10: Abbreviations ........................................................................ 102 
11 REFERENCES ..................................................................................................... 105 
 
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LIST OF TABLES 
Table 1 
Derivation of Child-Pugh Classification Score 1 ......................................... 35 
Table 2 
Determination of Hepatic Encephalopathy Grade 1 ..................................... 36 
Table 3 
Study Interventions ................................................................................... 51 
Table 4 
Allocation Schedule .................................................................................. 53 
Table 5 
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events .......................................................................... 65 
Table 6 
Postdose Pharmacokinetic (Blood) Collection Windows ............................ 71 
Table 7 
Protocol-required Safety Laboratory Assessments ...................................... 84 
 
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LIST OF FIGURES 
Figure 1 
Study Schema ........................................................................................... 23 
 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: An Open-Label, Single-Dose Study to Investigate the Influence of Hepatic 
Impairment on the Pharmacokinetics of MK-6482 
Short Title: MK-6482 Hepatic Impairment Study 
Acronym: Not Applicable  
Hypotheses, Objectives, and Endpoints: 
The following objectives will be evaluated in male and female participants with moderate 
hepatic impairment and matched control participants with normal hepatic function. 
Objectives 
Endpoints 
Primary 
 
• To compare the plasma PK of MK-6482 
following a single oral 80 mg dose of 
MK-6482 in participants with moderate 
hepatic impairment to that of healthy 
matched control participants. 
• Estimation: The plasma PK (AUC0-inf 
and Cmax) of MK-6482 following a 
single oral 80 mg dose of MK 6482 to 
participants with moderate hepatic 
impairment will be estimated and 
compared to those in healthy matched 
control participants. 
• AUC0-inf, AUC0-24, Cmax, Tmax, 
and apparent terminal t½ of plasma 
MK-6482. 
Secondary 
 
• To evaluate the safety and tolerability 
of a single oral 80 mg dose of MK-6482 
in participants with moderate hepatic 
impairment. 
• AEs and discontinuation from study 
due to AEs. 
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Overall Design: 
Study Phase 
Phase 1 
 
Primary Purpose 
Treatment 
 
Indication 
Renal Cell Carcinoma 
 
Population 
Adult male and female participants with moderate hepatic 
impairment and healthy adult male and female 
participants 
 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
This is a multi-site study 
 
Type of Control 
Healthy matched control participants 
 
Study Blinding 
Unblinded Open-label 
 
Blinding Roles 
No Blinding 
 
Estimated Duration of Study 
The Sponsor estimates that the study will require 
approximately 8 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact. 
Number of Participants: 
Approximately 16 participants will be allocated as described in Section 9.10. 
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Intervention Groups and Duration: 
Intervention 
Groups 
 
Intervention 
Group Name 
Drug 
Dose 
Level 
Dose 
Frequency 
Route of 
Administr
ation 
Treat
ment 
Period 
Use 
Moderate 
Hepatic 
Impairment 
Group 
MK-6482 
80 mg 
Single dose  
Oral 
1 day 
Experim
ental 
Healthy Control 
Group 
MK-6482 
80 mg 
Single dose  
Oral 
1 day 
Experim
ental 
Other current or former name or alias for study intervention is as follows: 
PT2977. 
 
Total 
Number of 
Intervention 
Groups/ 
Arms 
2 
 
Duration of 
Participation 
Each participant will participate in the study for approximately 6 weeks 
from the time the participant provides documented informed consent 
through the final contact.  
 
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Study Governance Committees: 
Executive Oversight Committee 
No 
 
Data Monitoring Committee 
No 
 
Clinical Adjudication Committee 
No 
 
There are no governance committees in this study. Regulatory, ethical, and study 
oversight considerations for the study are outlined in Appendix 1. 
Study Accepts Healthy Volunteers: Yes 
A list of abbreviations is in Appendix 10. 
 
 
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1.2 
Schema 
The study design is depicted in Figure 1. 
Figure 1 Study Schema 
 
 
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1.3 
Schedule of Activities 
All Groups 
 
Scr 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
-1 
(C-I) 
1 
2 
3 
4 
5 
6 
Poststudy (follow-up) will occur approximately 14 days 
after study intervention administration [Sec. 8.11.4]. 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Screening will occur within 28 days prior to study 
intervention administration [Sec. 8.1.1.1]. 
Informed Consent for Future Biomedical 
Research 
X 
 
 
 
 
 
 
 
 
Sec. 8.1.1.2. 
Assignment of Screening Number 
X 
 
 
 
 
 
 
 
 
Sec. 8.1.7. 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Only specific criteria will be reviewed at check-in. 
[Sec. 5.1 and 5.2]. 
Medical History 
X 
 
 
 
 
 
 
 
 
Includes review of substance usage (illicit drugs, alcohol, 
tobacco, and caffeine). 
Prior/Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sec. 6.5. 
Assignment of Treatment/Allocation 
Number 
 
 
X 
 
 
 
 
 
 
Sec. 8.1.8. 
Domiciling 
 
X 
X 
X 
X 
X 
X 
X 
 
Sec. 8.1.12. 
Safety Procedures 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
 
X 
To be conducted also for participants who 
discontinue/withdraw from the study. 
Symptom-driven Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
 
Only to be conducted if the participant’s symptoms 
warrant an examination or at the investigator’s or 
designee discretion. 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
X 
BMI to be calculated only at Screening. 
HR, BP, and RR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, and at 24, 48, 72, 96 
and 120 hours postdose, and poststudy or prior to early 
termination from the study. 
T 
X 
X 
X 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, and at 24, 48, 72, 96 
and 120 hours postdose, and poststudy or prior to early 
termination from the study. 
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All Groups 
 
Scr 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
-1 
(C-I) 
1 
2 
3 
4 
5 
6 
Poststudy (follow-up) will occur approximately 14 days 
after study intervention administration [Sec. 8.11.4]. 
12-lead ECG 
X 
X 
 
X 
 
X 
 
X 
X 
To be performed at Day -1, and at 24, 72, and 120 hours 
postdose, and poststudy or prior to early termination from 
the study. 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, and at 24, 48, 72, 96 
and 120 hours postdose, and poststudy or prior to early 
termination from the study. 
Child-Pugh Classification  
X 
 
 
 
 
 
 
 
 
To be for participants with hepatic impairment only. At 
least five (5) participants will be required to have total 
bilirubin within the range of >1.5X ULN and ≤3X ULN. 
NCI-ODWG Classification  
X 
 
 
 
 
 
 
 
 
To be for participants with hepatic impairment only. At 
least five (5) participants will be required to have total 
bilirubin within the range of >1.5X ULN and ≤3X ULN. 
Blood for UGT2B17 Genotyping 
X 
 
 
 
 
 
 
 
 
At least 2 UGT2B17 IM and at least 2 UGT2B17 EM 
will be enrolled per group. 
Blood for CYP2C19 Genotyping 
X 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal females 
only) 
X 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B and C screen  
X 
 
 
 
 
 
 
 
 
 
Urine/Saliva Drug Screen  
X 
X 
 
 
 
 
 
 
 
 
Urine/Blood/Breathalyzer Alcohol 
Screen 
X 
X 
 
 
 
 
 
 
 
 
Hem, Serum Chem, and UA 
X 
X 
 
X 
 
X 
 
X 
X 
To be performed at Day -1, and at 24, 72, and 120 hours 
postdose, and poststudy or prior to early termination from 
the study. 
Coagulation 
X 
 
 
 
 
 
 
 
X 
To be performed also for participants who 
discontinue/withdraw from the study. 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sec. 8.4 or poststudy contact details. 
Study Intervention Administration 
 
 
 
 
 
 
 
 
 
 
MK-6482 Administration 
 
 
X 
 
 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
Blood for Plasma MK-6482 and PT3317 
Assay 
 
 
X 
X 
X 
X 
X 
X 
 
To be collected at predose, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 
9, 12, 24, 36, 48, 72, 96, and 120 hours postdose. 
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All Groups 
 
Scr 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
-1 
(C-I) 
1 
2 
3 
4 
5 
6 
Poststudy (follow-up) will occur approximately 14 days 
after study intervention administration [Sec. 8.11.4]. 
Blood for Protein Binding 
 
 
X 
 
 
 
 
 
 
To be collected at predose. 
Pharmacodynamics 
 
 
 
 
 
 
 
 
 
 
Blood for Erythropoietin  
 
 
X 
X 
X 
X 
X 
X 
X 
To be collected at predose, and at 24, 48, 72, 96, and 120 
hours postdose and poststudy. 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
Blood for Genetic Analysis 
 
 
X 
 
 
 
 
 
 
To be collected predose from enrolled participants only 
[Sec. 8.8]. 
Abbreviations: AE=adverse event, BMI=body mass index, BP=blood pressure, C-I=check-in, Chem=chemistry, CRU=clinical research unit, CYP=cytochrome P450, 
ECG=electrocardiogram, EM=extensive metabolizer, EPO=erythropoietin, ET=early termination, FSH=follicle-stimulating hormone, Hem=hematology, HIV=human 
immunodeficiency virus, HR=heart rate, IM=intermediate metabolizer, NCI-ODWG=National Cancer Institute - Organ Dysfunction Working Group, RR=respiratory rate, SAE=serious 
adverse event(s), Scr=screening, T=body temperature, UA=urinalysis, UGT=uridine 5'-diphospho-glucuronosyltransferase. 
 
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2 
INTRODUCTION 
MK-6482 (belzutifan) is a potent oral small molecule inhibitor of HIF-2α, that is indicated 
for the treatment of adult patients with VHL-RCC, CNS hemangioblastomas, or pancreatic 
neuroendocrine tumors not requiring immediate surgery. MK-6482 is also being evaluated as 
a treatment option for patients with solid tumor and patients with advanced RCC. HIF-2α is a 
transcription factor that is overexpressed in many cancers and promotes tumorigenesis. 
HIF-2α forms a heterodimeric complex with HIF-1β (also called ARNT), and subsequently 
binds to hypoxic response elements of target genes which regulate hypoxic signaling, tumor 
cell growth and survival. MK-6482 binds to HIF-2α, preventing its heterodimerization with 
HIF-1β, and resulting in decreased transcription and expression of HIF-2α target genes. The 
proposed therapeutic dose of MK-6482 is 120 mg once daily.  
2.1 
Study Rationale 
The liver is involved in the clearance of many drugs through a variety of oxidative and 
conjugative metabolic pathways and/or through biliary excretion of the unchanged drug or 
metabolites. Alterations of excretion and metabolism by hepatic insufficiency can lead to 
lower drug clearance. Hepatic disease can alter the absorption and disposition of drugs as 
well as their efficacy and safety. In accordance with the FDA hepatic impairment guidance 
(FDA 2003), a Sponsor should evaluate the PK of its investigational drug in hepatic impaired 
participants when hepatic metabolism and/or excretion accounts for a substantial portion 
(>20% of the absorbed drug) of the elimination of the parent or active metabolite. 
In vitro, MK-6482 is a substrate of UGT2B17, CYP2C19 and CYP3A4. UGT2B17 and 
CYP2C19 are polymorphic enzymes and the relative contribution of these 2 enzymes to the 
elimination of MK-6482 has been elucidated by multiple means including an exploratory 
pharmacogenetic analysis, a population PK analysis, and a clinical evaluation of the impact 
of specific UGT2B17 and CYP2C19 variants on the single-dose PK of MK-6482. The 
collective results of these analyses indicate that UGT2B17 is the major route of elimination 
in individuals who express this enzyme. MK-6482 glucuronide (PT3317), represents the 
major circulating human metabolite formed by UGT2B17. Accordingly, PT3317 exposures 
are greatly reduced in participants who have decreased or absent UGT2B17 activity. In 
individuals with absent UGT2B17 activity, CYP2C19 is a major route of elimination. The 
overall contribution of CYP3A4 to MK-6482 metabolism is anticipated to be minor in 
individuals with intact UGT2B17 and CYP2C19 enzyme activity. A human ADME study 
(MK-6482-008) is currently ongoing, and anticipated to confirm that hepatic metabolism 
represents a major elimination pathway (>20% of the absorbed drug) for MK-6482. 
Since MK-6482 is anticipated to be predominantly eliminated by hepatic metabolism, 
evaluation of the impact of hepatic impairment on MK-6482 PK is useful. The primary 
objective of this study is to investigate the impact of moderate hepatic impairment on 
MK-6482 PK. 
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2.2 
Background 
Refer to the IB for detailed background information on MK-6482. 
2.2.1 
Pharmaceutical and Therapeutic Background 
MK-6482 is a potent and selective inhibitor of HIF-2α both in vitro and in vivo. HIF-2α is 
known to form a heterodimeric complex with HIF-1β, which is also referred to as ARNT; the 
heterodimer can then bind to hypoxic response elements in target genes and induce their 
transcription. The PAS domains of HIF are essential for heterodimerization of the 
HIF-2α:HIF-1β subunits, a prerequisite for target gene induction. A unique ligand-binding 
pocket has been identified in the PAS-B domain of HIF-2α (Scheuermann et al., 2013). 
MK-6482 binds in this pocket, thereby disrupting HIF-2α:ARNT heterodimerization and 
directly inhibiting the function of HIF-2α. 
In tumor cells in which HIF-2α is activated, MK-6482 block the transcription of several 
genes involved in oncogenesis, including cyclin D1, VEGF-A, and the glucose transporter 
SLC2A1. MK-6482 has showed antitumor activity in mouse VHL-deficient tumor xenograft 
models with nearly complete regression of established tumors after oral administration of 
MK-6482 at 0.3 mg/kg bid. No activity was observed with MK-6482 treatment in 
VHL-proficient ccRCC tumors. MK-6482 showed no off-target activity against a panel of 
76 receptors and 8 ion channels (at concentrations up to 12.5 µM), and no off-target activity 
at 10 µM against a panel of 40 protein kinases and 2 protein phosphatases. 
2.2.2 
Preclinical and Clinical Studies 
2.2.2.1 
Preclinical Pharmacokinetics and Metabolism 
MK-6482 PK was evaluated in mice, rats, dogs, and monkeys. MK-6482 has low aqueous 
solubility and high permeability (BCS Class 2) and is well absorbed following oral 
administration in animals at clinically relevant doses. The oral bioavailability of MK-6482 
was shown to be high in mice (approximately 100%), moderate in dogs and monkeys (33% 
and 53%, respectively), and low in rats (18%). The in vitro plasma protein binding of 
MK‑6482 ranged from 45 to 61% across species (45% in human plasma). 
Following an oral dose of [14C]MK-6482 in rats, radioactivity distributed rapidly to most 
tissues and was reversible. The mean overall recovery of dose ranged from 93.9% to 97.1%. 
Biliary excretion accounted for 85% and 80.2% of the radioactive dose in bile-duct 
cannulated male and female rats, respectively. 
In vitro and in vivo metabolism studies for MK-6482 revealed primarily oxidation and 
O glucuronidation biotransformation pathways. The oxidation biotransformation pathways 
were greatest in rats, and similar between humans and dogs. PT3317, the primary metabolite 
of MK-6482 found in dog and monkey plasma samples, was confirmed by chemical 
synthesis to be a glucuronide. UGT reaction phenotyping with recombinant UGTs was used 
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to determine that PT3317 formation is mediated by UGT2B17, which is mainly expressed in 
the small intestine. Importantly, PT3317 has no activity against HIF-2α. 
Urinary excretion was found to be a minor pathway for elimination of MK-6482 (≤4% of 
dose) and PT3317 (≤13% of dose) for rats, dogs and monkeys. 
A summary of MK-6482 nonclinical PK and metabolism is contained in the IB supplied by 
the Sponsor. The IB should be reviewed in conjunction with this study protocol. 
2.2.2.2 
Preclinical Toxicology 
MK-6482 was not genotoxic in the in vitro bacterial mutagenicity assay (Ames), nor in the in 
vitro micronucleus assay, indicating a low genotoxic risk from MK-6482 exposure. 
The in vivo safety pharmacology assessments of the cardiovascular, central nervous, and 
respiratory systems included in general toxicology studies did not yield any adverse findings. 
The cardiovascular system was assessed by hemodynamic and electrocardiographic 
parameters in the GLP 28-day and 13-week repeat-dose toxicity studies in dogs, and no 
change from baseline was observed with MK-6482 treatment. 
The toxicity of orally administered MK-6482 was evaluated in 28-day and 13-week repeat 
dose GLP studies in rats and dogs. Effects on the RBC compartment were observed 
consistently in both species, where RBC count, hemoglobin and hematocrit levels were 
decreased by approximately 30 to 50 % at all doses. The effects on the RBC compartment 
were reversed once MK-6482 administration stopped and are considered an “on-target” 
pharmacologic activity of HIF-2α antagonism on EPO production. 
In the rat toxicity studies with MK-6482, off-target organ toxicity was identified in the male 
reproductive system. The MK-6482 related effects involved testes (smaller/soft testes and 
decreased weight associated with hypo-spermatogenesis, germ cell degeneration and 
multinucleated giant cells), and epididymis (oligospermia), and were not reversible within 
26-week recovery periods. These findings were associated with decreased sperm motility and 
sperm counts, and increased number of abnormal sperms in the sperm analysis. No effects on 
sperm evaluation and histopathology of testes/epididymides were observed in male dogs. No 
effects on the female reproductive organs were observed in either rats or dogs. 
In a preliminary embryofetal toxicity study where pregnant rats were administered MK-6482, 
a significant level of post implantation loss indicative of embryofetal lethality and/or reduced 
fetal body weight, reduced ossification, and malformations in surviving fetuses was observed 
at an exposure close to the clinically relevant exposure at 120 mg/day.  
A summary of MK-6482 nonclinical toxicology is contained in the IB supplied by the 
Sponsor. The IB should be reviewed in conjunction with this study protocol. 
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2.2.2.3 
Clinical Studies 
As of a cutoff date of 15-JUN-2021, MK-6482 has been administered as single or multiple 
doses to a total of 135 healthy participants. In addition, MK-6482 is being evaluated as 
monotherapy or in combination with other anticancer treatments in participants with solid 
tumors. 
Based on the overall integrated safety summary of MK-6482 monotherapy (N=181) across 
MK-6482-001 and MK-6482-004 studies, the adverse drug reactions identified for MK-6482 
include anemia due to decreased EPO, fatigue, nausea, dyspnea, hypoxia, and dizziness. 
Most anemia events were ≤Grade 2. Anemia is an on-target effect of MK-6482 because of 
the impact of HIF on EPO expression and reduction in EPO and HGB levels with MK-6482 
administration. Anemia has been medically managed with erythropoiesis stimulating agent 
administration and/or blood transfusion as indicated and dose interruption/reduction. 
Hypoxia is managed by oxygen supplementation as indicated and dose 
interruption/reduction. Anemia due to decreased EPO and hypoxia should be closely 
monitored and medically managed as indicated. 
Single MK-6482 doses up to 200 mg have been evaluated in 4 completed single-dose Phase 1 
studies in healthy participants, and multiple daily doses up to 7 days of 120 mg have been 
administered to healthy participants in the completed midazolam DDI study (MK-6482-009). 
MK-6482 was generally well tolerated in these studies. All reported AEs were categorized as 
either mild or moderate in intensity. In healthy participant studies, there have been no SAEs 
and no discontinuations due to AEs attributed to MK-6482 treatment. There have been no 
reports of anemia, hypoxia, or fatigue in the completed healthy participant studies. In 
addition, no clinically significant reductions in HGB or HCT have occurred in healthy 
participants in the 4 completed single-dose Phase 1 studies. Mean reductions in HGB and 
HCT of about 12% from baseline were observed in the completed midazolam DDI study 
(MK-6482-009) after multiple daily doses of 120 mg, consistent with the anticipated on-
target effect of EPO suppression for MK-6482. 
A summary of the MK-6482 clinical development program is contained in the IB supplied by 
the Sponsor. The IB should be reviewed in conjunction with this study protocol. 
CCI
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 In the 
ongoing trials, MK-6482 appears to have a tolerable and manageable safety profile with low 
numbers of discontinuations due to an AE and most AEs being mild to moderate in severity. 
 
 The Sponsor considers 
that there is no conclusive evidence to support a causal relationship between MK-6482 and 
the aforementioned events since there were several confounding factors in the causality 
assessment reported for these AEs, including but not limited to prior/concomitant 
medications, daily alcohol consumption and possible concurrent illnesses. However, the 
Sponsor cannot definitively exclude the possibility of a causal relationship between 
MK-6482 treatment and the reported events. Of note, more than 600 participants with solid 
tumors/advanced RCC have received MK-6482 as monotherapy or in combination with other 
anticancer treatments and no other case of multiple organ failure has been reported. The 
Sponsor will continue to monitor the safety profile of MK-6482 in the clinical program. 
2.3 
Benefit/Risk Assessment 
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine. An indirect health benefit to the participants 
enrolled in this study is the free medical tests received at screening and during the study. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents. 
The safety monitoring practices employed by this protocol (ie, 12-lead ECG, pulse oximetry, 
vital signs, clinical laboratory tests, AE questioning, and physical examination) are adequate 
to protect the participants’ safety and should detect all expected treatment-emergent AEs. 
CCI
PPD
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3 
HYPOTHESES, OBJECTIVES, AND ENDPOINTS 
The following objectives will be evaluated in male and female participants with moderate 
hepatic impairment and matched control participants with normal hepatic function. 
Objectives 
Endpoints 
Primary 
 
• To compare the plasma PK of MK-6482 
following a single oral 80 mg dose of 
MK-6482 in participants with moderate 
hepatic impairment to that of healthy 
matched control participants. 
• Estimation: The plasma PK (AUC0-inf and 
Cmax) of MK-6482 following a single oral 
80 mg dose of MK 6482 to participants 
with moderate hepatic impairment will be 
estimated and compared to those in healthy 
matched control participants. 
• AUC0-inf, AUC0-24, Cmax, Tmax, 
and apparent terminal t½ of plasma 
MK-6482 
Secondary 
 
• To evaluate the safety and tolerability of a 
single oral 80 mg dose of MK-6482 in 
participants with moderate hepatic 
impairment. 
• AEs and discontinuation from study 
due to AEs. 
Tertiary/Exploratory 
 
• To compare the plasma PK profile of 
PT3317 following a single oral 80 mg dose 
of MK-6482 in participants with moderate 
hepatic impairment to that of healthy 
matched control participants 
• AUC0-inf, AUC0-24, Cmax, Tmax 
and apparent terminal t½ 
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• To evaluate and compare erythropoietin 
levels following a single oral 80 mg dose 
of MK-6482 in participants with moderate 
hepatic impairment to that of healthy 
matched control participants. 
• Erythropoietin levels 
• To explore the PK of MK-6482 following 
a single oral 80 mg dose of MK-6482 in 
participants with moderate hepatic 
impairment by the NCI classification. 
• AUC0-inf, AUC0-24, Cmax, Tmax, 
and apparent terminal t½ plasma 
MK-6482 
• To explore the relationship between 
genetic variation and response to the 
treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study. 
• Germline genetic variation and 
association to clinical data collected 
in this study. 
• To investigate the relationship between the 
genetic polymorphisms of UGT2B17 and 
CYP2C19 and the PK of MK-6482. 
Variation in UGTB17 and CYP2C19 
alleles may be analyzed for association 
with any laboratory or clinical data 
collected in this study. 
• Germline genetic variation in 
UGT2B17 and CYP2C19 and 
association to clinical data collected 
in this study. 
4 
STUDY DESIGN 
4.1 
Overall Design 
This is a nonrandomized, parallel-group, multi-site, open-label study of MK-6482 in 
participants with moderate hepatic impairment and healthy matched control participants.  
Screening of participants will occur within 28 days prior to study intervention administration. 
A total of approximately 16 adult male (vasectomized or surgically sterilized) and female 
(non-childbearing potential only) participants will be enrolled: 8 participants with moderate 
hepatic impairment and 8 matched control participants with normal hepatic function.  
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Assignment to hepatic function group will be as follows: 
Impairment Stage 
N 
Child-Pugh Score a 
Moderate 
8 b 
7-9 c 
Healthy 
8 b 
Not applicable 
a. A Child-Pugh classification will be performed only for participants with 
impaired hepatic function at Screening. 
b. At least 2 UGT2B17 IMs and at least 2 EMs will be enrolled per group. 
c. 
At least five (5) participants with moderate hepatic impairment will be required 
to have total bilirubin within the range of >1.5X ULN and ≤3X ULN. 
Following enrollment of all participants with moderate hepatic impairment, the healthy 
matched control participants will be enrolled. Each healthy control participant will be 
matched to the mean age (± 15 years) and mean BMI (±20%), sex (similar males/female ratio 
in each group), and UGT2B17 genotype (at least 2 IMs and 2 EMs) of participants with 
moderate hepatic impairment. If a UGT2B17 PM moderate hepatic impairment participant is 
enrolled in the study, a UGT2B17 PM healthy matched control participant will be included. 
If after reasonable efforts, a UGT2B17 PM healthy matched control participant is not 
enrolled, an additional participant with moderate hepatic impairment (ie, a 9th moderate 
hepatic impairment participant), who is not UGT2B17 PM, will be enrolled. This additional 
moderate hepatic impairment participant should be matched to the mean age (± 15 years) and 
BMI (± 20%) of the other 8 hepatically impaired participants. The final healthy matched 
control participant (ie, the 8th healthy control participant), who is also not UGT2B17 PM, 
should also be matched to the mean age (± 15 years), BMI (± 20%), and sex (with a similar 
male/female ratio in each group) of the 8 moderate hepatic impairment participants (ie, not 
including the 9th hepatically impaired participant). 
On Day 1, participants will receive a single oral dose of 80 mg MK-6482, followed by serial 
blood sampling collection up to 120 hours postdose to characterize the PK of MK-6482 and 
PT3317. Serial blood sampling will be collected up to poststudy for erythropoietin 
measurements. Safety will be monitored throughout the study. 
Because this is a Phase 1 assessment of MK-6482 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters. 
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8. 
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4.2 
Scientific Rationale for Study Design 
Available preclinical data indicate that MK-6482 is anticipated to be predominantly 
eliminated by hepatic metabolism, therefore hepatic impairment may affect the PK of 
MK-6482. The purpose of this study is to compare PK of MK-6482 in participants with 
moderate hepatic impairment to the PK in participants with normal hepatic function.  
This study employs healthy control participants with normal hepatic function that will be 
reasonably matched to the mean demographic parameters of the moderate hepatic 
impairment group to control for the influence of covariates.  
The sample size of approximately 8 participants enrolled in each group (moderate hepatic 
impairment and healthy control) has been selected following the FDA Guidance for Industry: 
Pharmacokinetics in Patients with Impaired Hepatic Function (FDA 2003). Additional 
participant(s) may be enrolled if a participant discontinues from the study before the 
completion of the PK assessment to ensure there are at least 8 evaluable participants in each 
group. 
The Child-Pugh classification (Table 1) will be used to categorize hepatic impairment due to 
its widespread use and acceptance by regulatory agencies (including the US FDA 
[FDA 2003]). The general study design is aligned with the relevant FDA guidelines for drugs 
that undergo substantial hepatic metabolism. A survey by the FDA of several PK studies 
conducted in participants with varying degrees of hepatic impairment, where Child-Pugh 
scale was used to assess hepatic impairment, has demonstrated a correlation between oral 
drug clearance and degree of hepatic impairment. In the current study, participants with 
chronic, stable moderate hepatic insufficiency will be enrolled using the Child-Pugh scale. 
The scale employs five clinical measures of liver disease as listed in Table 1 and Table 2. 
Assessment of each clinical measure is scored on a scale of 1 to 3, with 3 indicating most 
severe derangement. A composite of all five scores for each clinical measure is determined 
for each participant. Participants with composite scores of 7 to 9 on this Child-Pugh scale are 
classified as having moderate hepatic impairment.  
Table 1 
Derivation of Child-Pugh Classification Score 1 
Parameter 
1 point 
2 points 
3 points 
Serum albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
Total serum bilirubin (mg/dL) 
<2 
2 to 3 
>3 
International normalized ratio 
or prothrombin time (sec 
prolonged) 
<1.7 
<4 
1.7 to 2.2 
4 to 6 
>2.2 
>6 
Ascites 
Absent 
Slight or participant on 
one medication to 
control ascites 
Moderate or 
participant on 
medications to 
control ascites 
Hepatic encephalopathy grade 
(see Table 2)  
None 
Grade 1 or 2(or 
suppressed with 
medication)  
Grade 3 or 4 
 
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Table 2 
Determination of Hepatic Encephalopathy Grade 1 
Hepatic 
Encephalopathy 
Grade 
Definition 
0 
Normal consciousness, personality, neurological examination, 
electroencephalogram 
1 
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 
5 cycles/sec waves 
2 
Lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow 
triphasic waves 
3 
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower 
waves 
4 
Unrousable coma, no personality/behavior, decerebrate, slow 2 to 3 cycles/sec 
delta activity 
1 Adapted from U.S. Department of Health and Human Services. Guidance for Industry. 
Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, 
and Impact on Dosing and Labeling (2003). 
An alternative classification system for hepatic impairment has been developed by the NCI 
ODWG to guide chemotherapy dosing for NCI sponsored clinical trials (Patel et al., 2004). 
The NCI classification system is a simpler method to employ in a clinical practice setting 
since it uses 2 laboratory parameters to grade hepatic dysfunction: total bilirubin and 
aspartate aminotransferase. Of note, discordance between the Child-Pugh and NCI 
classifications for categorizing hepatic impairment was recently reported, which may have 
implications for dosing recommendations for oncology therapeutics (Elmeliegy et al., 2021). 
To ensure that the majority of participants in this study would be categorized as having 
moderate hepatic impairment using both classification methods, at least five (5) participants 
with moderate hepatic impairment will be required to have total bilirubin values at screening 
within the range of >1.5X ULN and ≤3X ULN. 
Mild hepatic impairment, as defined using the NCI classification, was not identified as a 
significant covariate based on a population PK analysis using concentration data across 
multiple MK-6482 clinical studies. Specifically, the geometric mean for steady-state AUC 
was ~1.37-fold for participants categorized as having mild hepatic impairment (N=8) 
compared to participants with normal hepatic function (N=109) (23.34 µg*h/mL versus 
17.06 µg*h/mL). As noted above, discordance between the Child-Pugh and NCI 
classifications for hepatic dysfunction was reported (Elmeliegy et al., 2021). Specifically, 
64.9%, 73.7%, and 61.5% of participants with mild, moderate, and severe hepatic 
impairment, respectively, via Child-Pugh were classified as at least 1 category less impaired 
via NCI. Since the Child-Pugh scale is more commonly used in PK studies in participants 
with hepatic impairment and recommended by both FDA and EMA for these types of 
studies, it will be used to determine participant eligibility and to assess hepatic impairment in 
this study.  
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4.2.1 
Rationale for Endpoints 
4.2.1.1 
Pharmacokinetic Endpoints 
The primary endpoints for this study will include the PK parameters of AUC0-inf and Cmax 
of MK-6482. Plasma PK parameters included in this primary endpoint will be evaluated and 
compared between participants with moderate hepatic impairment with Child-Pugh 
classification compared to participants with healthy hepatic function, using GMR and CI to 
assess differences between two groups. Additional PK parameters include AUC0-last, 
AUC0-24, Tmax, apparent terminal t½, C24, CL/F, and Vz/F. 
The exploratory endpoints will include comparison of MK-6482 PK parameters between 
participants with hepatic impairment by NCI classification compared to participants with 
healthy hepatic function.  
In addition to assessing the parent MK-6482 levels, the PT3317 metabolite PK parameters 
will be evaluated as exploratory endpoints in healthy and hepatically impaired participants. 
This assessment will help in understanding the role of hepatic impairment in formation of 
PT3317 metabolite. 
4.2.1.2 
Safety Endpoints 
Safety and tolerability of MK-6482 monotherapy has been studied in Phase 1 and Phase 2 
clinical studies. Overall, MK-6482 has a tolerable and manageable safety profile with low 
numbers of discontinuations due to an AE and most AEs being mild to moderate in severity. 
The most common adverse drug reactions identified based on the integrated aggregate safety 
assessment of all available information includes hypoxia, anemia, fatigue, dyspnea, 
dizziness. Therefore, the standard safety monitoring of AEs, physical examinations, 12-lead 
ECGs, pulse oximetry, vital signs, laboratory tests (hematology, serum chemistry, and 
urinalysis), obtained throughout the study should be adequate to assess safety and tolerability 
of MK-6482 in this study. 
4.2.1.3 
Pharmacodynamic Endpoints 
Circulating serum levels of erythropoietin will be used as a pharmacodynamic marker of 
MK-6482 activity. Erythropoietin expression is regulated by HIFs, therefore MK-6482 
inhibition of HIF is expected to cause erythropoietin reduction which could cause decrease in 
hemoglobin levels.  
4.2.1.4 
Planned Exploratory Biomarker Research 
4.2.1.4.1 
Planned Genetic Analysis 
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME; mechanism of action of the drug; disease etiology; and/or 
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molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a sample will be collected for DNA analysis from consenting participants. 
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions. 
In addition to studying variation across the human genome, UGT2B17 and CYP2C19 
polymorphisms will be investigated specifically for their impact on MK-6482 PK and drug 
response. 
4.2.1.5 
Future Biomedical Research 
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study. 
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6. 
4.3 
Justification for Dose 
The proposed MK-6482 dose for this trial is 80 mg daily. Since MK-6482 clearance is 
predicted to occur predominantly by hepatic metabolism, MK-6482 exposures in patients 
with moderate hepatic impairment are anticipated to be increased compared to healthy 
control participants. Based on a population PK analysis using concentration data across 
multiple MK-6482 clinical studies, the geometric mean for steady-state AUC for 120 mg 
daily is ~1.37-fold for participants categorized as having mild hepatic impairment (N=8) 
using the NCI classification compared to participants with normal hepatic function (N=109) 
(23.34 µg*h/mL versus 17.06 µg*h/mL). By leveraging the previously reported relationship 
between Child Pugh and NCI classifications (Elmeliegy M et al. 2021), the geometric mean 
for steady-state AUC for MK-6482 120 mg daily is estimated to be ~2.13-fold for 
participants categorized as having moderate hepatic impairment (Child-Pugh B) compared to 
participants with normal hepatic function (36.29 µg*h/mL versus 17.06 µg*h/mL). To 
minimize the possibility of exposing participants with moderate hepatic impairment to 
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unanticipated higher exposures, a lower dose (80 mg) than the clinical dose for MK-6482 
(120 mg) will be evaluated in this trial. 
Multiple daily doses of 240 mg daily and 120 mg twice daily of MK-6482 have been 
administered to patients with advanced solid tumors, which were associated with 1.5 and 
2.3-fold increases in AUC compared to 120 mg, respectively. The predicted higher exposures 
following a single 80 mg dose in patients with moderate hepatic impairment are within the 
range of observed exposures in the MK-6482 clinical development program. 
4.4 
Beginning and End-of-Study Definition 
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator). 
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open. 
4.4.1 
Clinical Criteria for Early Study Termination 
There are no prespecified criteria for terminating the study early. 
5 
STUDY POPULATION 
Vasectomized or surgically sterilized male participants and female participants of 
nonchildbearing potential between the ages of 18 and 75 years (inclusive) will be enrolled in 
this study.  
Participants with normal hepatic function will match to the mean demographic parameters of 
the moderate hepatic impairment group. Healthy control participants will be matched for the 
mean age (± 15 years), mean BMI (±20%), sex (similar males/female ratio in each group), 
and UGT2B17 genotype (at least 2 IMs and 2 EMs in each group). If a UGT2B17 PM 
moderate hepatic impairment participant is enrolled in the study, a UGT2B17 PM healthy 
matched control participant will be included. If after reasonable efforts, a UGT2B17 PM 
healthy matched control participant is not enrolled, an additional participant with moderate 
hepatic impairment (ie, a 9th moderate hepatic impairment participant), who is not UGT2B17 
PM, will be enrolled. This additional moderate hepatic impairment participant should be 
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matched to the mean age (± 15 years) and BMI (± 20%) of the other 8 hepatically impaired 
participants. The final healthy matched control participant (ie, the 8th healthy control 
participant), who is also not UGT2B17 PM, should also be matched to the mean age 
(± 15 years), BMI (± 20%), and sex (with a similar male/female ratio in each group) of the 
8 moderate hepatic impairment participants (ie, not including the 9th hepatically impaired 
participant). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
5.1.1 
Inclusion Criteria for Participants With Healthy Hepatic Function 
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria: 
Type of Participant and Disease Characteristics 
1. Is in good health based on medical history, physical examination, vital sign 
measurements, and ECGs performed at the prestudy (screening) visit and before 
administration of study intervention. 
2. Is in good health based on laboratory safety tests obtained at the prestudy (screening) 
visit and before administration of study intervention. Appendix 2 provides a table of 
laboratory safety tests to be performed. Appendix 9 provides an algorithm for the 
assessment of out-of-range laboratory values. 
3. Has a BMI 18.0-40.0 kg/m2, inclusive. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2. BMI must be within ± 20% of the 
mean BMI in the hepatic impairment group. 
Demographics 
4. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent. Age must be within ± 15 years of the mean age in the hepatic 
impairment group. 
Male Participants 
5. Male participants are eligible to participate if they have been vasectomized or undergone 
surgical sterilization for at least 4 months or more prior to study intervention 
administration and agree to the following during the intervention period and for at least 
7 days (time needed for MK-6482 to be eliminated) after administration of study 
intervention: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
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OR 
• Must agree to use contraception as detailed below: 
- 
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration. 
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Female Participants  
6. A female participant is eligible to participate if:  
– She is a WONCBP, as defined in Appendix 5. 
Informed Consent 
7. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR. 
5.1.2 
Inclusion Criteria for Participants With Moderate Hepatic Impairment  
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria: 
Type of Participant and Disease Characteristics 
1. With exception of the hepatic impairment, is in good health, in the opinion of the 
investigator, based on medical history, physical examination, vital sign measurements, 
and ECGs performed at the prestudy (screening) visit and before administration of the 
study intervention. 
2. With exception of the hepatic impairment, is in good health, in the opinion of the 
investigator, based on laboratory safety tests obtained at the prestudy (screening) visit 
and before administration of study intervention. Appendix 2 provides a table of 
laboratory safety tests to be performed. Appendix 9 provides an algorithm for the 
assessment of out-of-range laboratory values. 
3. Has a BMI 18.0-40.0 kg/m2, inclusive. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2.  
4. Has a score on the Child-Pugh scale of B (a score of 7-9 on Child-Pugh Score) at the 
prestudy (screening) visit. At least five (5) participants with moderate hepatic impairment 
will be required to have total bilirubin range within >1.5X ULN and ≤3X ULN. 
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5. Has a diagnosis of chronic (>6 months), stable (no acute episodes of illness within the 
previous 30 days from administration of study intervention due to deterioration in hepatic 
function) hepatic impairment. 
Demographics 
6. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent. 
Male Participants 
7. Male participants are eligible to participate if they have been vasectomized or undergone 
surgical sterilization for at least 4 months or more prior to study intervention 
administration and agree to the following during the intervention period and for at least 
7 days (time needed for MK-6482 to be eliminated) after administration of study 
intervention: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception as detailed below: 
- 
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration. 
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Female Participants  
8. A female participant is eligible to participate if:  
– She is a WONCBP, as defined in Appendix 5. 
Informed Consent 
9. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR. 
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5.2 
Exclusion Criteria 
5.2.1 
Exclusion Criteria for Participants with Healthy Hepatic Function  
The participant must be excluded from the study if the participant meets any of the following 
criteria: 
Medical Conditions 
1. Has a history of clinically significant endocrine, GI, cardiovascular, hematological, 
hepatic, immunological, renal, respiratory, genitourinary, or major neurological 
(including stroke and chronic seizures) abnormalities or diseases. Participants with a 
remote history of uncomplicated medical events (eg, uncomplicated kidney stones, as 
defined as spontaneous passage and no recurrence in the last 5 years from administration 
of study intervention, or childhood asthma) may be enrolled in the study at the discretion 
of the investigator. 
2. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years from administration of study 
intervention. Participants who have had situational depression may be enrolled in the 
study at the discretion of the investigator. 
3. Has a history of cancer (malignancy). 
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies that have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies that have 
been successfully treated ≥10 years prior to the prestudy [screening] visit). 
4. Has an estimated CrCl ≤70 mL/min based on the CG Equation. 
Cockcroft-Gault Equation:  
CrCl = (140-age[yr])(body wt [kg]) 
(72)(serum creatinine [mg/dL]) 
[When creatinine is measured in µmol/L, use this formula] 
CrCl = (140-age[yr])(body wt[kg]) 
(72)(serum creatinine [µmol/L] x 0.0113) 
For females, multiply the result by 0.85. 
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl. 
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5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or nonprescription drugs or food. 
6. Is positive for HBsAg, hepatitis C antibodies, or HIV. 
7. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit. 
Prior/Concomitant Therapy 
8. Is unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs (with the exception of prescription drugs that are approved by 
the investigator and Sponsor) or herbal remedies as indicated in Section 6.5 for the 
prohibited period of time. There may be certain medications that are permitted (see 
Section 6.5). 
9. Has received any nonlive vaccine starting from 14 days prior to study intervention or is 
scheduled to receive any nonlive vaccine through 30 days following study intervention. 
Exception: COVID-19 vaccine may be administered. Study intervention must be given at 
least 72 hours following or at least 48 hours prior to any COVID-19 vaccination. 
Prior/Concurrent Clinical Study Experience 
10. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to study intervention administration. The window will be 
derived from the date of the last study intervention administration in the previous study. 
Diagnostic Assessments 
11. Has a UGT2B17 and CYP2C19 genotype consistent with a dual poor metabolizer 
phenotype. 
12. Has hemoglobin level below the lower limit of the normal range at the prestudy 
(screening visit) or check-in. 
13. Has a pulse oximetry reading <92% at rest at the prestudy (screening visit) or check-in. 
14. Has a QTc interval >470 msec at the prestudy (screening visit) or check-in, has a history 
of risk factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history 
of long QT syndrome), has uncorrected hypokalemia or hypomagnesemia, is taking 
concomitant medications that prolong the QT/QTc interval.  
Other Exclusions 
15. Is under the age of legal consent. 
16. Is a heavy smoker or heavy user of nicotine-containing products (>20 cigarettes or 
equivalent/day). 
17. Smokers who do not agree to consume ≤10 cigarettes or equivalent/day from the time of 
the prestudy (screening) visit and until the last PK sample collection.  
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18. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages 
per day may be enrolled at the discretion of the investigator. 
19. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day. 
20. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 2 years prior to the prestudy (screening) visit. Participants 
must have a negative drug screen at the prestudy (screening) visit or before 
administration of study intervention. 
21. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study. 
22. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).  
23. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study. 
5.2.2 
Exclusion Criteria for Participants With Moderate Hepatic Impairment 
The participant must be excluded from the study if the participant meets any of the following 
criteria: 
Medical Conditions 
1. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years from administration of study 
intervention. Participants who have had situational depression may be enrolled in the 
study at the discretion of the investigator. 
2. Has a history of cancer (malignancy). 
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies that have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies that 
have been successfully treated ≥10 years prior to the prestudy [screening] visit). 
3. Has an estimated CrCl ≤60 mL/min based on the CG Equation. 
Cockcroft-Gault Equation:  
CrCl = (140-age[yr])(body wt [kg]) 
(72)(serum creatinine [mg/dL]) 
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[When creatinine is measured in µmol/L, use this formula] 
CrCl = (140-age[yr])(body wt[kg]) 
(72)(serum creatinine [µmol/L] x 0.0113) 
For females, multiply the result by 0.85. 
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl. 
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (ie, systemic 
allergic reaction) to prescription or nonprescription drugs or food. 
5. Has fluctuating or rapidly deteriorating hepatic function within the prestudy (screening) 
period, in the opinion of the investigator. 
6. History of liver or other solid organ transplantation. 
7. Has transjugular intrahepatic portosystemic shunt and/or has undergone portacaval 
shunting. 
8. Has encephalopathy Grade 3 or worse within 28 days before administration of study 
intervention. 
9. Is positive for HIV. HBsAg positive participants are allowed to enroll if HBV DNA is 
below 1000 copies/mL in the plasma. Participants who are positive for HCVAb can be 
enrolled but must not have detectable HCV RNA in the plasma. 
10. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit. 
Prior/Concomitant Therapy 
11. Is unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs (with the exception of prescription drugs that are approved by 
the investigator and Sponsor) or herbal remedies as indicated in Section 6.5 for the 
prohibited period of time. There may be certain medications that are permitted (see 
Section 6.5). 
12. Has received any nonlive vaccine starting from 14 days prior to study intervention or is 
scheduled to receive any nonlive vaccine through 30 days following study intervention. 
Exception: COVID-19 vaccine may be administered. Study intervention must be given 
at least 72 hours following or at least 48 hours prior to any COVID-19 vaccination. 
Prior/Concurrent Clinical Study Experience 
13. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to study intervention administration. The window will be 
derived from the date of the last study intervention administration in the previous study. 
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Diagnostic Assessments 
14. Has a UGT2B17 and CYP2C19 genotype consistent with a dual poor metabolizer 
phenotype. 
15. Has hemoglobin level below 9.5 g/dL at the prestudy (screening visit) or check-in. 
Participants with hemoglobin ≥9.0g/dL may be enrolled to the study at discretion of the 
investigator and following consultation with the Sponsor. 
16. Has a pulse oximetry reading <92% at rest at the prestudy (screening visit) or check-in. 
17. Has a QTc interval >480 msec at the prestudy (screening visit) or check-in, has a history 
of risk factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family 
history of long QT syndrome), has uncorrected hypokalemia or hypomagnesemia, is 
taking concomitant medications that prolong the QT/QTc interval.  
Other Exclusions 
18. Is under the age of legal consent. 
19. Is a heavy smoker or heavy user of nicotine-containing products (>20 cigarettes or 
equivalent/day). 
20. Smokers who do not agree to consume ≤10 cigarettes or equivalent/day from the time of 
the prestudy (screening) visit and until the last PK sample collection.  
21. Consumes greater than 3 glasses of alcoholic beverages or equivalent (1 glass is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or 
distilled spirits [29.5 mL/1 ounce]) per day. Participants who consume 4 glasses of 
alcoholic beverages per day may be enrolled at the discretion of the investigator. 
22. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day. 
23. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 2 years prior to the prestudy (screening) visit. Participants 
must have a negative drug screen at the prestudy (screening) visit or before 
administration of study intervention. 
24. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study. 
25. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).  
26. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study. 
 
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5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
5.3.1.1 
Diet Restrictions 
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Appendix 2. 
On Day 1, participants will fast from all food and drinks, except water, for at least 10 hours 
before study intervention administration and until at least 4 hours postdose. Thereafter, there 
will be no restrictions (other than those provided in Section 5.3.1) regarding meals and 
snack(s). While in the CRU, participants will fast from all food and drinks except water 
between meals and snacks. Otherwise, there are no dietary restrictions other than those 
defined below. 
After study intervention administration, if a participant exhibits symptom(s) of 
hypoglycemia, a sugary beverage may be provided at the discretion of the investigator, and 
must be documented. 
Water will be provided during study intervention administration. Water will be restricted 
1 hour before and 1 hour after study intervention administration. 
5.3.1.2 
Fruit Juice Restrictions 
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the study intervention, 
throughout the study and until the last PK sample collection. 
Participants also will refrain from the consumption of all fruit juices at least 24 hours before 
and after study intervention administration. On all other days during the study, consumption 
of fruits and fruit juices (except for grapefruit juice, grapefruits, and grapefruit products) is 
allowed. 
5.3.2 
Caffeine, Alcohol, and Tobacco Restrictions 
5.3.2.1 
Caffeine Restrictions 
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from at least 12 hours before the prestudy and poststudy visits and from at least 
12 hours before and after study intervention administration. At all other times, caffeinated 
beverages or xanthine-containing products will be limited to no more than 6 servings per day 
(1 unit = 120 mg of caffeine). 
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5.3.2.2 
Alcohol Restrictions 
Participants will refrain from consumption of alcohol at least 24 hours before the prestudy 
and poststudy visits and from at least 48 hours before study intervention administration and 
until last PK sample collection. At all other times, alcohol consumption is limited to no more 
than approximately 3 glasses of alcoholic beverages or equivalent (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. 
5.3.2.3 
Tobacco Restrictions 
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the CRU. 
5.3.3 
Activity Restrictions 
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the of study 
intervention, throughout the study (including washout intervals between treatment periods) 
and until the poststudy visit. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen-failure information may be 
included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen-failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.  
5.5 
Participant Replacement Strategy 
If a participant withdraws from the study a replacement participant may be enrolled if 
deemed appropriate by the investigator and Sponsor. The replacement participant will 
generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique 
treatment/allocation number. The study site should contact the Sponsor for the replacement 
participant’s treatment/allocation number. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
Clinical supplies (eg, MK-6482) will be packaged to support enrollment and replacement 
participants as required. When a replacement participant is required, the Sponsor or designee 
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needs to be contacted before dosing the replacement participant. Clinical supplies will be 
affixed with a clinical label in accordance with regulatory requirements. 
6.1 
Study Intervention(s) Administered 
The study intervention to be used in this study is outlined in Table 3. 
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Table 3 
Study Interventions 
Arm Name 
Arm Type 
Intervention 
Name 
Intervention 
Type 
Dose 
Formulation 
Unit Dose 
Strength 
Dosage 
Level 
Route of 
Administration
Treatment 
Period 
Use 
IMP/ 
NIMP 
Sourcing 
Moderate 
Hepatic 
Impairment 
Group 
 
Experimental 
 
MK-6482 
 
Drug 
 
Tablet 
 
40 mg 
 
80 mg 
 
Oral 
 
1 day 
 
Experimental 
 
IMP 
 
Sponsor 
 
Healthy 
Control 
Group 
Experimental 
MK-6482 
Drug 
Tablet 
40 mg 
80 mg 
Oral 
1 day 
Experimental 
IMP 
Sponsor 
IMP=investigational medicinal product; NIMP=noninvestigational medicinal product. 
The classification of IMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed. 
 
 
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All supplies indicated in Table 3 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc). 
Refer to Section 8.1.9 for details regarding administration of the study intervention. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Dose Preparation 
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3. 
6.2.2 
Handling, Storage, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations. 
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6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Intervention Assignment  
Each participant will be assigned a unique identification number upon screening. Participants 
who complete the study screening assessments and meet all the eligibility criteria will be 
assigned a unique treatment/allocation number at the time of dosing, different from the 
screening number, and will receive the study intervention. 
Participants will receive the treatment on one occasion, as depicted in Table 4. 
Table 4 
Allocation Schedule 
Group 
N 
Treatment 
Moderate hepatic impairment 
participants 
8 
80 mg MK-6482 
Healthy participants 
8 
80 mg MK-6482 
6.3.2 
Stratification 
No stratification based on age, sex, or other characteristics will be used in this study. 
6.3.3 
Blinding 
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered. 
6.4 
Study Intervention Compliance 
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the 
participants have swallowed the study intervention. Once a participant has finished the 
dosing water, the qualified designee will use a flashlight and a tongue depressor to check the 
participant’s mouth. Participants’ hands will also be verified to ensure that the study 
intervention was ingested. 
6.5 
Concomitant Therapy 
Participants with Hepatic Impairment Only 
Participants with moderate hepatic impairment, who are taking medications to treat 
manifestations of hepatic disease or medications needed to treat stable diseases (eg, diuretics, 
angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta-blockers, 
lactulose, or rifaximin or antibiotics used for spontaneous bacterial peritonitis like 
fluoroquinolones) may be allowed to participate in the study at the discretion of the 
investigator and following consultation with the Sponsor. Participants are required to be on 
stable medication regimen (steady-dose, drug, and regimen) for at least 14 days before 
administration of study intervention and be able to withhold the use of their maintenance 
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medication until after at least 4 hours postdose. Phosphate binders containing aluminum, 
calcium, or lanthanum salts; iron supplements or other metal cations; or multivitamins 
containing iron or zinc must be withheld for at least 8 hours before administration of study 
intervention and for at least 6 hours postdose. 
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
during the ongoing study (ie, after intervention allocation)] must first be discussed between 
the investigator and Sponsor before administration, unless appropriate medical care 
necessitates that therapy or vaccination should begin before the investigator and Sponsor can 
consult. The participant will be allowed to continue in the study if both the Sponsor and the 
investigator agree. 
Participants with Normal Hepatic Function Only 
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of 
study intervention administration, they may be included in the study if the investigator can 
rationalize that the specific use of a prior medication is not clinically relevant within the context 
of the study. 
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
during the ongoing study (ie, after intervention allocation)] must first be discussed between 
the investigator and Sponsor before administration, unless appropriate medical care 
necessitates that therapy or vaccination should begin before the investigator and Sponsor can 
consult. The participant will be allowed to continue in the study if both the Sponsor and the 
investigator agree. 
All Participants 
Any drugs known to be inhibitors or inducers of UGT2B17 or CYP2C19, and any drugs 
known to be strong or moderate inhibitors or inducers of CYP3A4 enzymes will be restricted 
for at least 28 days before administration of study intervention and until the last PK sample 
collection. Drugs known to be weak inhibitors or inducers of CYP3A may be allowed as per 
investigator discretion following consultation with the Sponsor. Appropriate sources (eg, 
Flockhart Table™) will be consulted to confirm lack of PK/pharmacodynamic interaction 
with study intervention. 
Following administration of study intervention, acetaminophen (up to 2 g per 24 hours) may 
be administered for minor ailments at the discretion of the intervention or designee. 
Participants must not have received another investigational agent within 4 weeks (or 
5 half-lives, whichever is greater) before administration of study intervention. 
All medications taken by participants during the course of the study will be recorded. 
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Nonlive vaccines may only be administered in consultation with the Sponsor prior to or 
following the receipt of study intervention according to the time frames specified in 
Exclusion Criteria (Section 5.2). 
Exception: COVID-19 vaccine may be administered. Study intervention must be given at 
least 72 hours following or at least 48 hours prior to any COVID-19 vaccination. 
6.5.1 
Rescue Medications and Supportive Care 
No rescue or supportive medications are specified for use in this study. 
6.6 
Dose Modification (Escalation/Titration/Other) 
The dose and administration of the study intervention to any participant may not be modified. 
If necessary, a participant must be discontinued for the reasons described in Section 7. 
6.7 
Intervention After the End of the Study 
There is no study-specified intervention after the end of the study. 
6.8 
Clinical Supplies Disclosure 
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided. 
7 
 DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention. Therefore, participants who receive a single-dose intervention 
cannot discontinue study intervention.  
7.2 
Participant Withdrawal From the Study 
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study. 
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits. 
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.10. The procedures to be performed should a participant repeatedly fail to return 
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for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3. 
7.3 
Lost to Follow-up 
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed: 
• The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule. 
• The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should 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 managed via the 
prespecified statistical data handling and analysis guidelines. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent). 
• All study-related medical decisions must be made by an investigator who is a qualified 
physician. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA. 
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• Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations. 
The maximum amount of blood collected from each participant over the duration of the study 
will not exceed 193 or 228 mL (Appendix 8). 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
8.1 
Administrative and General Procedures 
8.1.1 
Informed Consent 
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place. 
8.1.1.1 
General Informed Consent 
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion. 
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) 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/favorable opinion in advance of use. The 
participant or their legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature. 
Specifics about the study and the study population are to be included in the study informed 
consent form. 
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Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. 
8.1.1.2 
Consent and Collection of Specimens for Future Biomedical Research 
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of their 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR. 
8.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study. 
8.1.3 
Genotyping of UGT2B17 and CYP2C19 
After the participant provides written informed consent using IRB-approved study ICF, 
CYP2C19 genotype and UGT2B17 polymorphisms will be investigated as a genetic 
screening. 
8.1.4 
Participant Identification Card 
Not applicable as the study site will use its SOP for participant identification.  
8.1.5 
Medical History 
A medical history will be obtained by the investigator or qualified designee. 
8.1.6 
Prior and Concomitant Medications Review 
8.1.6.1 
Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before administration of study intervention. 
8.1.6.2 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. 
8.1.7 
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 that occur before intervention. Each participant will 
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be assigned only 1 screening number. Screening numbers must not be reused for different 
participants. 
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1. 
8.1.8 
Assignment of Treatment/Allocation Number 
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment allocation. The treatment/allocation number 
identifies the participant for all procedures occurring after treatment allocation. Once a 
treatment/allocation number is assigned to a participant, it can never be reassigned to another 
participant. 
A single participant cannot be assigned more than 1 treatment/allocation number. 
8.1.9 
Study Intervention Administration 
Administration of study intervention will be monitored by the investigator and/or study staff. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
participant, as per the allocation scheme. 
Participants will be instructed not to crush, split, or chew the study intervention. 
8.1.9.1 
Timing of Dose Administration 
On Day 1, 80 mg (2x40 mg tablets) MK-6482 will be administered at Hour 0.  
The study intervention will be administered with approximately 240 mL of water following 
at least a 10-hour fast and participants will continue to fast for at least 4 hours postdose. See 
Section 5.3.1 for additional information on meal restrictions throughout the study. 
The exact clock time of study intervention administration will be recorded. 
8.1.10 
Discontinuation and Withdrawal 
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.11.4] to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a 
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follow-up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any 
AEs have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4. 
8.1.10.1 
Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received. 
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed. 
8.1.11 
Participant Blinding/Unblinding 
This is an open-label study; there is no blinding for this study.  
8.1.12 
Domiciling 
Participants will be admitted to the CRU on Day -1, at the time indicated by the CRU, and 
will be housed until 120 hours postdose on Day 6. Participants may be admitted earlier than 
Day -1 for testing not related to study protocol as per CRU requirements (eg, COVID-19 
testing). 
At all times, a participant may be required to remain at the CRU for longer at the discretion 
of the investigator or designee. 
8.1.13 
Calibration of Equipment 
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site. 
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8.2 
Efficacy/Immunogenicity Assessments 
There are no direct efficacy assessments in this study. 
8.3 
Safety Assessments 
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 10.8 
(Appendix 8). 
Planned time points for all safety assessments are provided in the SoA. 
8.3.1 
Physical Examinations 
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded. 
Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the investigator or designee. 
BMI 
BMI equals a person’s weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up. 
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed. 
8.3.2 
Vital Signs 
Single measurements of T, RR, BP, and HR, will be measured as outlined in SoA 
(Section 1.3). Additional vital signs may be taken at any other times, if deemed necessary. 
BP and HR measurements will be performed with participants in a seated position for at least 
5 minutes before assessing vital signs, except when they are supine or semi-reclined because 
of study procedures and/or AEs (eg, nausea, dizziness) or if deemed necessary by the 
investigator or designee. 
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8.3.3 
Electrocardiograms 
• Single 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA 
(Section 1.3) using an ECG machine that automatically calculates the HR and measures 
PR, QRS, QT, and QTc intervals. Additional ECGs may be taken at any other times, if 
deemed necessary by the investigator or designee.  
• ECGs will be performed with participants in a supine position, for at least 5 minutes 
before the measurement. All ECG tracings will be reviewed by the investigator or 
designee. 
• Special care must be taken for proper lead placement by qualified personnel. Skin should 
be clean and dry before lead placement. Participants may need to be shaved to ensure 
proper lead placement. Female participants may need to remove interfering garments. 
• The correction formula to be used for QTc is Fridericia. 
• If a participant demonstrates an increase in QTc interval ≥60 msec compared with the 
predose baseline measurement, the ECG will be repeated twice within 5 minutes. The 
median value of the QTc interval from the 3 ECGs will represent the value at that time 
point. If the median QTc interval increase from baseline for any postdose time point is 
≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs every 
15 minutes for at least 1 hour or until the QTc is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study 
cardiologist may be appropriate and the Sponsor should be notified.  
• If a participant demonstrates a QTc interval ≥500 msec on a postdose ECG, the ECG will 
be repeated twice within 5 minutes. The median value of the QTc interval from the 
3 ECGs will represent the value at that time point. If the median QTc interval is 
≥500 msec, the Sponsor should be notified and the ECGs should be reviewed by a 
cardiologist. The participant should be telemetry monitored (until the QTc is <500 msec) 
or should be considered for transfer to a location where closer monitoring and definitive 
care (eg, a CCU or ICU) is available. 
• If at any time the QRS duration is prolonged ≥200 msec (and change is not considered 
rate related or pacing induced), then the Sponsor should be notified. The ECGs should be 
reviewed by a cardiologist and the participant should be considered for transfer to a 
location where closer monitoring and definitive care (eg, a CCU or ICU) is available. 
• If the participant has unstable hemodynamics, or has any clinically significant 
dysrhythmias noted on telemetry, the participant should be immediately transferred to an 
acute care setting for definitive therapy. 
• If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec. 
• A cardiologist may be consulted by the investigator as needed to review ECG tracings 
with significant abnormalities. 
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8.3.4 
Pulse Oximetry 
Pulse oximetry will be obtained as outlined in the SoA (Section 1.3). Each participant will 
have a baseline pulse oximetry (oxygen levels as saturation [%] and HR) reading done at 
check-in. 
Readings may be taken at other times, if deemed necessary by the investigator or designee.  
Any oxygen saturation reading deemed clinically significant by the investigator will be 
documented. 
8.3.5 
Clinical Safety Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
• The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
• All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA. 
• If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate eCRF (eg, SLAB). 
• For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 1 day after the dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator. 
8.3.6 
Photograph of Rash 
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption or rash occurrence in determining etiology and drug relationship. 
8.4 
Adverse Events, Serious Adverse Events, 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 completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3. 
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Adverse events, 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 and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. 
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality. 
8.4.1 
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information 
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator for randomized participants only if the event causes the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including, but 
not limited to washout or discontinuation of usual therapy, diet, placebo, or a procedure. 
From the time of intervention allocation through approximately 14 days after cessation of 
intervention, all AEs, SAEs and other reportable safety events must be reported by the 
investigator. 
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention. 
Investigators are not obligated to actively seek AEs or SAEs 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 the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify 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 5. 
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention. 
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Table 5 
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events 
Type of Event 
Reporting Time 
Period: 
Consent to 
Randomization/ 
Allocation 
(Randomized 
participants 
only) 
Reporting Time 
Period: 
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period 
Reporting Time 
Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor: 
NSAE 
Report if: 
- due to protocol-
specified 
intervention 
- causes 
exclusion 
- participant is 
receiving placebo 
run-in or other 
run-in treatment 
Report all 
Not required 
Per data entry 
guidelines 
SAE 
Report if: 
- due to protocol-
specified 
intervention 
- causes 
exclusion 
- participant is 
receiving placebo 
run-in or other 
run-in treatment 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 24 hours of 
learning of event 
Pregnancy/Lactati
on Exposure 
Report if: 
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment 
including 
placebo run-in) 
Exception: A 
positive 
pregnancy test at 
the time of initial 
screening is not a 
reportable event. 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 24 hours of 
learning of event 
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Type of Event 
Reporting Time 
Period: 
Consent to 
Randomization/ 
Allocation 
(Randomized 
participants 
only) 
Reporting Time 
Period: 
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period 
Reporting Time 
Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor: 
ECI (require 
regulatory 
reporting) 
Report if: 
- due to 
intervention 
- causes 
exclusion 
Report 
- potential DILI 
- require 
regulatory 
reporting 
Not required 
Within 24 hours of 
learning of event 
ECI (do not 
require regulatory 
reporting) 
Report if: 
- due to 
intervention 
- causes 
exclusion 
Report 
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting 
Not required 
Within 5 calendar 
days of learning of 
event 
Cancer 
Report if: 
- due to 
intervention 
- causes 
exclusion 
Report all 
Not required 
Within 5 calendar 
days of learning of 
event 
(unless serious) 
Overdose 
Report if: 
- receiving 
placebo run-in or 
other run-in 
medication  
Report all 
Not required 
Within 24 hours of 
learning of event 
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event. 
8.4.2 
Method of Detecting AEs, SAEs, and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence. 
8.4.3 
Follow-up of AE, SAE, and Other Reportable Safety Event Information 
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 pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3. 
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8.4.4 
Regulatory Reporting Requirements for SAE 
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 
safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.5 
Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
8.4.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs 
Not applicable. 
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8.4.7 
Events of Clinical Interest 
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5. 
2. For healthy control participants only: 
An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent). 
It may also be appropriate to conduct additional evaluation for an underlying etiology in 
the setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and 
alkaline phosphatase that do not meet the criteria noted above. In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this study. 
3. An AE of anemia. 
4. An AE of hypoxia. 
5. An AE of dyspnea. 
8.5 
Treatment of Overdose 
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor. 
8.6 
Pharmacokinetics 
Plasma samples for evaluation of MK-6482 and PT3317 PK will be collected at scheduled 
time points as delineated in the SoA.  
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The decision as to which plasma samples collected will be measured for evaluation of PK 
will be collaboratively determined by the Sponsor. If indicated, these samples may also be 
measured and/or pooled for assay in an exploratory manner for metabolites. 
8.6.1 
Blood Collection for Plasma MK-6482 and PT3317 
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual. 
8.7 
Pharmacodynamics 
Blood samples for erythropoietin analysis will be collected at scheduled time points as 
delineated in the SoA. 
8.8 
Biomarkers 
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA: 
• Blood for genetic analysis 
8.8.1 
Planned Genetic Analysis Sample Collection 
The planned genetic analysis sample will be drawn for UGT2B17 and CYP2C19 genotyping 
and for planned analysis of the association between genetic variants in DNA and drug 
response. If the IRB/IEC does not approve of the planned analysis of the association between 
DNA variation and drug response, or if there is a local law or regulation prohibiting the 
same, data analysis will be limited to UGT2B17 and CYP2C19. Leftover extracted DNA will 
be stored for FBR if the participant provides documented informed consent for FBR. 
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the operations/laboratory manual. 
8.9 
Future Biomedical Research Sample Collection 
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR: 
• Leftover DNA for future research 
8.10 
Health Economics Medical Resource Utilization and Health Economics 
Not applicable 
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8.11 
Visit Requirements 
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in sections below. 
8.11.1 
Screening 
Approximately 28 days before administration of study intervention, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5. 
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation/randomization if 
there are Day -1 procedures planned per protocol. 
8.11.2 
Treatment Period 
Refer to the SoA (Section 1.3). 
8.11.3 
Discontinued Participants Continuing to be Monitored in the Study 
At any point if a participant discontinues from the study but continues to be monitored in the 
study, all study procedures specified in the SoA may be completed at the discretion of the 
investigator and with Sponsor agreement. 
8.11.4 
Poststudy (Follow-up) 
All participants who received the study intervention (including participants who terminate 
the study early) will return to the CRU approximately 14 days after study intervention 
administration for poststudy (follow-up) procedures, and to determine if any AE has occurred 
since the last study visit. If the poststudy visit occurs less than 14 days after administration of 
study intervention, a subsequent follow-up telephone call should be made at 14 days post 
administration of study intervention to determine if any AEs have occurred since the 
poststudy clinic visit. 
8.11.5 
Critical Procedures Based on Study Objectives: Timing of Procedure 
For this study, the blood sample for MK-6482 and PT3317 is the critical procedure. 
At any postdose time point, the blood sample for MK-6482 and PT3317 need to be collected 
as close to the exact time point as possible. All other procedures should be completed as 
close to the prescribed/scheduled time as possible. Study procedures can be performed before 
or after the prescribed/scheduled time. 
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director. 
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Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
The following variance in procedure collection times will be permitted. 
• PK Collection as outlined in Table 6. 
Table 6 
Postdose Pharmacokinetic (Blood) Collection Windows 
PK Collection 
(relative to dosing) 
PK Collection Window 
(relative to scheduled time for collection) 
0 to 2 hours 
5 min 
>2 to 12 hours 
15 min 
>12 to 48 hours 
1 hour 
>48 to 120 hours 
2 hours 
 
• Postdose standard safety evaluations: vital signs, ECG, pulse oximetry, and laboratory 
safety tests 
- 
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical 
sampling time 
- 
Between 24-hours and 48-hours postdose may be obtained within 1 hour of the 
theoretical sampling time 
- 
From 48-hours to 120-hours postdose may be obtained within 2 hours of the 
theoretical sampling time. 
8.11.6 
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters 
This is a Phase 1 assessment of MK-6482 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to clinical or laboratory procedures currently outlined may be required to 
achieve the scientific goals of the study objectives and/or to ensure appropriate safety 
monitoring of the study participants. 
• Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data 
• Modification of the PK/pharmacodynamic sample processing and shipping details based 
on newly available data 
The PK sampling scheme currently outlined in the protocol may be modified during the study 
based on newly available PK data (eg, to obtain data closer to the time of peak plasma 
concentrations). If indicated, these collected samples may also be assayed in an exploratory 
manner for metabolites and/or pharmacodynamic markers. 
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Up to additional 50 mL of blood may be drawn for safety and/or PK analyses. The total 
blood volume withdrawn from any single participant will not exceed the maximum allowable 
volume during their participation in the entire study (Appendix 8). 
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, pulse oximetry, etc) may be modified during the study based on newly 
available data. Additional safety laboratory tests may be added to blood samples previously 
drawn to obtain additional safety information. These changes will not increase the number of 
study procedures for a given participant during their participation in the entire study. 
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator. 
9 
STATISTICAL ANALYSIS PLAN 
Data will be handled and process according to Celerion SOPs, which are written based on the 
principles of GCP. 
9.1 
Statistical Analysis Plan Summary 
This section contains a brief summary of the statistical analyses for this study. Full detail is 
in the SAP to be provided separately. 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in an SAP. The SAP will be prepared by Celerion and agreed upon with 
the Sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoints definition and/or its analysis will also be 
reflected in a protocol amendment. Additional statistical analyses other than those described 
in this section may be performed if deemed appropriate. 
9.2 
Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be conducted by the Data 
Management and Biometrics department at Celerion. 
If, after the study has begun, changes are made to the statistical analysis stated below, then 
these deviations to the plan will be listed, along with an explanation as to why they occurred, 
in the CSR. 
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9.3 
Hypotheses/Estimation 
Primary Estimation: 
Estimation 1: The plasma PK (AUC0-inf and Cmax) of MK-6482 following a single oral 
80 mg dose of MK-6482 to participants with moderate hepatic impairment will be estimated 
and compared to those in healthy matched control participants. 
9.4 
Analysis Endpoints 
The primary PK endpoints will be AUC0-inf and Cmax of MK-6482 following a single oral 
dose of MK-6482 to participants with moderate hepatic impairment compared to those in 
healthy matched control participants. 
Additional PK endpoints will be other PK parameters of MK-6482 including AUC0-last, 
AUC0-24, AUC%extrap, C24, Tmax, apparent terminal t½, λz, CL/F and Vz/F. Relevant PK 
parameters for PT3317 will also be presented. 
9.5 
Analysis Populations 
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the study intervention(s) they actually 
received. 
All Participants as Treated (APaT): The All Participants as Treated Population consists of all 
participants who received the study intervention. This population will be used for 
assessments of safety and tolerability. 
Per-Protocol (PP): The Per-Protocol Population consists of the subset of participants who 
comply with the protocol sufficiently to ensure that generated data will be likely to exhibit 
the effects of treatment, according to the underlying scientific model. Compliance covers 
such considerations as exposure to treatment, availability of measurements and absence of 
important protocol deviations. Important protocol deviations will be identified to the extent 
possible prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data considered sufficient to exhibit the effect of treatment will be included in the 
Per-Protocol dataset. This population will be used for the PK analyses. 
9.6 
Statistical Methods 
9.6.1 
PK Descriptive Statistics 
Individual values will be listed for each PK parameter by group and analyte, and the 
following (non-model-based) descriptive statistics will be provided: N (number of 
participants with non-missing data), arithmetic mean, standard deviation, arithmetic percent 
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CV (calculated as 100 x standard deviation/arithmetic mean), median, minimum, maximum, 
geometric mean, and geometric percent CV (calculated as 100 x sqrt(exp(s2) – 1), where s2 is 
the observed variance on the natural log-scale. 
9.6.2 
PK Statistical Analysis 
Separately for each PK parameter, individual values of MK-6482 AUC0-inf, AUC0-24, and 
Cmax will be natural log-transformed and evaluated with a linear mixed effects model 
containing a fixed effect for population (hepatic impairment group and normal hepatic 
function group). An unstructured covariance matrix will be used to allow for unequal 
population variances via the REPEATED and GROUP statement in SAS PROC MIXED. 
Kenward and Roger’s method will be used to calculate the denominator degrees of freedom 
for the fixed effect (DDFM=KR). Ninety percent (90%) CIs for the least squares means for 
each population will be constructed on the natural log scale and will reference the 
t-distribution. Exponentiating the least-squares means and their corresponding 90% CIs will 
yield estimates for the population geometric means and confidence intervals about the 
geometric means on the original scale. Sample SAS code is given below: 
proc mixed data=data;  
class population;  
model lnpk = population /ddfm=kr;  
repeated/ group= population type=UN;  
lsmeans population /cl alpha=0.1; 
run;  
 
To compare participants with hepatic impairment to participants with normal hepatic 
function, a two sided 90% CI for the difference in least-squares means (hepatic impairment – 
normal hepatic function) will be calculated for each PK parameter using the aforementioned 
model. These confidence limits will be exponentiated to obtain the 90% confidence interval 
for the ratio of geometric means (hepatic impairment/normal hepatic function) for each PK 
parameter. A sensitivity analysis may be performed without poor metabolizers at UGT2B17 
or CYP2C19 if applicable as deemed clinically appropriate. 
Figures showing summary concentration-time profiles by hepatic impairment category for 
both MK-6482 and PT3317 (linear plot with arithmetic mean (±SD) for concentration and 
semi-log plot with arithmetic mean) will be provided. Individual participant concentration-
time profiles may also be provided in the appendix separately and/or as overlays using 
hepatic impairment category as grouping variable. A table showing summary PK parameter 
values with GMs (%GCV) by population, will be provided for PK parameters, AUC0-inf, 
AUC0-last, AUC0-24, Cmax, C24, Tmax, apparent terminal t½, CL/F (parent only), and 
Vz/F (parent only). A table showing the GMR (hepatic impairment/normal hepatic function) 
and corresponding 90% CI will be provided for PK parameters, AUC0-inf, AUC0-24, and 
Cmax. 
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Individual values will be listed for each PK parameter for MK-6482 (AUC0-inf, AUC0-last, 
AUC0-24, Cmax, C24, Tmax, apparent terminal t½, CL/F, Vz/F, AUC%extrap[percentage of 
AUC0-inf obtained by extrapolation], λz [terminal elimination rate constant]) and PT3317 
(AUC0-inf, AUC0-last, AUC0-24, Cmax, C24, Tmax, apparent terminal t½, MPR for Cmax 
[metabolite to parent ratio for Cmax] and MPR for AUC0-inf [metabolite to parent ratio for 
AUC0-inf]) by group, and the following (non-model-based) descriptive statistics will be 
provided: N (number of participants with non-missing data), arithmetic mean, standard 
deviation, arithmetic percent CV (calculated as 100 x standard deviation/arithmetic mean), 
median, minimum, maximum, geometric mean, and geometric percent CV (calculated as 
100 x sqrt(exp(s2) - 1), where s2 is the observed variance on the natural log-scale). PK 
concentration listings for MK-6482 in plasma and PT3317 will also be provided for each 
participant. Descriptive statistics may be provided based on UGT2B17 and/or CYP2C19 
phenotypes separately. 
The relationship between MK-6482 PK and hepatic impairment will be examined in an 
exploratory manner via a scatter plot of PK values (AUC0-inf, AUC0-24, Cmax, Tmax, and 
apparent terminal t½) versus the Child-Pugh score. Plots of PK values (AUC0-inf, AUC0-24, 
Cmax, Tmax, and apparent terminal t½) and the baseline laboratory components of the 
Child-Pugh score (ie, bilirubin, albumin levels, and prothrombin time) will be provided. Plots 
of PK parameter values (AUC0-inf, AUC0-24, Cmax, Tmax, and apparent t½) versus age 
and BMI will also be provided.  
Descriptive statistics for aforementioned PK parameters will also be provided by NCI 
classification. 
9.6.3 
Safety Analysis 
For safety, all AEs, vital signs, ECGs, pulse oximetry, and safety laboratory values will be 
listed for each participant and tabulated by group. Summary statistics for the safety 
laboratory tests, vital signs, and/or ECGs may also be computed and provided, as deemed 
clinically appropriate. 
9.7 
Pharmacodynamics Analysis  
Summary statistics by time point and plots may be generated for erythropoietin as well as for 
change from baseline, as deemed clinically appropriate. 
9.8 
Interim Analyses 
Not applicable 
9.9 
Multiplicity 
Not applicable 
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9.10 
Sample Size and Power Calculations 
The sample size selected for each population to evaluate the effect of hepatic impairment on 
the PK of MK-6482 was not chosen to satisfy any a priori statistical requirement. This 
sample size (N=8 per group) has historically been shown to be sufficient for studies of this 
type and should provide adequate data to support the planned analyses. Nevertheless, 
estimates of the expected precision of the estimates, based on these sample sizes and the 
known variability obtained from hepatic PK studies are presented below. 
The precision of the estimated GMRs (hepatic impairment / normal hepatic function) of PK 
parameters obtained from this study can be assessed by calculating the half-width of the 90% 
CIs expected for the given sample size and assumed variability. The observed between-
participant coefficients of variation were 62.44% (~0.574 standard deviation on the log scale) 
and 56.29% (~0.525 standard deviation on the log scale) for AUC0-inf from food-effect 
study (Protocol MK-6482-002) and comparative bioavailability study (Protocol 
MK-6482-006), respectively. Assuming a sample size of 8 participants per population and 
observed between-participant SD is 0.574 on the log scale, then the half width of the 90% CI 
of GMR for MK-6482 AUC0-inf on the log scale will be 0.472. The lower and upper 90% 
confidence limits for the GMR will be given by OBS/1.60 and OBS*1.60 for AUC0-inf, 
where OBS is the observed GMR. Thus, for example, if the observed GMR for AUC0-inf 
was 1.50, then the approximate 90% CI for the GMR would be [0.94 to 2.40]. 
Similarly, the observed between-participant coefficients of variation were 26.04% (~0.256 
standard deviation on the log scale) and 25.25% (~0.249 standard deviation on the log scale) 
for Cmax from Protocols 002 and 006, respectively. Assuming a sample size of 8 participants 
per population and observed between-participant SD is 0.256 on the log scale, then the half 
width of the 90% CI of GMR for MK-6482 Cmax on the log scale will be 0.211. The lower 
and upper 90% confidence limits for the GMR will be given by OBS/1.23 and OBS*1.23 for 
Cmax. Thus, for example, if the observed GMR for Cmax was 1.50, then the approximate 
90% CI for the GMR would be [1.22 to 1.85]. 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Code of Conduct for Clinical Trials 
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD) 
Code of Conduct for Interventional Clinical Trials 
I. Introduction 
A. Purpose 
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope 
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD. 
II. Scientific Issues 
A. Trial Conduct 
1. Trial Design 
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc. 
The design (ie, participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial.  
2. Site Selection 
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial. 
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation. 
3. Site Monitoring/Scientific Integrity 
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified. 
B. Publication and Authorship 
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity. 
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications. 
III. Participant Protection 
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC]) 
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations. 
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations. 
B. Safety 
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care. 
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them. 
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C. Confidentiality 
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name. 
D. Genomic Research 
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee. 
IV. Financial Considerations 
A. Payments to Investigators 
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts. 
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants. 
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding. 
C. Funding for Travel and Other Requests 
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices. 
V. Investigator Commitment 
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards. 
 
10.1.2 
Financial Disclosure 
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide their financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
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The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.  
10.1.3 
Data Protection 
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations. 
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. 
The participant 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 the participant.  
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.3.1 
Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol. 
10.1.3.2 
Confidentiality of Participant Records 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor. 
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations. 
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10.1.3.3 
Confidentiality of IRB/IEC Information 
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies. 
10.1.4 
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 practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments. 
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements. 
10.1.5 
Compliance with Study Registration and Results Posting Requirements 
Under the terms of the FDAAA of 2007 and the 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, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.6 
Compliance with Law, Audit, and Debarment 
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
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all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study. 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials. 
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor. 
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study. 
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority 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 by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor 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 investigator’s knowledge, threatened. 
10.1.7 
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 (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the 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. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs. 
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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 
entered into 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 regulatory requirements. 
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies 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. 
10.1.8 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
10.1.9 
Study and Site Closure 
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s). 
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10.2 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 7 will be performed by the local laboratory with the exception 
of the UGT2B17 and CYP2C19 genotyping screening which will be performed by a 
central laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 7 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
HGB 
HCT 
Chemistry a 
BUN 
Potassium 
AST/SGOT 
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
above the ULN) 
 
Albumin 
Bicarbonate 
Chloride 
Phosphorous 
 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
 
Glucose [fasting] 
Calcium 
Alkaline 
phosphatase 
 
Coagulation 
INR 
PT 
 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
• 
Microscopic examination (if protein, blood, nitrite and/or leukocyte esterase are 
abnormal) 
Other Tests 
• 
FSH (postmenopausal females only) 
• 
Urine/blood/breath alcohol and urine/saliva drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
• 
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) b 
• 
UGT2B17 genotyping 
• 
CYP2C19 genotyping 
• 
Erythropoietin 
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Laboratory 
Assessments 
Parameters 
a Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts or rechecks, 
participants may not have fasted for 8 hours prior to the serum chemistry sample is taken. 
b For participants with moderate hepatic impairment only: HBsAg positive participants are allowed to enroll if HBV 
DNA is below 1000 copies/mL in the plasma. Participants who are positive for HCVAb can be enrolled but must not 
have detectable HCV RNA in the plasma. 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CYP=cytochrome P450; 
DNA=deoxynucleic acid; FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface antigen; HBV=hepatitis B 
virus; HCT=hematocrit; HCV=hepatitis C virus; HGB=hemoglobin; HIV=human immunodeficiency virus; 
INR=International Normalized Ratio; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
PT=prothrombin time; RBC=red blood cell; RNA=ribonucleic acid; SGOT=serum glutamic-oxaloacetic transaminase; 
SGPT=serum glutamic-pyruvic transaminase; UGT=uridine 5'-diphospho-glucuronosyltransferase; ULN=upper limit of 
normal; WBC=white blood cell. 
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report. 
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10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
• Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention. 
• Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), 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 results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator. 
• Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms 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.” 
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Events NOT meeting the AE definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the 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). 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
• Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened. 
• Refer to Section 8.4.6 for protocol-specific exceptions. 
 
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
• The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. 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 length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history. 
d. Results in persistent 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 experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
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e. Is a congenital anomaly/birth defect 
• In offspring of participant taking the product regardless of time to diagnosis. 
f. Other important medical events 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
10.3.3 
Additional Events Reported 
Additional events that require reporting 
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor. 
• Is a cancer 
• Is associated with an overdose 
10.3.4 
Recording AE and SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.  
• The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.  
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.  
• 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, 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. 
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Assessment of intensity /toxicity 
• An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe. 
 
• 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, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated). 
- Moderate: An event that causes sufficient discomfort to interfere 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 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 an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information. 
• The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE: 
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)? 
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors. 
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- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced? 
◦ 
If yes, did the AE resolve or improve? 
◦ 
If yes, this is a positive dechallenge. 
◦ 
If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.) 
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study? 
◦ 
If yes, did the AE recur or worsen? 
◦ 
If yes, this is a positive rechallenge. 
◦ 
If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC. 
• Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology? 
• The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements. 
• Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship). 
- Yes, there is a reasonable possibility of Sponsor’s product relationship: 
◦ 
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause. 
- No, there is not a reasonable possibility of Sponsor’s product relationship: 
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◦ 
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.) 
• The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes. 
• 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, 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 their opinion of 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. 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations 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 investigations, histopathological examinations, or 
consultation with other health care professionals.  
• New or updated information will be recorded in the CRF.  
• The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.5 
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool 
• The primary mechanism for reporting to the Sponsor will be the EDC tool. 
- 
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent). 
- 
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form. 
◦ 
Reference Section 8.4.1 for reporting time requirements. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
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• After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section). 
• Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent). 
 
SAE reporting to the Sponsor via paper CRF 
• If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated 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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10.4 
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up 
 
Not applicable 
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10.5 
Appendix 5: Contraceptive Guidance 
10.5.1 
Definitions  
Women of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
• Premenopausal female with 1 of the following: 
- Documented hysterectomy 
- Documented bilateral salpingectomy 
- Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female 
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
◦ 
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.  
- Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
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10.6 
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research 
1. Definitions 
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1  
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2 
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2 
d. DNA: Deoxyribonucleic acid. 
e. RNA: Ribonucleic acid. 
 
2. Scope of Future Biomedical Research3, 4 
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand: 
• The biology of how drugs/vaccines work 
• Biomarkers responsible for how a drug/vaccine enters and is removed by the body 
• Other pathways with which drugs/vaccines may interact 
• The biology of disease 
The specimen(s) may be used for future assay development and/or drug/vaccine 
development. 
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor. 
3. Summary of Procedures for Future Biomedical Research3, 4 
a. Participants for Enrollment 
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research. 
b. Informed Consent 
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or their designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
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delayed, present consent at next possible Participant Visit. Consent forms signed by 
the participant will be kept at the clinical study site under secure storage for 
regulatory reasons. 
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. 
c. eCRF Documentation for Future Biomedical Research Specimens 
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed. 
d. Future Biomedical Research Specimen(s) 
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes. 
4. Confidential Participant Information for Future Biomedical Research3, 4 
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results. 
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube. 
5. Biorepository Specimen Usage3, 4 
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor. 
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6. Withdrawal From Future Biomedical Research3, 4 
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received. 
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens3, 4 
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed. 
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database. 
8. Data Security3, 4 
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access. 
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9. Reporting of Future Biomedical Research Data to Participants3, 4 
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation. 
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation. 
10. Future Biomedical Research Study Population3, 4 
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research. 
11. Risks Versus Benefits of Future Biomedical Research3, 4 
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent. 
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused. 
12. Questions 
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com. 
13. References 
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618 
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html  
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/  
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/  
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10.7 
Appendix 7: Country-specific Requirements  
Not applicable 
 
 
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10.8 
 Appendix 8: Blood Volume Table 
All Participants 
Prestudy 
Treatment 
Period 
Poststudy 
Total 
Collections 
mL Per 
Collection 
Total mL/ 
Test 
Safety Laboratory Safety Tests 
(including hematology, serum 
chemistry, FSH) 
1 
4 
1 
6 
12.5 
75 
INR/PT 
1 
-- 
1 
2 
3.5 
7 
Blood for Planned Genetic 
Analysis  
-- 
1 
-- 
1 
8.5 
8.5 
Blood for MK-6482 and PT3317 
PK 
-- 
17 
-- 
17 
4 
68 
Blood for Protein Binding 
-- 
1 
-- 
1 
4 
4 
Blood for UGT2B17 Genotyping 
1 
-- 
-- 
1 
3 
3 
Blood for CYP2C19 Genotyping 
1 
-- 
-- 
1 
3 
3 
Blood for Serum Erythropoietin 
-- 
6 
1 
7 
3.5/8.5 a 
24.5/59.5 
Total Blood Volume per Participant b 
193/228 mL 
a Blood for serum erythropoietin samples may be collected in either 3.5 mL or 8.5 mL collection tubes. 
b If additional PK/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) may be 
obtained.  
 
 
 
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10.9 
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values 
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation: 
A. If all protocol-specified laboratory values are normal, the participant may enter the study. 
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study. 
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available: 
a. The participant may be excluded from the study. 
b. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety 
test source document). 
c. The participant may be included in the study if the abnormality is consistent with 
a pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report. 
OR 
d. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values). 
a. If the repeat test value is within the normal range, the participant may 
enter the study. 
b. If the repeat test value is still abnormal, the study investigator will 
evaluate the potential participant with a complete history and physical 
examination, looking especially for diseases that could result in the 
abnormal laboratory value in question. If such diseases can be ruled out, 
and if the abnormal laboratory value is not clinically relevant, then the 
participant may enter the study. 
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study. 
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10.10 Appendix 10: Abbreviations 
Abbreviation 
Expanded Term 
AE 
adverse event  
ALT 
alanine aminotransferase 
ARNT 
aryl hydrocarbon receptor nuclear translocator 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCS 
Biopharmaceutics Classification System 
bid 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
ccRCC 
clear cell renal cell carcinoma 
CG 
Cockcroft-Gault 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form  
CRU 
clinical research unit 
CSR 
clinical study report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid  
ECG 
electrocardiogram  
ECI 
event of clinical interest 
eCRF 
electronic case report form 
EDC 
electronic data collection  
EM 
extensive metabolizer 
EMA 
European Medicines Agency 
EPO 
erythropoietin 
FBR 
future biomedical research 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice  
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCT 
hematocrit 
HCV 
hepatitis C virus 
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Abbreviation 
Expanded Term 
HGB 
hemoglobin 
HIF-1α 
hypoxia-inducible factor 1 alpha 
HIF-2α 
hypoxia-inducible factor 2 alpha 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure  
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IM 
intermediate metabolizer 
IND 
investigational new drug  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
NCS 
not clinically significant 
PK 
pharmacokinetic 
PM 
poor metabolizer 
PP 
per-protocol 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RNA 
ribonucleic acid 
RR 
respiratory rate 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SLAB 
supplemental laboratory test(s) 
SoA 
schedule of activities 
SOP 
standard operating procedures 
SUSARs 
suspected unexpected serious adverse reaction  
T 
body temperature 
Tmax 
time to maximum plasma concentration 
t½ 
half life 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
Vd/F  
apparent volume of distribution 
VHL-RCC 
von Hippel-Lindau disease-associated renal cell carcinoma 
WBC 
white blood cell 
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24-NOV-2022 
 
 
Abbreviation 
Expanded Term 
WONCBP 
woman/women of nonchildbearing potential 
08Q365


PRODUCT:  MK-6482   
105 
PROTOCOL/AMENDMENT NO.:  020-02   
 
 
 
MK-6482-020-02 FINAL PROTOCOL 
24-NOV-2022 
 
 
11 REFERENCES 
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dosing recommendations for Oncology Compounds. J. Clin. Pharmacol. 2021;61:105-115.  
Food and Drug Administration: Center for Drug Evaluation and Research (CDER). Guidance 
for Industry Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, 
Data Analysis, and Impact on Dosing and Labeling — General Considerations (May 2003). 
Available at: https://www.fda.gov/media/71311/download. 
Patel H, Egorin M, Remick S, Mulkern D, Takimoto CHM, Doroshow JH et al. Comparison 
of Child-Pugh (CP) criteria and NCI organ dysfunction working group (NCIODWG) criteria 
for hepatic dysfunction (HD): implications for chemotherapy dosing. J. Clin. Oncol. 2004; 
22(14_suppl): 6051-6051. 
Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, et al. Allosteric inhibition of 
hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 2013;9:271-6. 
 
08Q365