Clinical trial NCT04994522
Conditions: End Stage Renal Disease Renal Impairment
Sponsor: Merck Sharp & Dohme LLC
Start date: 2022-07-12; Completion date: 2024-04-11
Enrollment: 14 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 120 mg dose in participants with end stage renal disease (ESRD) before and after hemodialysis (HD) to each other and also to that of healthy matched control participants. This study will also evaluate the safety and tolerability of a single oral 120 mg dose of belzutifan in participants with ESRD and the extent of belzutifan removed by HD.

Detailed description:

Arms: arm 1: In period 1, participants with ESRD will receive a single, oral dose of belzutifan 120 mg on Day 1 after HD. In period 2, participants with ESRD will receive a single, oral dose of belzutifan 120 mg on Day 1 before HD. Each period is 4 days. arm 2: In period 1, healthy participants will receive a single, oral dose of belzutifan 120 mg on Day 1 of a 4-day period.
Interventions: intervention 1: Belzutifan
Intervention descriptions: intervention 1: Three 40 mg tablets given as a single oral 120 mg dose.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
NCT04994522
Protocol/Amendment No.: 021-02 An Open-
Label, Single-Dose Study to Investigate the
Influence of Renal Impairment on the
Pharmacokinetics of MK-6482
17-Apr-2023


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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 Renal 
Impairment on the Pharmacokinetics of MK-6482 
Protocol Number: 021-03 
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: 17 April 2023 
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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 03 
17-Apr-2023 
Protocol amended to widen the allowable range of body 
mass index (BMI) in the inclusion criterion to facilitate 
recruitment of participants with end stage renal disease 
(ESRD). 
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 add the 
exclusion of UGT2B17 and CYP2C19 dual poor 
metabolizers. 
Original Protocol 
30-Jun-2021 
Not applicable 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Amendment: 03 
Overall Rationale for the Amendment:  
The upper limit of the BMI is being increased from 40 to 46 kg/m2. This increase in the upper limit of the BMI is to facilitate 
recruitment. Based on review of the site database of eligible participants, the Sponsor was informed that many of the ESRD patients 
have BMIs that exceed 40 kg/m2. The upper limit of the BMI for the Sponsor clinical database for MK-6482, that includes adult 
patients with von Hippel-Lindau (VHL) who require therapy for associated renal cell carcinoma (RCC), is 52 kg/m2. Therefore, the 
Sponsor has clinical experience with the use of MK-6482 in patients with BMIs exceeding 40 kg/m2. Based on a population 
pharmacokinetic (PK) model, body weight (which is highly correlated with BMI) does not have a clinically meaningful effect on the 
PK of MK-6482. 
Related sections within the protocol were updated to reflect this change, as noted in chronological order below. 
Summary of Changes Table: 
Section # and Name 
Description of Change 
Brief Rationale 
5.1.1 Inclusion Criteria 
for Participants With 
Healthy Renal Function 
The BMI upper limit in criterion #3 was increased. 
from: Have a BMI 18.0-40.0 kg/m2, inclusive, at 
prestudy (screening). 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 ESRD 
group. 
to: Have a BMI 18.0-46.0 kg/m2, inclusive, at 
prestudy (screening). See Section 8.3.1 for criteria 
on rounding to the nearest whole number. 
BMI = weight (kg)/height (m)2. BMI must be 
Inclusion criterion for BMI widened to facilitate 
recruitment of participants with ESRD. As the 
participants with healthy renal function are 
required to match the demographics of the 
participants with ESRD, the BMI of the healthy 
participants was also widened. 
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Section # and Name 
Description of Change 
Brief Rationale 
within ± 20% of the mean BMI in the ESRD 
group. 
5.1.2 Inclusion Criteria 
for Participants With 
ESRD 
The BMI upper limit in criterion #3 was increased. 
from: Have a BMI 18.0-40.0 kg/m2, inclusive, at 
prestudy (screening). See Section 8.3.1 for criteria 
on rounding to the nearest whole number. 
BMI = weight (kg)/height (m)2. 
to: Have a BMI 18.0-46.0 kg/m2, inclusive, at 
prestudy (screening). See Section 8.3.1 for criteria 
on rounding to the nearest whole number. 
BMI = weight (kg)/height (m)2. 
Inclusion criterion for BMI widened to facilitate 
recruitment of participants with ESRD. 
 
 
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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. 
9.6.3 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 categorical effect for 
population (participants with ESRD before and 
after HD, control participants with normal renal 
function). 
to: Separately for each PK parameter, individual 
values of MK-6482 AUC0-inf, AUC0-24, and 
Cmax will be natural log-transformed and 
Changes were made to correct details in the 
statistical analysis language. 
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Section # and Name 
Description of Change 
Brief Rationale 
evaluated with a mixed effects model containing a 
fixed effect for population (participants with 
ESRD before and after HD, control participants 
with normal renal function). 
 
from: To address the primary estimation objective 
and compare participants with ESRD before and 
after HD to participants with normal renal 
function, a two sided 90% CI for the difference in 
means (ESRD before HD – normal renal function, 
ESRD after HD – normal renal function) will be 
calculated for each PK parameter using the mean 
square error from the model and referencing a 
t-distribution. 
to: To address the primary estimation objective 
and compare participants with ESRD before and 
after HD to participants with normal renal 
function, a two sided 90% CI for the difference in 
least-squares means (ESRD before HD – normal 
renal function, ESRD after HD – normal renal 
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, 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  
1.1 Synopsis 
3 Hypotheses, Objectives, 
and Endpoints 
 
In the Objectives/Endpoints table, 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 of study intervention 
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. 
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 
Information updated to be more current. 
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Section # and Name 
Description of Change  
Brief Rationale  
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.  
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). 
4.1 Overall Design 
5 Study Population 
5.1.1 Inclusion Criteria for 
Participants With Healthy 
Renal Function 
• 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 the time 
needed for MK-6482 to be eliminated. 
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Section # and Name 
Description of Change  
Brief Rationale  
5.1.2 Inclusion Criteria for 
Participants With ESRD 
5.2.1 Exclusion Criteria for 
Participants with Healthy 
Renal Function 
5.2.2 Exclusion Criteria for 
Participants With ESRD 
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. 
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.   
 
CYP2C19 genotyping added for eligibility 
assessment. 
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 abbreviation “CNS.” 
Abbreviation added for completeness. 
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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 
1.3.1 
ESRD Group ................................................................................................24 
1.3.2 
Healthy Control Group ................................................................................28 
2 
INTRODUCTION..........................................................................................................31 
2.1 
Study Rationale ....................................................................................................31 
2.2 
Background ..........................................................................................................31 
2.2.1 
Pharmaceutical and Therapeutic Background .............................................32 
2.2.2 
Preclinical and Clinical Studies ...................................................................32 
2.2.2.1 
Preclinical Pharmacokinetics and Metabolism ..................................32 
2.2.2.2 
Preclinical Toxicology .......................................................................33 
2.2.2.3 
Clinical Studies ..................................................................................34 
2.2.3 
Ongoing Clinical Studies .............................................................................34 
2.3 
Benefit/Risk Assessment ......................................................................................35 
3 
HYPOTHESES, OBJECTIVES, AND ENDPOINTS ................................................36 
4 
STUDY DESIGN ............................................................................................................37 
4.1 
Overall Design ......................................................................................................37 
4.2 
Scientific Rationale for Study Design .................................................................39 
4.2.1 
Rationale for Endpoints ...............................................................................40 
4.2.1.1 
Pharmacokinetic Endpoints ...............................................................40 
4.2.1.2 
Safety Endpoints ................................................................................40 
4.2.1.3 
Planned Exploratory Biomarker Research .........................................40 
4.2.1.3.1 
Planned Genetic Analysis ........................................................40 
4.2.1.4 
Future Biomedical Research ..............................................................41 
4.3 
Justification for Dose ...........................................................................................41 
4.4 
Beginning and End-of-Study Definition ............................................................41 
4.4.1 
Clinical Criteria for Early Study Termination .............................................42 
5 
STUDY POPULATION ................................................................................................42 
5.1 
Inclusion Criteria .................................................................................................43 
5.1.1 
Inclusion Criteria for Participants With Healthy Renal Function ................43 
5.1.2 
Inclusion Criteria for Participants With ESRD ............................................44 
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5.2 
Exclusion Criteria ................................................................................................45 
5.2.1 
Exclusion Criteria Participants With Healthy Renal Function ....................45 
5.2.2 
Exclusion Criteria for Participants With ESRD ...........................................48 
5.3 
Lifestyle Considerations ......................................................................................50 
5.3.1 
Meals and Dietary Restrictions ....................................................................50 
5.3.1.1 
Diet Restrictions .................................................................................50 
5.3.1.2 
Fruit Juice Restrictions ......................................................................50 
5.3.2 
Caffeine, Alcohol, and Tobacco Restrictions ..............................................51 
5.3.2.1 
Caffeine Restrictions ..........................................................................51 
5.3.2.2 
Alcohol Restrictions ...........................................................................51 
5.3.2.3 
Tobacco Restrictions ..........................................................................51 
5.3.3 
Activity Restrictions ....................................................................................51 
5.4 
Screen Failures .....................................................................................................51 
5.5 
Participant Replacement Strategy ......................................................................51 
6 
STUDY INTERVENTION ............................................................................................52 
6.1 
Study Intervention(s) Administered ...................................................................52 
6.2 
Preparation/Handling/Storage/Accountability .................................................54 
6.2.1 
Dose Preparation ..........................................................................................54 
6.2.2 
Handling, Storage, and Accountability ........................................................54 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................55 
6.3.1 
Intervention Assignment ..............................................................................55 
6.3.2 
Stratification .................................................................................................55 
6.3.3 
Blinding........................................................................................................55 
6.4 
Study Intervention Compliance ..........................................................................55 
6.5 
Concomitant Therapy ..........................................................................................56 
6.5.1 
Rescue Medications and Supportive Care ...................................................57 
6.6 
Dose Modification ................................................................................................57 
6.7 
Intervention After the End of the Study ............................................................57 
6.8 
Clinical Supplies Disclosure ................................................................................57 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL ............................................................................................................58 
7.1 
Discontinuation of Study Intervention ...............................................................58 
7.2 
Participant Withdrawal From the Study ...........................................................58 
7.3 
Lost to Follow-up .................................................................................................59 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................59 
8.1 
Administrative and General Procedures ...........................................................60 
8.1.1 
Informed Consent.........................................................................................60 
8.1.1.1 
General Informed Consent .................................................................60 
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8.1.1.2 
Consent and Collection of Specimens for Future Biomedical 
Research .............................................................................................61 
8.1.2 
Inclusion/Exclusion Criteria ........................................................................61 
8.1.3 
Genotyping of UGT2B17 and CYP2C19 ....................................................61 
8.1.4 
Participant Identification Card .....................................................................61 
8.1.5 
Medical History ...........................................................................................61 
8.1.6 
Prior and Concomitant Medications Review ...............................................61 
8.1.6.1 
Prior Medications ...............................................................................61 
8.1.6.2 
Concomitant Medications ..................................................................62 
8.1.7 
Assignment of Screening Number ...............................................................62 
8.1.8 
Assignment of Treatment/Allocation Number .............................................62 
8.1.9 
Study Intervention Administration ..............................................................62 
8.1.9.1 
Timing of Dose Administration .........................................................62 
8.1.10 
Discontinuation and Withdrawal .................................................................63 
8.1.10.1 
Withdrawal From Future Biomedical Research ................................63 
8.1.11 
Participant Blinding/Unblinding ..................................................................63 
8.1.12 
Domiciling ...................................................................................................64 
8.1.13 
Calibration of Equipment .............................................................................64 
8.2 
Efficacy/Immunogenicity Assessments ..............................................................64 
8.3 
Safety Assessments ...............................................................................................64 
8.3.1 
Physical Examinations .................................................................................64 
8.3.2 
Vital Signs ....................................................................................................65 
8.3.3 
Electrocardiograms ......................................................................................65 
8.3.4 
Pulse Oximetry.............................................................................................66 
8.3.5 
Hemodialysis (for ESRD Participants Only) ...............................................66 
8.3.6 
Clinical Safety Laboratory Assessments .....................................................67 
8.3.7 
Photograph of Rash ......................................................................................67 
8.4 
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events ....................................................................................................................67 
8.4.1 
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................68 
8.4.2 
Method of Detecting AEs, SAEs, and Other Reportable Safety Events ......70 
8.4.3 
Follow-up of AE, SAE, and Other Reportable Safety Event Information ...70 
8.4.4 
Regulatory Reporting Requirements for SAE .............................................70 
8.4.5 
Pregnancy and Exposure During Breastfeeding ..........................................71 
8.4.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs ............................................................................................71 
8.4.7 
Events of Clinical Interest ............................................................................71 
8.5 
Treatment of Overdose ........................................................................................72 
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8.6 
Pharmacokinetics .................................................................................................72 
8.6.1 
Blood Collection for Plasma MK-6482 .......................................................72 
8.7 
Pharmacodynamics ..............................................................................................72 
8.8 
Biomarkers ...........................................................................................................73 
8.8.1 
Planned Genetic Analysis Sample Collection..............................................73 
8.9 
Future Biomedical Research Sample Collection ...............................................73 
8.10 
Health Economics Medical Resource Utilization and Health Economics .......73 
8.11 
Visit Requirements...............................................................................................73 
8.11.1 
Screening......................................................................................................73 
8.11.2 
Treatment Period ..........................................................................................74 
8.11.3 
Participants Discontinued From Study Intervention Continuing to be 
Monitored in the Study ................................................................................74 
8.11.4 
Poststudy (Follow-up) ..................................................................................74 
8.11.5 
Critical Procedures Based on Study Objectives: Timing of Procedure .......74 
8.11.6 
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................75 
9 
STATISTICAL ANALYSIS PLAN .............................................................................76 
9.1 
Statistical Analysis Plan Summary.....................................................................76 
9.2 
Responsibility for Analyses .................................................................................76 
9.3 
Hypotheses/Estimation ........................................................................................76 
9.4 
Analysis Endpoints ..............................................................................................77 
9.5 
Analysis Populations ............................................................................................77 
9.6 
Statistical Methods ...............................................................................................77 
9.6.1 
PK Descriptive Statistics..............................................................................77 
9.6.2 
Renal Function Assessment .........................................................................78 
9.6.3 
PK Statistical Analysis .................................................................................78 
9.6.4 
Safety Analysis ............................................................................................80 
9.7 
Interim Analyses ..................................................................................................80 
9.8 
Multiplicity ...........................................................................................................80 
9.9 
Sample Size and Power Calculations .................................................................80 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .....................................................................................................82 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........82 
10.1.1 
Code of Conduct for Clinical Trials .............................................................82 
10.1.2 
Financial Disclosure .....................................................................................84 
10.1.3 
Data Protection.............................................................................................85 
10.1.3.1 
Confidentiality of Data ......................................................................85 
10.1.3.2 
Confidentiality of Participant Records...............................................85 
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10.1.3.3 
Confidentiality of IRB/IEC Information ............................................86 
10.1.4 
Publication Policy ........................................................................................86 
10.1.5 
Compliance with Study Registration and Results Posting Requirements ...86 
10.1.6 
Compliance with Law, Audit, and Debarment ............................................86 
10.1.7 
Data Quality Assurance ...............................................................................87 
10.1.8 
Source Documents .......................................................................................88 
10.1.9 
Study and Site Closure .................................................................................88 
10.2 
Appendix 2: Clinical Laboratory Tests..............................................................89 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...............................................................91 
10.3.1 
Definition of AE ..........................................................................................91 
10.3.2 
Definition of SAE ........................................................................................92 
10.3.3 
Additional Events Reported .........................................................................93 
10.3.4 
Recording AE and SAE ...............................................................................93 
10.3.5 
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................96 
10.4 
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................98 
10.5 
Appendix 5: Contraceptive Guidance ................................................................99 
10.5.1 
Definitions....................................................................................................99 
10.6 
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research ..........................................................................................100 
10.7 
Appendix 7: Country-specific Requirements ..................................................104 
10.8 
Appendix 8: Blood Volume Table ....................................................................105 
10.9 
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....106 
10.10 Appendix 10: Abbreviations .............................................................................107 
11 REFERENCES .............................................................................................................110 
 
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LIST OF TABLES 
Table 1 
Study Intervention ......................................................................................53 
Table 2 
Allocation Schedule ...................................................................................55 
Table 3 
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events .................................................................69 
Table 4 
Postdose Pharmacokinetic (Blood) Collection Windows ..........................75 
Table 5 
Protocol-required Safety Laboratory Assessments ....................................89 
 
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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 Renal 
Impairment on the Pharmacokinetics of MK-6482 
Short Title: MK-6482 Renal Impairment Study 
Acronym: Not Applicable 
Hypotheses, Objectives, and Endpoints: 
The following objectives will be evaluated in male and female participants with ESRD and 
matched control participants with normal renal function. 
Objectives 
Endpoints 
Primary 
 
• To compare the plasma PK of MK-6482 
following administration of a single oral 
120 mg dose of MK-6482 to 
participants with ESRD before and after 
HD to each other and also to that of 
healthy matched control participants. 
• Estimation: The plasma PK (AUC0-inf 
and Cmax) of MK-6482 following a 
single oral 120 mg dose of MK-6482 to 
participants with ESRD before and after 
HD will be estimated and compared to 
each other and 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 120 mg dose of 
MK-6482 in participants with ESRD. 
• AEs and discontinuation of study 
intervention due to AEs 
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• To investigate the extent of MK-6482 
removed by HD. 
• Estimation: The extent to which 
MK-6482 is removed by HD from the 
plasma (eg, CLD, plasma) will be 
estimated. 
• CLD, plasma as a measure of the extent 
of MK-6482 removal by HD 
 
Overall Design: 
Study Phase 
Phase 1 
 
Primary Purpose 
Treatment 
 
Indication 
Renal Cell Carcinoma 
 
Population 
Adult male and female participants with ESRD and 
healthy adult male and female participants 
 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
This is a single-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 5 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. 
 
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Number of Participants: 
Approximately 12 participants will be allocated as described in Section 9.9. 
Intervention Groups and Duration: 
Intervention 
Groups 
 
Intervention 
Group Name 
Drug 
Dose 
Level 
Dose 
Frequency 
Route of 
Administration 
Treatm
ent 
Period 
Use 
ESRD 
Group 
Period 1  MK-6482 
120 mg 
Single Dose 
Oral 
1 day 
Experi
mental 
Period 2  MK-6482 
120 mg 
Single Dose 
Oral 
1 day 
Experi
mental 
Healthy Matched 
Control Group 
MK-6482 
120 mg 
Single 
Dose 
Oral 
1 day 
Experi
mental 
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 in the ESRD group will participate in the study for 
approximately 7 weeks from the time the participant provides documented 
informed consent through the final contact. Each participant in the healthy 
control group 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 
1.3.1 
ESRD Group 
Period 1 for ESRD Group 
Study Period: 
Screening 
Intervention 
Notes 
Scheduled Day 
 
-1 
(C-I) 
1 
2 
3 
4 
Administrative Procedures 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Screening will occur within 28 days prior to the first study 
intervention administration [Sec. 8.1.1.1]. 
Informed Consent for FBR 
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 Sec. 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 
Sec. 6.5 
Assignment of Treatment/Allocation Number 
 
 
X 
 
 
 
Sec. 8.1.8 
Domiciling 
 
X 
X 
X 
X 
X 
Sec. 8.1.12 
Safety Procedures 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
Symptom-driven Physical Examination 
 
X 
X 
X 
X 
X 
Only to be conducted if the participant’s symptoms warrant an 
examination or at the investigator’s discretion. 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
BMI to be calculated only at the prestudy (screening) visit. 
HR, BP, and RR 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, and at 24, 48, and 
72 hours postdose. 
T 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, and at 24, 48, and 
72 hours postdose. 
12-lead ECG 
X 
X 
 
X 
 
X 
To be performed at Day -1, and at 24 and 72 hours postdose. 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, and at 24, 48, and 
72 hours postdose. 
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Period 1 for ESRD Group 
Study Period: 
Screening 
Intervention 
Notes 
Scheduled Day 
 
-1 
(C-I) 
1 
2 
3 
4 
Hem, Serum Chem, and UA 
X 
X 
 
X 
 
X 
To be performed at Day -1, and at 24 and 72 hours postdose. 
Urine samples will be collected whenever possible, as some 
participants may not be able to produce urine. For participants 
who are anuric, urine samples for UA will not be collected. 
Coagulation 
X 
 
 
 
 
 
 
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 
 
 
 
 
 
AE/SAE Review 
X 
X 
X 
X 
X 
X 
See Sec. 8.11.4 for poststudy contact details. 
Study Intervention Administration 
 
 
 
 
 
 
 
MK-6482 Administration 
 
 
X 
 
 
 
To be administered immediately following the Friday or 
Saturday scheduled HD session. 
There will be a washout period of at least 7 days between 
study intervention administrations in each period. 
Pharmacokinetics 
 
 
 
 
 
 
 
Blood for Plasma MK-6482 Assay 
 
 
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, and 72 hours postdose. 
Blood for Protein Binding 
 
 
X 
 
 
 
To be collected at predose. 
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, CYP=cytochrome P450, ECG=electrocardiogram, EM=extensive 
metabolizer, ESRD=end stage renal disease, FBR=future biomedical research, FSH=follicle-stimulating hormone, HD=hemodialysis, Hem=hematology, HIV=human 
immunodeficiency virus, HR=heart rate, IM=intermediate metabolizer, RR=respiratory rate, SAE=serious adverse event(s), T=body temperature, UA=urinalysis, UGT=uridine 5’-
diphospho-glucuronosyltransferase. 
 
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Period 2 for ESRD Group 
Study Period: 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
-1 
(C-I) 
1 
2 
3 
4 
Poststudy (follow-up) will occur approximately 14 days after 
the last study intervention administration [Sec. 8.11.4]. 
Administrative Procedures 
 
 
 
 
 
 
 
Prior/Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
Sec. 6.5 
Domiciling 
X 
X 
X 
X 
X 
 
Sec. 8.1.12 
Safety Procedures 
 
 
 
 
 
 
 
Complete Physical Examination 
 
 
 
 
 
X 
To be conducted also for participants who 
discontinue/withdraw from the study. 
Symptom Driven Physical Examination 
X 
X 
X 
X 
X 
 
Only to be conducted if the participant’s symptoms warrant 
an examination or at the investigator’s discretion. 
Weight 
 
 
 
 
 
X 
 
HR, BP, and RR 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, at 24, 48, and 72 hours 
postdose, and poststudy or prior to early termination from the 
study. 
T 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, at 24, 48, and 72 hours 
postdose, and poststudy or prior to early termination from the 
study. To be also performed at poststudy. 
12-lead ECG 
X 
 
X 
 
X 
X 
To be performed at Day -1, at 24 and 72 hours postdose, and 
poststudy or prior to early termination from the study. 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, at 24, 48, and 72 hours 
postdose, and poststudy or prior to early termination from the 
study. 
Hem, Serum Chem, and UA 
X 
 
X 
 
X 
X 
To be performed at Day -1, at 24 and 72 hours postdose, and 
poststudy or prior to early termination from the study. 
Coagulation 
 
 
 
 
 
X 
To be performed also for participants who 
discontinue/withdraw from the study. 
Urine/Saliva Drug Screen 
X 
 
 
 
 
 
 
Urine/Blood/Breathalyzer Alcohol 
Screen 
X 
 
 
 
 
 
 
AE/SAE Review 
X 
X 
X 
X 
X 
X 
See Sec. 8.11.4 for poststudy contact details. 
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Period 2 for ESRD Group 
Study Period: 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
-1 
(C-I) 
1 
2 
3 
4 
Poststudy (follow-up) will occur approximately 14 days after 
the last study intervention administration [Sec. 8.11.4]. 
Study Intervention Administration 
 
 
 
 
 
 
 
MK-6482 Administration 
 
X 
 
 
 
 
To be administered approximately 2 hours prior to the Friday 
or Saturday scheduled HD session. 
There will be a washout period of at least 7 days between 
study intervention administrations in each period. 
HD 
 
X 
 
 
 
 
The 4-hour HD session will be initiated immediately 
following the 2-hour PK blood draw. 
Pharmacokinetics 
 
 
 
 
 
 
 
Blood for Plasma MK-6482 
 
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, and 72 hours postdose. 
Dialyzer Samples for Plasma MK-6482  
 
X 
 
 
 
 
A pre-dialyzer plasma sample to be collected at the start of 
HD. Pre-dialyzer and post-dialyzer plasma samples to be 
collected at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4 hours 
(immediately before HD completion) from the start of HD. 
Abbreviations: AE=adverse event; BP=blood pressure, C-I=check-in, Chem=chemistry, ECG=electrocardiogram, ESRD=end stage renal disease, ET=early termination, 
HD=hemodialysis, Hem=hematology, HR=heart rate, PK=pharmacokinetic, RR=respiratory rate, SAE=serious adverse event(s), T=body temperature, UA=urinalysis. 
 
 
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1.3.2 
Healthy Control Group  
Study Period in Healthy Control Group 
Study Period: Screening 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
 
-1 
(C-I) 
1 
2 
3 
4 
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 FBR 
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 Sec. 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 
Sec. 6.5 
Assignment of Treatment/Allocation Number 
 
 
X 
 
 
 
 
Sec. 8.1.8 
Domiciling 
 
X 
X 
X 
X 
X 
 
Sec. 8.1.12 
Safety Procedures 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
X 
 
Symptom-driven Physical Examination 
 
X 
X 
X 
X 
X 
 
Only to be conducted if the participant’s symptoms 
warrant an examination or at the investigator’s discretion. 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
BMI to be calculated only at the prestudy (screening) 
visit. 
HR, BP, and RR 
X 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, at 24, 48, and 
72 hours postdose, and poststudy or prior to early 
termination from the study. 
T 
X 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, at 24, 48, and 
72 hours postdose, and poststudy or prior to early 
termination from the study. 
12-lead ECG 
X 
X 
 
X 
 
X 
X 
To be performed at Day -1, at 24 and 72 hours postdose, 
and poststudy or prior to early termination from the 
study. 
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Study Period in Healthy Control Group 
Study Period: Screening 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
 
-1 
(C-I) 
1 
2 
3 
4 
Poststudy (follow-up) will occur approximately 14 days 
after study intervention administration [Sec. 8.11.4]. 
Pulse Oximetry 
X 
X 
X 
X 
X 
X 
X 
To be performed at Day -1, predose, at 24, 48, and 
72 hours postdose, and poststudy or prior to early 
termination from the study. 
Hem, Serum Chem, and UA 
X 
X 
 
X 
 
X 
X 
To be performed at Day -1, at 24 and 72 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. 
Renal Function Assessment 
X 
 
 
 
 
 
 
eGFR will be determined using the MDRD equation. 
All healthy control participants will also have a measured 
CLcr as determined by a 24-hour urine collection. This 
assessment can be done any time prior to Day -1 
check-in. 
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 
 
 
 
 
 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
See Sec. 8.11.4 for poststudy contact details. 
Study Intervention Administration 
 
 
 
 
 
 
 
 
MK-6482 Administration 
 
 
X 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
Blood for Plasma MK-6482 Assay 
 
 
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, and 72 hours postdose. 
Blood for Protein Binding 
 
 
X 
 
 
 
 
To be collected at predose. 
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Study Period in Healthy Control Group 
Study Period: Screening 
Intervention 
Poststudy 
or ET 
Notes 
Scheduled Day 
 
-1 
(C-I) 
1 
2 
3 
4 
Poststudy (follow-up) will occur approximately 14 days 
after study intervention administration [Sec. 8.11.4]. 
Biomarkers 
 
 
 
 
 
 
 
 
Blood for Genetic Analysis 
 
 
X 
 
 
 
 
Collect 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, CLcr=creatinine clearance, CYP=cytochrome P450, 
ECG=electrocardiogram, eGFR=estimated glomerular filtration rate, EM=extensive metabolizer, FBR=future biomedical research, FSH=follicle-stimulating hormone, 
Hem=hematology, HIV=human immunodeficiency virus, HR=heart rate, IM=intermediate metabolizer, MDRD=Modification of Diet in Renal Disease, RR=respiratory rate, 
SAE=serious adverse event(s), 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 purpose of this study is to determine the impact of markedly impaired renal function on 
the single-dose PK of MK-6482. 
In vitro, MK-6482 is a substrate of UGT2B17, CYP2C19 and CYP3A4. Both 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 approaches. The collective results 
of these analyses indicate that UGT2B17 is the major route of elimination in individuals who 
express this enzyme, while CYP2C19 is also a relevant clearance pathway. 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 is anticipated to confirm that hepatic metabolism represents a 
major elimination pathway (>20% of the absorbed drug) for MK-6482. 
Renal excretion is not anticipated to represent a major clearance route for MK-6482. 
However, impaired renal function has been demonstrated to alter drug metabolism and 
transport pathways in the liver and gut, and these effects are more prominent in patients with 
severely impaired renal function (Dreisbach, 2009). As an example, CYP2C19 activity was 
reported to be reduced by 25% in patients with chronic renal impairment characterized by a 
GFR <50 mL/min (Dreisbach, 2009). There are no published reports on the impact of renal 
impairment on UGT2B17 activity. Furthermore, since nephron-sparing surgery is often the 
treatment of choice for amenable RCC lesions, VHL-RCC patients may undergo multiple 
sequential renal surgeries, which can lead to progressive worsening of renal function. In a 
retrospective analysis of 72 VHL patients with a median follow-up period of 61.5 months, 
30% of patients who underwent RCC surgery developed chronic kidney disease while 5% of 
patients developed ESRD and required HD (Kwon et al., 2014). 
2.2 
Background 
Refer to the IB for detailed background information on MK-6482. 
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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 blocks 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 
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. 
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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, HGB, and HCT 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. 
2.2.3 
Ongoing Clinical Studies 
There are 14 ongoing clinical studies with MK-6482 which include: 5 Phase 1 studies, 
1 Phase 1b/2 study, 5 Phase 2 studies, and 3 Phase 3 studies. The Phase 1 studies include an 
assessment of safety, tolerability, PK, pharmacodynamic properties, and anti-tumor activity 
of MK-6482 in participants with advanced solid tumors (MK-6482-001); investigation of 
absorption, metabolism, excretion, and mass balance of MK-6482 in healthy participants 
(MK-6482-008); evaluation of MK-6482 as monotherapy and in combination with lenvatinib 
with or without pembrolizumab in China participants with advanced RCC (MK-6482-010); 
evaluation of safety and tolerability of MK-6482 in participants with advanced ccRCC 
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(MK-6482-018); and evaluation of the impact of crystalline drug substance on MK-6482 PK 
in healthy participants (MK-6482-019). The Phase 1b/2 study is an evaluation of immune and 
targeted combination therapies in participants with RCC (MK-3475-U03). The Phase 2 
studies include an evaluation of efficacy and safety of MK-6482 in patients with VHL-RCC 
an evaluation of efficacy and safety of MK-6482 in combination with cabozantinib in adult 
participants with advanced ccRCC (MK-6482-003); evaluation of efficacy and safety of 
MK-6482 in patients with VHL-RCC (MK-6482-004); evaluation of efficacy and safety of 
MK-6482 in patients with advanced RCC (MK-6482-013); evaluation of efficacy and safety 
of MK-6482 monotherapy in participants with advanced pheochromocytoma/paraganglioma 
or pancreatic neuroendocrine tumor (MK-6482-015); and evaluation of efficacy and safety of 
pembrolizumab plus lenvatinib in combination with MK-6482 in multiple solid tumors 
(MK-6482-016). The ongoing Phase 3 studies include an evaluation of the efficacy and 
safety of MK-6482 in patients with advanced RCC (MK-6482-005); evaluation of MK-6482 
in combination with lenvatinib versus cabozantinib in participants with advanced RCC 
(MK-6482-011); and an evaluation of the efficacy and safety of pembrolizumab in 
combination with MK-6482 and lenvatinib, versus pembrolizumab and lenvatinib in 
participants with advanced ccRCC (MK-6482-012). 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.   
One case of multiple organ dysfunction syndrome resulting in death was reported in 
MK-6482-005 for a participant with advanced RCC, who received MK-6482 120 mg daily 
for approximately 2 weeks. The participant was also reported as experiencing disseminated 
intravascular coagulation, hepatic failure, hypocalcemia and sepsis. 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, 
 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 the prestudy (screening) visit 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. 
PPD
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The safety monitoring practices employed by this protocol (ie, 12-lead ECG, pulse oximetry, 
vital signs, clinical safety laboratory tests, AE questioning, and physical examinations) are 
adequate to protect the participants’ safety and should detect all expected treatment-emergent 
AEs. 
3 
HYPOTHESES, OBJECTIVES, AND ENDPOINTS 
The following objectives will be evaluated in males and females with ESRD and matched 
control participants with normal renal function:  
Objectives 
Endpoints 
Primary 
 
• To compare the plasma PK of MK-6482 
following administration of a single oral 
120 mg dose of MK-6482 to participants 
with ESRD before and after HD to each 
other and also to that of healthy matched 
control participants. 
• Estimation: The plasma PK (AUC0-inf 
and Cmax) of MK-6482 following a 
single oral 120 mg dose of MK-6482 to 
participants with ESRD before and after 
HD will be estimated and compared to 
each other and 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 120 mg dose of MK-6482 
in participants with ESRD. 
• AEs and discontinuation of study 
intervention due to AEs 
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• To investigate the extent of MK-6482 
removed by HD. 
• Estimation: The extent to which 
MK-6482 is removed by HD from the 
plasma (eg, CLD, plasma) will be 
estimated. 
• CLD, plasma as a measure of the extent 
of MK-6482 removal by HD 
Tertiary/Exploratory 
 
• 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 UGT2B17 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, single-site, open-label study of MK-6482 in 
participants with ESRD and healthy matched control participants. 
Screening of participants will occur within 28 days prior to first study intervention 
administration. 
A total of approximately 12 adult male (vasectomized or surgically sterilized) and female 
(nonchildbearing potential only) participants will be enrolled: 6 participants with ESRD and 
6 healthy matched control participants with normal renal function.  
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Assignment to renal function group will be as follows: 
Group 
N 
eGFR (mL/min/1.73m2) 
ESRD 
6 a 
Require dialysis 
Healthy matched control 
6 a 
≥ 90 b 
a. 
At least 2 UGT2B17 IMs and at least 2 EMs will be enrolled per group. 
b. The eGFR based on the MDRD equation will be calculated at screening. Baseline eGFR will be 
assessed during the screening period for study eligibility. If a repeat measurement is obtained, the 
mean of the two values will be used to assess study eligibility. At the discretion of the 
investigator, a measured CLcr as determined by a 24-hour urine collection may be used to 
determine eligibility for enrollment. Participants with an eGFR (using the MDRD equation) up to 
10% below 90 mL/min/1.73 m2 (ie, ≥81 mL/min/1.73 m2) may be eligible for the study if their 
measured CLcr (based on a 24-hour urine collection) is ≥90 mL/min. 
Following enrollment of the ESRD group, the healthy control group will be enrolled. Each 
healthy control participant will be matched to the mean age (± 15 years), BMI (± 20%), sex 
(with a similar male/female ratio in each group), and UGT2B17 genotype (at least 2 IMs and 
2 EMs) of participants with ESRD. If a UGT2B17 PM ESRD participant is enrolled in the 
study, a UGT2B17 PM healthy matched control participant should be included in the control 
group. If after reasonable efforts, a UGT2B17 PM healthy matched control participant cannot 
be enrolled, an additional ESRD participant (ie, a 7th ESRD participant), who is not 
UGT2B17 PM, will be enrolled. This additional ESRD participant should be matched to the 
mean age (± 15 years) and BMI (± 20%) of the other 6 ESRD participants. The final healthy 
matched control participant (ie, the 6th 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 6 ESRD participants (ie, not including the 7th 
ESRD participant). 
ESRD participants will receive a single oral dose of 120 mg MK-6482 on 2 separate 
occasions. In Period 1, ESRD participants will receive a single oral dose of 120 mg 
MK-6482 immediately following completion of their normally scheduled HD, followed by 
72 hours of blood sampling for PK assessment of MK-6482. For participants following a 
Monday, Wednesday, Friday HD schedule, MK-6482 will be administered immediately 
following their Friday HD session. For participants following a Tuesday, Thursday, Saturday 
HD schedule, study intervention will be administered immediately following their Saturday 
HD session. The participant’s next regularly scheduled HD session (either Monday or 
Tuesday) should initiate immediately following the 72-hour blood draw. If HD must be 
initiated before 72 hours postdose, a sample for MK-6482 analysis will be collected prior to 
HD. There will be a washout period of at least 7 days between MK-6482 administrations in 
each period.  
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In Period 2, ESRD participants will receive a single oral dose of 120 mg MK-6482 
approximately 2 hours prior to their normally scheduled HD followed by 72 hours blood 
sampling for PK assessment of MK-6482. For participants following a Monday, Wednesday, 
Friday HD schedule, MK-6482 will be administered approximately 2 hours prior to their 
Friday HD session. For participants following a Tuesday, Thursday, Saturday HD schedule, 
MK-6482 will be administered approximately 2 hours prior to their Saturday HD session. 
The 4-hour HD session should initiate immediately following the 2-hour PK blood draw. A 
pre-dialyzer plasma sample will be collected at the start of HD. During this dialysis session, 
pre- and post-dialyzer plasma samples will be collected approximately every 30 minutes 
during HD for MK-6482 analysis.  
Healthy matched control participants will receive a single oral dose of 120 mg MK-6482, 
followed by 72 hours of blood sampling for PK assessment of MK-6482. 
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. 
4.2 
Scientific Rationale for Study Design 
The primary objective of this trial is to investigate the impact of markedly impaired renal 
function on MK-6482 PK. MK-6482 is anticipated to be eliminated predominantly by hepatic 
metabolism. Although renal excretion is not anticipated to represent a major clearance route 
for MK-6482, impaired renal function can alter drug metabolism and transport pathways in 
the liver and gut. Since these effects are more prominent in patients with severely 
compromised renal function, this study will evaluate and compare MK-6482 PK in ESRD 
patients requiring HD to healthy control participants with normal renal function that are 
reasonably matched to the mean demographic parameters of participants with ESRD to 
control for the influence of covariates. In addition, the impact of HD on MK-6482 PK will 
also be assessed.  
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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 ESRD before and after HD compared to participants 
with healthy renal function, using GMR and CI to assess differences between these two 
groups.  
The secondary endpoint of this study is to evaluate the extent of MK-6482 removal by HD 
from plasma (CLD, plasma). The plasma parameter included in this secondary endpoint will be 
evaluated and compared between participants with ESRD before and after HD compared to 
participants with healthy renal function. 
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 in VHL-RCC and RCC patients of all available information include: hypoxia, 
anemia, fatigue, dyspnea, and dizziness. Therefore, the standard safety monitoring of AEs, 
physical examinations, 12-lead ECGs, pulse oximetry, vital signs, clinical safety laboratory 
tests (hematology, serum chemistry, and urinalysis), obtained throughout the study are 
appropriate to assess safety and tolerability of MK-6482 in this study. 
4.2.1.3 
Planned Exploratory Biomarker Research 
4.2.1.3.1 
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 
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. 
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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. 
4.2.1.4 
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 clinical dose for MK-6482 is 120 mg daily, which will be evaluated in this 
study. Single MK-6482 doses up to 200 mg, which was associated with a 1.6-fold increase in 
AUC compared to 120 mg, have been previously administered to healthy participants and 
were generally well tolerated. Furthermore, multiple daily doses of up to 240 mg daily and 
120 mg twice daily have been administered to patients with advanced solid tumors.  
Renal impairment was not identified as a significant covariate based on a population PK 
analysis using MK-6482 concentration data across multiple MK-6482 clinical studies, which 
was anticipated since renal clearance represents a minor elimination pathway for MK-6482 in 
humans. 
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 
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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 renal function will match to the mean demographic parameters of 
the ESRD group. Healthy control participants will be matched for the mean age (± 15 years), 
mean BMI (± 20%), sex (with a similar male/female ratio in each group), and UGT2B17 
genotype (at least 2 IMs and 2 EMs) of the ESRD group. If a UGT2B17 PM ESRD 
participant is enrolled in the study, a UGT2B17 PM healthy matched control participant 
should be included in the control group. If after reasonable efforts, a UGT2B17 PM healthy 
matched control participant cannot be enrolled, an additional ESRD participant (ie, a 7th 
ESRD participant), who is not UGT2B17 PM, will be enrolled. This additional ESRD 
participant should be matched to the mean age (± 15 years) and BMI (± 20%) of the other 
6 ESRD participants. The final healthy matched control participant (ie, the 6th 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 
6 ESRD participants (ie, not including the 7th ESRD participant). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
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5.1 
Inclusion Criteria 
5.1.1 
Inclusion Criteria for Participants With Healthy Renal 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 the study intervention.  
2. Is in good health based on clinical laboratory safety tests obtained at the prestudy 
(screening) visit and before administration of study intervention. Appendix 2 provides a 
table of clinical laboratory safety tests to be performed. Appendix 9 provides an 
algorithm for the assessment of out-of-range laboratory values. 
3. Have a BMI 18.0-46.0 kg/m2, inclusive, at prestudy (screening). 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 ESRD 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 ESRD 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 
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. 
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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 ESRD 
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 renal 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 the initial administration 
of the study intervention. 
2. With exception of the renal impairment, is in good health, in the opinion of the 
investigator, based on clinical laboratory safety tests obtained at the prestudy (screening) 
visit and before the initial administration of study intervention. Appendix 2 provides a 
table of clinical laboratory safety tests to be performed. 
3. Have a BMI 18.0-46.0 kg/m2, inclusive, at prestudy (screening). See Section 8.3.1 for 
criteria on rounding to the nearest whole number. BMI = weight (kg)/height (m)2. 
4. Participant has ESRD maintained on stable regimen of at least 3 times per week HD for 
at least 3 months prior to the initial administration of the study intervention. 
Demographics 
5. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent. 
Male Participants 
6. Male participants are eligible to participate if they have been vasectomized or undergone 
surgical sterilization at least 4 months or more prior to the initial study intervention 
administration and agree to the following during the intervention period and for at least 
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7 days (time needed for MK-6482 to be eliminated) after the last 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 
7. A female participant is eligible to participate if:  
- 
She is a WONCBP, as defined in Appendix 5. 
Informed Consent 
8. 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. 
5.2 
Exclusion Criteria 
5.2.1 
Exclusion Criteria Participants With Healthy Renal 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 prior to the prestudy 
[screening] visit, or childhood asthma) may be enrolled in the study at the discretion of 
the investigator. 
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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 in the last 5 years prior to the prestudy 
[screening] visit. 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. Participant has an estimated eGFR <90 mL/min/1.73 m2 based on the MDRD equation. 
At the discretion of the investigator, a measured CLcr as determined by a 24-hour urine 
collection may be used to determine eligibility for enrollment. Participants with an eGFR 
(using the MDRD equation) up to 10% below 90 mL/min/1.73 m2 
(ie, ≥81 mL/min/1.73 m2) may be eligible for the study if their measured CLcr (based on 
a 24-hour urine collection) is ≥90 mL/min. 
MDRD Equation: 
eGFR (mL/min/1.73 m2) =  
175 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 [if female]) x (1.212 [if Black or 
African American]) 
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 at the prestudy (screening) visit. 
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. 
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Prior/Concurrent Clinical Study Experience 
10. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the initial 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 a history of anemia within 5 years prior to the prestudy (screening) visit. 
13. Has a pulse oximetry reading <92% at rest at the prestudy (screening) visit or check-in. 
14. Has a QTc interval >470 msec, 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 at the prestudy (screening) visit. 
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. 
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.  
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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 ESRD 
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 the 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder in the last 5 years prior to the prestudy 
(screening) visit. 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 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. 
4. Has required frequent emergent HD (≥3) within a year prior to the initial dose of study 
intervention. 
5. Is positive for HBsAg, hepatitis C antibodies, or HIV at the prestudy (screening) visit. 
6. 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 
7. 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). 
8. 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. 
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Prior/Concomitant Clinical Study Experience 
9. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the initial study intervention administration. The window 
will be derived from the date of the last study intervention administration in the previous 
study. 
Diagnostic Assessments 
10. Has a UGT2B17 and CYP2C19 genotype consistent with a dual poor metabolizer 
phenotype. 
11. Has HGB level <9.5 g/dL at the prestudy (screening visit) or check-in. Participants with 
HGB ≥9.0 g/dL may be enrolled to the study at the discretion of the investigator and 
following consultation with the Sponsor. 
12. Has a pulse oximetry reading <92% at rest at the prestudy (screening visit) or first 
check-in.  
13. Has a QTc interval >480 msec, 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 
14. Is under the age of legal consent at the prestudy (screening) visit. 
15. Is a heavy smoker or heavy user of nicotine-containing products (>20 cigarettes or 
equivalent/day). 
16. 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.  
17. 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. 
18. 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. 
19. 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 first check-in, unless 
the positive drug screen is due to prescription drug use that is approved by the 
investigator and Sponsor. 
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20. 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. 
21. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions). 
22. 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. 
 
5.3 
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 clinical laboratory 
safety evaluations are specified in Appendix 2. 
On Day 1 of each period (as applicable), 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 (initial) study 
intervention, throughout the study and until the last PK sample collection. 
Participants also will refrain from the consumption of all fruit juices 24 hours before and 
after (each) study intervention administration. On all other days during the study, 
consumption of fruits and fruit juices (except for grapefruit, grapefruit juices, and grapefruit 
products) is allowed. 
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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 12 hours before the prestudy (screening) and poststudy (follow-up) visits and 
from 12 hours before and after (each) study intervention administration. At all other times, 
caffeinated beverages or xanthine-containing products will be limited to no more than 6 units 
per day (1 unit = 120 mg of caffeine). 
5.3.2.2 
Alcohol Restrictions 
Participants will refrain from consumption of alcohol 24 hours before the prestudy 
(screening) and poststudy (follow-up) visits and from 48 hours before each study intervention 
administration and until last PK sample collection in each period. At all other times, alcohol 
consumption is limited to no more than approximately 3 alcoholic beverages or equivalent 
(1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], 
or distilled spirits [29.5 mL/1 ounce]) per day. 
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 study 
intervention, throughout the study (including washout intervals between treatment periods), 
and until the poststudy (follow-up) 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 discontinues from study intervention or 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 
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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 
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 1.
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Table 1 
Study Intervention 
Arm Name 
Arm Type 
Intervention 
Name 
Intervention 
Type 
Dose 
Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administra
tion 
Regimen/ 
Treatment 
Period 
Use 
IMP/ 
NIMP 
Sourcing 
ESRD Group 
(Period 1 and 
Period 2) 
 
Experimental 
 
MK-6482 
 
Drug 
 
Tablet 
 
40 mg 
 
120 mg 
 
Oral 
 
Period 1, 
Day 1 
Period 2, 
Day 1 
 
Exp
erim
ental 
 
IMP 
 
Sponsor 
 
Healthy 
Control 
Group 
Experimental 
MK-6482 
Drug 
Tablet 
40 mg 
120 mg 
Oral 
Period 1, 
Day 1 
Exp
erim
ental 
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 European Economic Area. 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 1 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 allocation number at the time of initial study intervention administration, 
different from the screening number, and will receive the study intervention. 
Participants will receive the treatment(s) as depicted in Table 2. 
Table 2 
Allocation Schedule 
Group 
N 
Period 1 
Period 2 a 
ESRD participants 
6 
120 mg MK-6482 (immediately 
after HD) 
120 mg MK-6482 
(approximately 2 hours prior 
to HD) 
Healthy participants 
6 
120 mg MK-6482 
Not applicable 
a There will be at least 7 days of washout between study intervention administrations in each 
period. 
 
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. 
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management. 
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6.5 
Concomitant Therapy 
Participants with ESRD only 
Participants who are taking certain prescription medications to treat manifestations of renal 
disease or medications needed to treat stable diseases (eg, angiotensin converting enzyme 
inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics) will be allowed to 
participate in the study at the discretion of the investigator and following consultation with 
the Sponsor. Participants must be on a stable regimen for at least 2 weeks (or 5 half-lives of 
the study drug, whichever is longer) prior to initial administration of the study intervention 
and is able to withhold the use within 4 hours prior to initial administration of the study 
intervention. 
Any medication (including over-the-counter) that would significantly alter eGFR, which, by 
the determination of the investigator, might interfere with the study (eg, cimetidine) must be 
discontinued at least 2 weeks (or 5 half-lives of the compound, whichever is longer) prior to 
initial administration of the study intervention.  
Phosphate binders containing aluminum, calcium, or lanthanum salts; iron supplements or 
other metal cations;H2-receptor antagonists (H2RAs [except cimetidine]); or multivitamins 
containing iron or zinc must be withheld at least 8 hours prior to each administration of the 
study intervention and at least 4 hours postdose. 
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
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 Renal 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, 
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, CYP2C19, and any drugs known 
to be strong or moderate inhibitors or inducers of CYP3A4 enzymes will be restricted for at 
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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 (initial) 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. 
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). 
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 
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. 
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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, healthy matched control participants who receive a 
single-dose intervention cannot discontinue study intervention.  
For ESRD participants only: 
Discontinuation of study intervention does not represent withdrawal from the study. 
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled 
follow-up, even if the participant has discontinued study intervention. Therefore, all 
participants who discontinue study intervention before completion of the protocol-specified 
treatment period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.1.10, or if available, a PCL. 
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10. 
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to discontinue 
study intervention. 
• The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention. 
• The participant has a positive drug screen at any time during the course of the study (with 
the exception for positive drug screen due to prescription drug use that is approved by the 
investigator and Sponsor). The drug screen can be confirmed by a recheck at the 
discretion of the investigator after discussion with the Sponsor. 
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. 
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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 
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. 
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• 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. 
• 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 ESRD participant and healthy 
participant over the duration of the study will not exceed 313.5 mL and 148 mL, respectively 
(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 ICF 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. 
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If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent. 
Specifics about the study and the study population are to be included in the study ICF. 
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 (initial) administration of study intervention. 
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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 allocation. Each 
participant will 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. 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 and for each study period (as applicable), 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 
ESRD Participants 
On Day 1 of Period 1, 120 mg (3x40 mg tablets) MK-6482 will be administered at Hour 0, 
immediately following completion of their normally scheduled HD. On Day 1 of Period 2, 
120 mg (3x40 mg tablets) MK-6482 will be administered at Hour 0, approximately 2 hours 
prior to their normally scheduled HD.  
Healthy Participants 
On Day 1, 120 mg (3x40 mg tablets) MK-6482 will be administered at Hour 0. 
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All Participants 
The study intervention will be administered with 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 
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. 
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8.1.12 
Domiciling 
ESRD participants will be admitted to the CRU on Day -1 of each period, at the time 
indicated by the CRU, and will be housed until after the 72 hours postdose and/or study 
procedures on Day 4. As per CRU preference, participants may be confined throughout the 
study (ie, washout periods). 
Healthy participants will be admitted to the CRU on Day -1 , at the time indicated by the 
CRU, and will be housed until after the 72 hours postdose and/or study procedures on Day 4.  
All 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. 
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 to be drawn over the course of the study (from prestudy 
[screening] to poststudy [follow-up] visits), including approximate blood volumes drawn 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. 
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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. 
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.  
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• 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. 
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 or designee 
will be documented. 
8.3.5 
Hemodialysis (for ESRD Participants Only) 
ESRD participants will receive HD as per their regular schedule.  
Period 1: For participants following a Monday, Wednesday, Friday HD schedule, study 
intervention will be administered immediately following their Friday HD session. For 
participants following a Tuesday, Thursday, Saturday HD schedule, study intervention will 
be administered immediately following their Saturday HD session. The participant’s next 
regularly scheduled HD session (either Monday or Tuesday) should initiate immediately 
following the 72-hour blood draw.  
Period 2: For participants following a Monday, Wednesday, Friday HD schedule, study 
intervention will be administered approximately 2 hours prior to their Friday HD session. For 
participants following a Tuesday, Thursday, Saturday HD schedule, study intervention will 
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be administered approximately 2 hours prior to their Saturday HD session. The HD session 
should initiate immediately following the 2-hour PK blood draw. The HD period will be of 
approximately 4 hours. A pre-dialyzer plasma sample will be collected at the start of HD. 
Blood samples collected during HD will be collected from both the pre-dialyzer and 
post-dialyzer blood lines. 
The blood flow, dialysate flow, and the make and model of the dialyzer will be recorded. 
8.3.6 
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 last 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. 
 
8.3.7 
Photograph of Rash 
Photographs of any 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 relationship to the study 
intervention. 
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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AEs, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator 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 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 3. 
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 3 
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 
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 
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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 (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. 
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. 
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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. 
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. 
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2. 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 PK will be collected at scheduled time points as 
delineated in the SoA.  
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 
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual. 
8.7 
Pharmacodynamics 
Not applicable. 
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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. 
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 (initial) 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 if there are Day -1 
procedures planned per protocol. 
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8.11.2 
Treatment Period 
Refer to the SoA (Section 1.3). 
8.11.3 
Participants Discontinued From Study Intervention Continuing to be 
Monitored in the Study 
At any point if a participant discontinues from study intervention or 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 at least one administration of study intervention (including 
participants who terminate the study early) will return to the CRU approximately 14 days 
after the last administration of study intervention 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 collection for MK-6482 is the critical procedure. 
At any postdose time point, the blood sample for MK-6482 needs 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. 
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 4. 
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Table 4 
Postdose Pharmacokinetic (Blood) Collection Windows 
PK Collection 
(relative to dosing) 
PK Collection Window 
(relative to scheduled time for collection) 
0 to 2 hour 
5 min 
>2 to 12 hours 
15 min 
>12 to 48 hours 
1 hour 
>48 to 72 hours 
2 hours 
 
• Postdose standard safety evaluations: vital signs, ECG, pulse oximetry, and clinical 
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 72-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. 
Up to an 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 
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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 processed 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. 
9.3 
Hypotheses/Estimation 
Primary Estimation: 
Estimation: The plasma PK (AUC0-inf and Cmax) of MK-6482 following a single oral 
120 mg dose of MK-6482 to participants with ESRD before and after HD will be estimated 
and compared to each other and to those in healthy matched control participants. 
Secondary Estimation: 
Estimation: The extent to which MK-6482 is removed by HD from the plasma 
(eg, CLD, plasma) will be estimated. 
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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 ESRD before and after HD to each other and to those 
in healthy matched control participants. 
Additional PK endpoints will include AUC0-last, AUC0-24, AUC%extrap, Cmax, C24, 
Tmax, apparent terminal t½, λz, CL/F, and Vz/F. 
For ESRD participants in Period 2, the secondary PK endpoint for plasma MK-6482 will 
include CLD, plasma. Additional PK endpoints for ESRD participants in Period 2 will include 
Ca, Cv, AUC(2-6)Ca, and AUC(2-6)Cv. 
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 at least one dose of 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 plasma 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 
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. 
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9.6.2 
Renal Function Assessment 
The following renal function parameters will be calculated for each participant. 
1. BSA normalized eGFR 
The MDRD (Modification of Diet in Renal Disease) equation will be used to estimate 
GFR standardized to a BSA of 1.73 m2: 
eGFR (mL/min/1.73m2) = 175 × standardized serum creatinine (mg/dL)-1.154× age-0.203 × 
(0.742 if female) × (1.212 if Black or African American). 
2. BSA un-normalized eGFR 
The MDRD equation provides an estimate of GFR standardized to a BSA of 1.73 m2, and 
it is therefore necessary to multiply this estimate by each participant’s ratio of BSA/1.73 
to determine the participant specific BSA un-normalized GFR:  
eGFR (mL/min) = eGFR (mL/min/1.73m2) × [BSA (m2) / 1.73]. 
The BSA of an individual is calculated using the following equation:  
BSA (m2) = [weight (kg)0.425 × height (cm)0.725] × 0.007184. (Dubois and Dubois, 1916, 
Wang et al., 1992) 
Note:  The participants categorized into different renal categories based on BSA 
normalized eGFR may not fall into the same renal categories after re-categorization based 
on BSA un-normalized eGFR. 
3. CLcr using the C-G Equation 
CLcr will be estimated using the following equation: 
CLcr  = {[140 - age(yr)] × [body wt (kg)] × (0.85 if female)} / [72 × serum creat 
(mg/dL)] 
Note:  The participants categorized into different renal categories based on eGFR using 
MDRD equation may not fall into the same renal categories after re-categorization based 
on CLcr by C-G equation. 
9.6.3 
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 (participants with ESRD before and after HD, control 
participants with normal renal function). An unstructured covariance matrix will be used to 
allow for unequal population variances and to model the correlation between repeated 
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measures (before and after HD) within each ESRD participant via the REPEATED and 
SUBJECT 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% confidence limits 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 subject;  
model lnpk = population /ddfm=kr;  
repeated population/ subject=subject type=UN;  
lsmeans population /cl alpha=0.10; 
lsmeans population/pdiff alpha=0.10;  
run;  
 
To address the primary estimation objective and compare participants with ESRD before and 
after HD to participants with normal renal function, a two sided 90% CI for the difference in 
least-squares means (ESRD before HD – normal renal function, ESRD after HD – normal 
renal function) will be calculated for each PK parameter using the aforementioned model. 
These confidence limits will be exponentiated to obtain the 90% CI for the ratio of geometric 
means (ESRD before HD/normal renal function, ESRD after HD/normal renal function) for 
each PK parameter. The same approach will be used to address the secondary estimation 
objective. The extent to which MK-6482 is removed from plasma by HD will be evaluated 
with the difference in means (ESRD before HD – ESRD after HD), the geometric mean ratio 
(ESRD before HD/ESRD after HD) and their 90% CIs. A sensitivity analysis may be 
performed without PMs at UGT2B17 or CYP2C19 if applicable as deemed clinically 
appropriate.  
Figures showing summary plasma concentration-time profiles by population for MK-6482 
(linear plot with arithmetic mean (±SD) for concentration and semi-log plot with arithmetic 
mean) will be provided. A table showing summary PK parameter values with GMs (%GCV) 
by population, will be provided for MK-6482 AUC0-inf, AUC0-24, Cmax, Tmax, and 
apparent terminal t½. A table showing the GMR (ESRD before HD /normal renal function, 
ESRD after HD/normal renal function, ESRD before HD/ESRD after HD) and corresponding 
90% CI will be provided for PK parameters, AUC0-inf and Cmax.  
Individual values will be listed for each PK parameter for MK-6482 (AUC0-inf, AUC0-last, 
AUC0-24, AUC%extrap ([percentage of AUC0-inf obtained by extrapolation from 24 hours 
to ∞], λz [terminal elimination rate constant], Cmax, Tmax, CL/F, Vz/F, λz, apparent 
terminal t½, CLD, plasma [dialysis clearance based on plasma], Ca [concentration in plasma 
samples from the pre-dialyzer line during the dialysis period], and Cv [concentration in 
plasma samples from the post-dialyzer line during the dialysis period]. The following 
(non-model-based) descriptive statistics will be provided: N (number of participants with 
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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). Descriptive statistics may be provided based on UGT2B17 
and/or CYP2C19 phenotypes separately. 
Individual participant PK parameter values will also be plotted against BSA normalized 
eGFR and against BSA un-normalized eGFR, using different symbols to identify participants 
from each population. For this analysis, eGFR may be calculated as the mean of the two 
values determined at the prestudy (screening) visit. Plots of PK parameters versus CLcr 
obtained from C-G equation may be provided. Additionally, plots of PK parameter values 
versus age and BMI may be provided. PK concentration listings for MK-6482 in plasma, 
including Ca and Cv concentrations, will be provided for each participant; AUC(2-6)Ca 
(plasma AUC values determined from Ca versus time profile during the dialysis period from 
2 hours to 6 hours postdose using ‘linear up, log down’ calculation method option in 
WinNonlin), AUC(2-6)Cv (plasma AUC values determined from Cv versus time profile 
during the dialysis period from 2 hours to 6 hours postdose using ‘linear up, log down’ 
calculation method option in WinNonlin) for MK-6482 during HD in Period 2 will be 
provided for each ESRD participant. 
9.6.4 
Safety Analysis 
All AEs, vital signs, ECGs, pulse oximetry, and clinical safety laboratory values will be 
listed for each participant and tabulated by population. Summary statistics for the clinical 
safety laboratory tests, vital signs, and/or ECGs may also be computed and provided, as 
deemed clinically appropriate. 
9.7 
Interim Analyses 
Not applicable. 
9.8 
Multiplicity 
Not applicable. 
9.9 
Sample Size and Power Calculations 
The sample size selected to evaluate the effect of renal impairment on the PK of MK-6482 
was not chosen to satisfy any a priori statistical requirement. This sample size (N=6 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 renal PK studies are presented below. 
The precision of the estimated GMRs (ESRD before or after HD / normal renal function) of 
PK parameters obtained from this study can be assessed by calculating the half-width of the 
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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 6 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 0.545. The lower and upper 90% 
confidence limits for the GMR will be given by OBS/1.72 and OBS*1.72 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 [0.87, 2.59]. 
Similarly, the observed between-participant coefficients of variation were 26.04% 
(~0.256 SD on the log scale) and 25.25% (~0.249 SD on the log scale) for Cmax from 
Protocol MK-6482-002 and Protocol MK-6482-006, respectively. Assuming a sample size of 
6 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 
0.243. The lower and upper 90% confidence limits for the GMR will be given by OBS/1.28 
and OBS*1.28 for Cmax. Thus, for example, if the observed GMR for Cmax was 1.50, then 
the approximate 90% CI for the GMR would be [1.18, 1.91]. 
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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/eCRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/eCRF 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 eCRF. 
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/eCRFs. 
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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 eCRF 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 5 will be performed by the local laboratory with the exception 
of the UGT2B17 and CYP2C19 genotyping at 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 5 
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 
Magnesium 
Coagulation 
INR 
PT 
 
 
Routine 
Urinalysis b 
• Specific gravity 
• pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
• FSH (postmenopausal females only) 
• Urine b/breath alcohol and urine b/saliva drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
• Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)  
• UGT2B17 genotyping 
• CYP2C19 genotyping 
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 when the serum chemistry sample is taken 
b. For participants with ESRD, urine samples will be collected whenever possible, as they may not be able to produce 
urine. For participants who are anuric, urine samples for urinalysis will not be collected. 
 
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ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CYP=cytochrome P450; 
FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface antigen; HCT=hematocrit; 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; 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 
clinical 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. 
e. Is a congenital anomaly/birth defect 
• In offspring of participant taking the product regardless of time to diagnosis. 
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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 
eCRFs/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 eCRF 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. 
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced? 
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◦ 
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 eCRFs/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: 
◦ 
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.) 
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• 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 eCRF. 
• 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. 
• 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). 
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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 
delayed, present consent at next possible Participant Visit. Consent forms signed by 
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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 
ESRD Participants Only 
Prestudy 
Treatment Periods Poststudy 
Total 
Collections 
mL Per 
Collection 
Total mL/ 
Test 
Safety Clinical Laboratory 
Tests (including 
hematology, serum 
chemistry, FSH [if 
scheduled at the same time]) 
1 
6 b 
1 
8 
12.5 
100 
Coagulation 
1 
-- 
1 
2 
3.5 
7 
Blood for Planned Genetic 
Analysis  
-- 
1 
-- 
1 
8.5 
8.5 
Blood for MK-6482  
-- 
30 
-- 
30 
4 
120 
Blood for Protein Binding 
-- 
1 
-- 
1 
4 
4 
Pre- and Post-dialyzer 
Plasma for MK-6482 
-- 
17 c  
-- 
17 
4 
68 
Blood for UGT2B17 
Genotyping 
1 
-- 
-- 
1 
3 
3 
Blood for CYP2C19 
Genotyping 
1 
-- 
-- 
1 
3 
3 
Total Blood Volume per Participant a 
313.5 mL 
a If additional PK and/or safety analysis is necessary, additional blood (up to 50 mL) may be obtained. 
b If the CRU decides to confine the participants throughout the study (ie, washout period), some clinical laboratory 
assessments at the second check-in may not be performed at the investigator’s discretion. 
c Dialyzer samples collected in Period 2 only. 
 
Healthy Participants Only 
Prestudy 
Treatment Period 
Poststudy 
Total 
Collections 
mL Per 
Collection 
Total mL/ 
Test 
Safety Clinical Laboratory 
Tests (including 
hematology, serum 
chemistry, FSH [if 
scheduled at 
the same time]) 
1 
3 
1 
5 
12.5 
62.5 
Coagulation 
1 
-- 
1 
2 
3.5 
7 
Blood for Planned Genetic 
Analysis  
-- 
1 
-- 
1 
8.5 
8.5 
Blood for MK-6482 
-- 
15 
-- 
15 
4 
60 
Blood for Protein Binding 
-- 
1 
-- 
1 
4 
4 
Blood for UGT2B17 
Genotyping 
1 
-- 
-- 
1 
3 
3 
Blood for CYP2C19 
Genotyping 
1 
-- 
-- 
1 
3 
3 
Total Blood Volume per Participant a 
148 mL 
a If additional PK 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 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event  
ALT 
alanine aminotransferase 
ARNT 
aryl hydrocarbon receptor nuclear translocator 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCS 
Biopharmaceutical Classification System 
bid 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BSA 
body surface area 
Ca 
concentration in plasma samples from the pre-dialyzer line during the 
dialysis period 
ccRCC 
clear cell renal cell carcinoma 
CCU 
cardiac/coronary care unit 
C-G 
Cockcroft-Gault 
CI 
confidence interval 
CL/F 
apparent clearance 
CLcr 
creatinine clearance 
CLD 
HD clearance based on dialysate, calculated as: AED,total/AUCD 
CLD, plasma 
dialysis clearance based on plasma 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CRF 
case report form  
CRU 
clinical research unit 
CSR 
clinical study report 
Cv 
concentration in plasma samples from the post-dialyzer line during the 
dialysis period 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid  
ECG 
electrocardiogram  
ECI 
event of clinical interest 
eCRF 
electronic case report form 
EDC 
electronic data collection  
eGFR 
estimated glomerular filtration rate 
EM 
extensive metabolizer 
EMA 
European Medicines Agency 
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Abbreviation 
Expanded Term 
EPO 
erythropoietin 
ESRD 
end stage renal disease 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FBR 
future biomedical research 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice  
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GMR 
geometric mean ratio 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCT 
hematocrit 
HD 
hemodialysis 
HGB 
hemoglobin 
HIF-1α 
hypoxia-inducible factor 1 alpha 
HIF-1β 
hypoxia-inducible factor 1 beta 
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 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IM 
intermediate metabolizer 
IMP 
investigational medicinal product 
IND 
investigational new drug  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
MDRD 
Modification of Diet in Renal Disease 
NCS 
not clinically significant 
NIMP 
noninvestigational medicinal product 
PAS 
Per-ARNT-Sim 
PCL 
protocol clarification letter 
PK 
pharmacokinetic 
PM 
poor metabolizer 
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Abbreviation 
Expanded Term 
PP 
per-protocol 
PR 
PR interval of ECG 
PRO 
patient-reported outcome 
PT 
prothrombin time 
QRS 
QRS interval of the ECG 
QT 
QT interval of the ECG 
QTc 
corrected QT interval 
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 
SLC2A1 
glucose transporter solute carrier family 2 member 1  
SoA 
schedule of activities 
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
T 
body temperature 
Tmax 
time to maximum plasma concentration 
t½ 
half life 
UA 
urinalysis 
UGT 
uridine 5´-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
VEGF-A 
vascular endothelial growth factor A 
VHL 
von Hippel-Lindau disease 
VHL-RCC 
von Hippel-Lindau disease-associated renal cell carcinoma 
WBC 
white blood cell 
WONCBP 
woman/women of nonchildbearing potential 
 
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11 REFERENCES 
Dreisbach AW. The influence of chronic renal failure on drug metabolism and transport. Clin 
Pharmacol Ther. 2009; 86(5):553-6. 
DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and 
weight be known. Arch Intern Medicine. 1916; 17:863-71. 
Kwon T, Jeong IG, Pak S, et al. Renal tumor size is an independent prognostic factor for 
overall survival in von Hippel-Lindau Disease. J Cancer Res Clin Oncol. 2014; 
140:171-1177. 
Scheuermann TH, Li Q, Ma HW, et al. Allosteric inhibition of hypoxia inducible factor-2 
with small molecules. Nat Chem Biol. 2013; 9(4):271-6. 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Draft Guidance for Industry: Pharmacokinetics in 
Patients with Impaired Renal Function —Study Design, Data Analysis, and Impact on 
Dosing. September 2020. 
Wang Y, Moss J, Thisted R. Predictors of body surface area. J Clin Anesth. 1992; 4(1):4-10. 
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