Clinical trial NCT02910739
Conditions: Amnestic Mild Cognitive Impairment Alzheimer's Disease Prodromal Alzheimer's Disease
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-10-11; Completion date: 2017-04-12
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of Part I and an optional Part II. The purpose of Part I is to compare the plasma pharmacokinetics of verubecestat (MK-8931) following administration of a single oral dose of 40 mg MK-8931 to participants with moderate hepatic insufficiency (HI) to that of healthy matched controls. An interim safety and pharmacokinetic analysis on the basis of Part I will be performed in order to support the decision to continue with the optional Part II. If a decision to continue with Part II is made, participants with mild HI will be enrolled to receive a single oral dose of 40mg MK-8931. If any healthy participants from Part I do not meet the matching criteria for Part II additional healthy participants will be enrolled.

Detailed description:

Arms: arm 1: Single oral dose of MK-8931 40 mg tablet in participants with moderate HI in fasted state (Part I) arm 2: Single oral dose of MK-8931 40 mg tablet in healthy matched participants in fasted state (Part I) arm 3: Single oral dose of MK-8931 40 mg tablet in participants with mild HI in fasted state (Part II) arm 4: Single oral dose of MK-8931 40 mg tablet in healthy matched participants in fasted state (Part II)
Interventions: intervention 1: MK-8931
Intervention descriptions: intervention 1: MK-8931 40 mg

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Two-Part, Open-Label Study to Investigate the Single-Dose 
Pharmacokinetics of MK-8931 when Administered to Subjects with 
Mild and Moderate Hepatic Insufficiency 
NCT number: 
NCT02910739 
Document Date: 
05-Jan-2017 


 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 1 
Confidential 
 
 
 
 
 
 
 
 
 
Celerion Project No.:  CA13011 
 
Merck Protocol No.:  MK-8931-016-01 
 
US IND No.:  110,186 
 
 
A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of 
MK-8931 when Administered to Subjects with Mild and Moderate Hepatic Insufficiency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance Statement 
Merck clinical studies will be conducted in compliance with local and/or national regulations 
and in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki. 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Merck. Any viewing or 
disclosure of such information that is not authorized in writing by Merck is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 2 
Confidential 
1 
PROTOCOL REVISION HISTORY 
Date/Name 
Description 
05 Jan 2017 
by 
 
Final Protocol Amendment 1 
This protocol amendment was generated to facilitate subjects’ 
recruitment by adding a second Investigator and clinical site and by 
modifying the inclusion and exclusion criteria for subjects with 
hepatic insufficiency (HI). Changes to the protocol are presented 
with new text in bold font and deleted text in strikethrough font. 
1. The 
 was added as a second 
clinical site, with 
 as the principal 
Investigator for the site.  
In Section 2 - Principal Investigator and Sponsor – Signatories, 
the titles were updated to indicate multiple investigators and 
clinical sites, and 
 was added as the second 
principal Investigator with contact information added as follows: 
 
 
 
 
 
 USA 
 Tel.:  
 
 E-mail:  
 
2. Subject lower age limit was reduced from 55 to 45 years of 
age, inclusive.  
In Section 5 – Synopsis, under Number of Subjects, the 
sentence was modified as follows: 
“Up to 32, adult, male and female subjects between 55 45 and 
85 years of age (inclusive) will be enrolled. 
In Section 9.2.1.1 – Subjects with Hepatic Insufficiency, 
Criterion #1 was modified as follows: 
“Adult male or female subjects, 55 45-85 years of age, 
inclusive, at screening.” 
In order to maintain the age match between subjects with HI 
and healthy subjects, the update in age limit was applied to 
healthy subjects as well. Thus, Section 9.2.1.2 – Healthy 
Control Subjects, the first sentence of Criterion #1 was 
modified as follows: 
“Healthy adult male or female subjects, 55 45-85 years of age, 
inclusive, at screening.” 
PPD
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P
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MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 3 
Confidential 
3. Since many subjects with HI suffer from hepatitis C (HCV) 
infection, the criterion was updated to exclude only subjects 
with HCV and decompensated liver disease. 
Section 
9.2.2.1 
- 
Subjects 
with 
Hepatic 
Insufficiency, 
Criterion #8 was modified as follows: 
“Positive results at screening for human immunodeficiency 
virus (HIV) 
or, 
hepatitis B 
surface 
antigen (HBsAg), 
or 
hepatitis C virus (HCV) (i.e., HCV antibody positive, HCV RNA 
positive) with decompensated liver disease. 
4. Fridericia’s correction of the QT interval (QTcF) upper limit for 
male subjects was increased from 460 msec to 480 msec. 
Section 
9.2.2.1 
- 
Subjects 
with 
Hepatic 
Insufficiency, 
Criterion #11 and Section 9.2.2.2 – Healthy Control Subjects, 
Criterion #11 were modified as follows: 
“QTcF interval is > 460 480 msec (males) or > 480 msec 
(females) or has ECG findings deemed abnormal with clinical 
significance by the Investigator or designee at screening.” 
5. The washout period from participation in a previous clinical trial 
was update to 28 days from the last dosing in the previous 
study only and not 28 days from the date of the last blood 
collection or dosing, whichever is later.  
Section 
9.2.2.1 
- 
Subjects 
with 
Hepatic 
Insufficiency, 
Criterion #18 and Section 9.2.2.2 - Healthy Control Subjects, 
Criterion #18 were modified as follows: 
“Participation in another clinical trial within 28 days prior to 
dosing. The 4-week window will be derived from the date of the 
last blood collection or dosing, whichever is later, in the 
previous study to Day 1 of the current study.” 
02 Sep 2016 
by 
 
Final Protocol 
  
 
PPD


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 4 
Confidential 
2 
PRINCIPAL INVESTIGATORS AND SPONSOR – SIGNATORIES 
A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of 
MK-8931 when Administered to Subjects with Mild and Moderate Hepatic Insufficiency 
 
SPONSOR: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck) 
One Merck Drive 
P.O. Box 100 
Whitehouse Station, New Jersey, 08889-0100, USA 
 
SPONSOR’S  
REPRESENTATIVE: 
 
 
 
Merck & Co., Inc. 
P.O. Box 2000 
Rahway, New Jersey 07065, USA 
Tel.:  
 
E-mail:  
 
 
 
 
 
 
Signature 
 Date 
PRINCIPAL INVESTIGATORS 
AND CLINICAL SITES: 
 
 
 
 USA 
Tel.:  
 
E-mail:  
 
 
 
 
 
 
 
 
 
Signature 
 Date 
 
 
  
 
 
 
 USA 
Tel.:  
 
E-mail:  
 
 
  
 
 
  
 
Signature 
 Date 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 5 
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3 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
 
Protocol Author 
 
 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec, H4M 2N8, Canada 
Tel.:  
 
Fax:  
 
E-mail:  
 
 
Certified Clinical Laboratory 
Reliable Research Laboratory 
1525 NW 167th Street Suite 140 
Miami Gardens, Florida 33169, USA 
Contact:  
 
Tel.:  
 
E-mail:  
 
 
Pharmacokinetic and Statistical Analyses 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec, H4M 2N8, Canada 
Tel.:  
 
Fax:  
 
 
and/or 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.:  
 
Fax:  
 
 
  
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 6 
Confidential 
4 
TABLE OF CONTENTS 
1 
PROTOCOL REVISION HISTORY ................................................................................... 2 
2 
PRINCIPAL INVESTIGATORS AND SPONSOR – SIGNATORIES ................................ 4 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY ......................................................... 5 
4 
TABLE OF CONTENTS ................................................................................................... 6 
5 
SYNOPSIS ........................................................................................................................ 9 
6 
STUDY EVENTS FLOW CHART ................................................................................... 12 
7 
BACKGROUND AND RATIONALE ............................................................................... 14 
7.1 Background ............................................................................................................. 14 
7.2 Rationale ................................................................................................................. 14 
7.2.1 
Rationale for this Study and Study Design ............................................... 14 
7.2.2 
Child-Pugh Classification of Hepatic Insufficiency .................................... 15 
7.2.3 
Rationale for Dose Selection .................................................................... 16 
7.2.4 
Rationale for Endpoints............................................................................. 16 
7.2.5 
Rationale for Planned Exploratory Biomarker Research .......................... 16 
7.2.6 
Rationale for Future Biomedical Research ............................................... 17 
8 
STUDY OBJECTIVES, ESTIMATIONS AND ENDPOINTS ........................................... 18 
8.1 Objectives and Estimations .................................................................................... 18 
8.1.1 
Primary ..................................................................................................... 18 
8.1.2 
Secondary ................................................................................................. 18 
8.1.3 
Planned Exploratory Biomarker (Parts 1 and 2) ....................................... 18 
8.2 Analysis Endpoints ................................................................................................. 19 
9 
INVESTIGATIONAL PLAN ............................................................................................. 20 
9.1 Overall Study Design and Plan ............................................................................... 20 
9.1.1 
Confinement, Return Visits and Follow-up ................................................ 20 
9.1.2 
Study Duration .......................................................................................... 21 
9.2 Selection of Study Population ................................................................................. 21 
9.2.1 
Inclusion Criteria ....................................................................................... 21 
9.2.1.1 Subjects with Hepatic Insufficiency ............................................. 21 
9.2.1.2 Healthy Control Subjects ............................................................ 23 
9.2.2 
Exclusion Criteria ...................................................................................... 24 
9.2.2.1 Subjects with Hepatic Insufficiency ............................................. 24 
9.2.2.2 Healthy Control Subjects ............................................................ 26 
9.2.3 
Subject Withdrawal/Discontinuation Criteria ............................................. 27 
9.2.3.1 Withdrawal/Discontinuation ........................................................ 27 
9.2.3.1.1 
Withdrawal from Future Biomedical Research ................ 28 
9.3 Study Restrictions ................................................................................................... 28 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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9.3.1 
Prohibitions and Concomitant Therapy ..................................................... 28 
9.3.2 
Meals ........................................................................................................ 30 
9.3.3 
Activity ...................................................................................................... 30 
9.4 Treatments .............................................................................................................. 31 
9.4.1 
Treatments Administered .......................................................................... 31 
9.4.2 
Method of Assigning Subjects to Treatment Groups ................................ 31 
9.4.3 
Blinding ..................................................................................................... 31 
9.4.4 
Treatment Compliance ............................................................................. 31 
9.4.5 
Study Design or Procedure Modifications Permitted within Protocol 
Parameters ............................................................................................... 31 
10 STUDY PROCEDURES .................................................................................................. 33 
10.1 Safety Assessment ................................................................................................. 33 
10.1.1 
Screening .................................................................................................. 33 
10.1.2 
Physical Examination ................................................................................ 33 
10.1.3 
Vital Signs ................................................................................................. 33 
10.1.4 
ECG Monitoring ........................................................................................ 33 
10.1.5 
Laboratory Tests ....................................................................................... 34 
10.1.6 
Assessing and Recording Adverse Events ............................................... 35 
10.1.6.1 Definition of an Overdose for This Protocol and Reporting 
of Overdose to the Sponsor ........................................................ 35 
10.1.6.2 Reporting of Pregnancy and Lactation to the Sponsor ............... 36 
10.1.6.3 Immediate Reporting of Adverse Events .................................... 36 
10.1.6.3.1 Serious Adverse Events .................................................. 36 
10.1.6.3.2 Events of Clinical Interest ............................................... 37 
10.1.6.4 Evaluating Adverse Events ......................................................... 38 
10.1.6.5 Sponsor Responsibility for Reporting Adverse Events ............... 41 
10.2 Pharmacokinetic Assessment ................................................................................. 41 
10.2.1 
Blood Sampling and Processing ............................................................... 41 
10.3 Planned Genetic Analysis Sample Collection ......................................................... 41 
10.4 Future Biomedical Research Samples ................................................................... 41 
10.5 Blood Volume Drawn for Study Assessments ........................................................ 42 
11 DATA ANALYSIS ........................................................................................................... 43 
11.1 Pharmacokinetic Parameters .................................................................................. 43 
11.2 Statistical Methods .................................................................................................. 43 
11.2.1 
Determination of Sample Size .................................................................. 44 
11.2.2 
Subjects to Analyze .................................................................................. 44 
11.2.3 
Descriptive Statistics ................................................................................. 44 
11.2.4 
Analysis Overview .................................................................................... 45 
11.2.5 
Other Analyses ......................................................................................... 45 
11.3 Safety Evaluation .................................................................................................... 46 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 8 
Confidential 
12 STUDY ADMINISTRATION ............................................................................................ 47 
12.1 Ethics ...................................................................................................................... 47 
12.1.1 
Institutional Review Board ........................................................................ 47 
12.1.2 
Ethical Conduct of the Study..................................................................... 47 
12.1.3 
Subject Information and Consent.............................................................. 47 
12.1.4 
Consent and Collection of Specimens for Future Biomedical 
Research .................................................................................................. 48 
12.2 Termination of the Study ......................................................................................... 48 
12.2.1 
Clinical Criteria for Early Trial Termination ............................................... 48 
12.3 Data Quality Assurance .......................................................................................... 48 
12.4 Data Management .................................................................................................. 48 
12.5 Direct Access to Source Data/Documents .............................................................. 49 
12.6 Drug Supplies, Packaging and Labeling ................................................................. 49 
12.7 Data Handling and Record Keeping ....................................................................... 49 
12.8 Report Format ......................................................................................................... 49 
12.9 Compliance with Law, Audit, and Debarment ......................................................... 49 
12.10 Publication Policy ................................................................................................ 51 
12.11 Privacy Notice ..................................................................................................... 51 
13 REFERENCES ................................................................................................................ 52 
 
LIST OF APPENDICES 
Appendix 1: Merck* Code of Conduct for Clinical Trials ................................................ 53 
Appendix 2: Collection and Management of Specimens for Future Biomedical 
Research .................................................................................................... 56 
Appendix 3: PAXgeneTM Blood for DNA Analysis .......................................................... 60 
Appendix 4: Procedures for the Collection Handling, Storage and Shipping of 
MK-8931 Pharmacokinetic Samples .......................................................... 64 
Appendix 5: Sample Handling Instructions for MK-8931 Protein Binding ...................... 67 
 
LIST OF TABLES 
Table 1: 
Child-Pugh Classification of the Severity of Liver Disease ........................ 16 
Table 2: 
Evaluating Adverse Events ........................................................................ 39 
Table 3: 
Time Deviation Window Allowed for Blood Sampling ................................ 41 
Table 4: 
Blood Volume During the Study ................................................................. 42 
 
 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 9 
Confidential 
5 
SYNOPSIS 
Compound: 
MK-8931 
Clinical Indication: 
Alzheimer’s Disease 
Study Phase and Type: 
Phase I – Interventional 
Study 
Objectives 
and 
Estimations: 
Part 1: 
Primary: 
Objective:  To compare the plasma pharmacokinetics (e.g., 
AUC0-∞, AUC0-last, AUC0-24hr, Cmax, C24hr, apparent 
terminal t½, and Tmax, as applicable) of MK-8931, following 
administration of a single oral dose of 40 mg MK-8931 to 
subjects with moderate hepatic insufficiency (HI) to that of 
healthy matched control subjects. 
Estimation:  The plasma pharmacokinetics (AUC0-∞ and Cmax) 
of MK-8931 following a single oral dose of MK-8931 to subjects 
with moderate HI will be estimated and compared to those in 
healthy matched control subjects. 
Secondary: 
Objective:  To evaluate the safety and tolerability of MK-8931 
following administration of a single oral dose in subjects with 
moderate HI. 
Part 2 (Optional): 
Primary: 
Objective:  To compare the plasma pharmacokinetics (e.g., 
AUC0-∞, AUC0-last, AUC0-24hr, Cmax, C24hr, apparent 
terminal t½, and Tmax, as applicable) of MK-8931, following 
administration of a single oral dose of 40 mg MK-8931 to 
subjects with mild HI to that of healthy matched control subjects. 
Estimation:  The plasma pharmacokinetics (AUC0-∞ and Cmax) 
of MK-8931 following a single oral dose of MK-8931 to subjects 
with mild HI will be estimated and compared to those in healthy 
matched control subjects. 
Secondary: 
Objective:  To evaluate the safety and tolerability of MK-8931 
following administration of a single oral dose in subjects with mild 
HI. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 10 
Confidential 
Parts 1 and 2: 
Planned Exploratory Biomarker: 
Objective:  To explore the relationship between genetic variation 
and 
response 
to 
the 
treatment(s) 
administered, 
and 
mechanisms of disease. Variation across the human genome 
may be analyzed for association with clinical data collected in 
this study. 
Summary of Study 
Design: 
This is a 2-part, non-randomized, open-label, single-dose study 
to evaluate the pharmacokinetics of MK-8931, in subjects with 
moderate (Part 1) and mild (Part 2) HI compared to those in 
healthy matched control subjects. 
Part 1 will be initiated with subjects with moderate HI. Healthy 
control subjects will be enrolled following completion of 
enrollment of all subjects with moderate HI (Part 1). Each 
healthy control subject will be matched to the mean body mass 
index (BMI; ± 10%) and age (± 15 years) of the subjects with 
moderate HI. The number of healthy subjects of each gender 
will match that of the moderate HI subjects [±1]. Following 
completion of the clinical portion, a safety and pharmacokinetic 
analysis will be performed in order to support the decision to 
continue the study to Part 2. 
If a decision is made to continue with Part 2, subjects with mild 
HI will be enrolled. If any of the healthy control subjects from 
Part 1 do not also meet the matching criteria for the mild HI in 
Part 2, additional healthy control subjects will be enrolled in 
Part 2 to acquire data from a total of 8 healthy subjects that 
match the mean BMI (± 10%) and age (± 15 years) of mild HI 
(Part 2). The gender of the additional healthy subject(s) will be 
selected to ensure the number of healthy subjects of each 
gender will match that of the mild HI subjects (±1). The 
comparison between mild HI and healthy control subjects will 
include only the healthy controls who meet the matching criteria 
for mild HI. 
On Day 1 of either part, a single oral dose of MK-8931 will be 
administered 
followed 
by 
pharmacokinetic 
sampling 
for 
120 hours. Blood samples for the potential assessment of 
protein binding of MK-8931 will be collected. 
Subjects (including subjects who terminate the study early) will 
return to the clinical research unit (CRU) approximately 14 days 
after study drug administration for follow-up procedures, and to 
determine if any adverse events have occurred since the last 
study visit. 
Blinding: 
This is an open-label study. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 11 
Confidential 
Number of Subjects: 
Up to 32, adult, male and female subjects between 45 and 
85 years of age (inclusive) will be enrolled. 
Eight (8) subjects with moderate HI (a score of 7 to 9, on the 
Child-Pugh scale) will be enrolled in Part 1. 
Eight (8) subjects with mild HI (a score of 5 to 6 on the 
Child-Pugh scale) will be enrolled in Part 2, if conducted. 
Eight (8) subjects with normal hepatic function will be enrolled 
once all subjects with moderate HI (Part 1) are enrolled.  
Each healthy control subject will be matched to the mean age 
(±15 years) and BMI (±10 %) of subjects with HI in Part 1. The 
number of healthy subjects of each gender will match that of the 
moderate HI subjects [±1]. If any of the healthy control subjects 
from Part 1 do not also meet the matching criteria for the mild HI 
in Part 2, additional healthy control subjects will be enrolled in 
Part 2 to acquire data from a total of 8 healthy subjects that 
match the mean BMI (± 10%) and age (± 15 years) of mild HI 
(Part 2). The gender of the additional healthy subject(s) will be 
selected to ensure the number of healthy subjects of each 
gender will match that of the mild HI subjects (±1). 
Dosage, Dosage Form, 
Route, and Dose 
Regimen: 
Each subject will receive a single oral dose of 40 mg MK-8931 
(1 x 40 mg tablet) in a fasted state. 
All study drugs will be administered orally with approximately 
240 mL of water. 
Key Assessments: 
Pharmacokinetics: 
The following pharmacokinetic parameters will be calculated for 
MK-8931 in plasma, as appropriate:  AUC0-∞, AUC0-last, 
AUC0-24hr, Cmax, C24hr, Tmax, CL/F, Vz/F, and apparent 
terminal t½.  
An analysis of covariance (ANCOVA) model will be used for the 
analysis of the natural log (ln)-transformed AUC0-∞, AUC0-last, 
AUC0-24hr, Cmax, and C24hr. 
Protein binding for MK-8931 may also be analyzed. If protein 
binding is analyzed, the fraction of unbound drug (fu) in plasma 
will be reported. 
Safety: 
Safety will be monitored through physical examination, vital 
signs, 12-lead electrocardiograms (ECGs), adverse events and 
clinical laboratory tests. Summary statistics for the laboratory 
safety tests, 12-lead ECGs, and/or vital signs may also be 
computed and provided, as deemed clinically appropriate. 
 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 12 
Confidential 
6 
STUDY EVENTS FLOW CHART 
Study Procedures a 
S b 
Study Days 
FU c 
Days → 
 
-1 
1 
2 
3 
4 
5 
6 
 
Hours → 
 
(C-I) d 
P 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 
24 
48 
72 
96 120 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent for Future Biomedical Research 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
X f 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X g 
Vital Signs (heart rate & blood pressure) 
X 
 
X f 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X g 
Vital Signs (respiratory rate & temperature) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Liver Function using Child-Pugh 
Classification h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Serum Chemistry i, and Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X g 
Serum Pregnancy Test (female subjects only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Monitoring 
X 
X 
X 
Concomitant Medication Monitoring 
X 
X 
 
Study Drug Administration / Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MK-8931 Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for MK-8931 Pharmacokinetics 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for MK-8931 Protein Binding 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Genetic Analysis j 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU k 
 
X 
 
Visit and Return Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 13 
Confidential 
 
a. 
For details on Procedures, refer to Section  10 and/or corresponding appendices. 
b. 
Within 28 days prior to the study drug administration. 
c. 
Subjects (including subjects who terminate the study early) will return to the CRU approximately 14 days after study drug administration for follow-up 
procedures, and to determine if any adverse events have occurred since the last study visit. 
d. 
Subjects will be admitted to the CRU on Day -1, at the time indicated by the CRU. 
e. 
A symptom-driven physical examination may be performed at other times at the Investigator’s discretion. 
f. 
To be performed within 24 hours prior to dosing. 
g. 
To be performed on the follow-up visit and prior to early termination from the study if occurs. 
h. 
To be performed in subjects with HI only. 
i. 
Samples for serum chemistry will be obtained following a fast of at least 8 hours; however, in case of dropouts or rechecks, subjects may not have fasted for 
8 hours before the serum chemistry sample is taken. 
j. 
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at 
the site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the 
sample is collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is 
not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR. 
k. 
At the Investigator’s discretion, subjects may be released from the CRU prior to Day 6; if so, subjects will then be asked to return to the CRU for subsequent 
study procedures.  
Abbreviations:  AE = Adverse events, C-I = Check-in, CRU = Clinical research unit, DNA = deoxyribonucleic acid, FBR = Future Biomedical Research, 
FSH = Follicle-stimulating hormone, FU = Follow-Up, HI = Hepatic insufficiency, HIV = Human immunodeficiency virus, IEC = Independent ethics committee, 
IRB = Institutional review board, P = Predose, S = Screening. 
 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 14 
Confidential 
7 
BACKGROUND AND RATIONALE 
7.1 
Background 
Alzheimer’s disease is a slowly developing neurodegenerative disease that is the leading 
cause of dementia and a leading cause of death in the elderly. Alzheimer’s disease is 
characterized by histopathological features in the brain including neurovascular and 
parenchymal amyloid deposits (plaques) composed of the Aβ peptides, intraneuronal 
neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein 
tau, neuronal and synaptic loss, and neuroinflammation. The Aβ peptides are hypothesized 
to be intimately involved in the etiology of AD via their aggregation to form toxic complexes. 
MK-8931 is a potent inhibitor of human β–site amyloid precursor protein (APP) cleaving 
enzyme (BACE1, also known as β-secretase), one of the enzymes responsible for 
production of the Aβ peptides, that is being developed for the treatment of Alzheimer’s 
disease. Inhibition of BACE1 by MK-8931 has been shown to reduce Aβ peptide levels in 
the plasma, cerebrospinal fluid, and brain/cortex of multiple animal species as well as in the 
plasma and cerebrospinal fluid in humans. Preclinical toxicology data with MK-8931 at the 
systemic exposures achieved, provide no contraindications to clinical trials with this 
compound via the oral route. 
Refer to the Confidential Clinical Investigator’s Brochure (IB) for detailed background 
information on MK-8931 in the following areas: 
• 
Physical, Chemical, and Pharmaceutical Properties and Formulation 
• 
Nonclinical Pharmacology 
• 
Safety Pharmacology and Supplemental Safety Pharmacology Studies 
• 
Pharmacokinetics and Product Metabolism in Animals 
• 
Toxicology (Preclinical Safety Assessment) 
• 
Effects in Humans and Clinical Experience 
7.2 
Rationale  
7.2.1 Rationale for this Study and Study Design 
In most AD patients, symptoms begin to appear in their mid-60s and progress slowly with 
age 1. Since advancing age is associated with reduction in renal and hepatic clearance 2, HI 
is an expected comorbidity in the target patient population for MK-8931. This study will 
evaluate the effect of hepatic insufficiency on the plasma pharmacokinetics of MK-8931 in 
order to guide dosing recommendations. This study will also evaluate the safety and 
tolerability of MK-8931 following administration of a single oral dose in subjects with 
moderate and mild HI. 
Results from an absorption, distribution, metabolism and elimination study (MK-8931-005) 
suggest that MK-8931 is 
 
 
CCI


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 15 
Confidential 
 
 
 
 Based on these data, it is anticipated that 
exposures of MK-8931 will be increased in subjects with moderate HI compared with healthy 
matched controls. 
A reduced study design enrolling subjects with moderate (Part 1) and mild (Part 2) HI is 
proposed. The decision to initiate Part 2 of the study will be made upon an analysis using 
preliminary pharmacokinetic data from Part 1. Once all subjects with moderate HI (Part 1) 
are enrolled, a healthy control group will be enrolled with demographics which are matched 
to the mean demographic parameters to control for the influence of covariates.  
In the target patient population, 60 mg MK-8931 QD was well-tolerated for up to 3 months, 
and provided an exposure ~1.5-fold above the exposure observed with a 40 mg dose, the 
highest dose being investigated in the Phase III studies. Accordingly, the pharmacokinetic 
condition to initiate Part 2 of the study will be met if the point estimate for the AUC0-∞ ratio 
of geometric means (subjects with moderate HI / healthy matched control subjects) exceeds 
1.5. Healthy control subjects from Part 1 who match the gender (±1) and mean BMI (± 10%) 
and age (± 15 years) of subjects with mild HI in Part 2 will be used as part of the control 
group for Part 2. Additional healthy adult subjects matching the subjects with mild HI may be 
enrolled in Part 2 to acquire data from a total of 8 healthy matching subjects.  
The Child-Pugh classification will be used to categorize HI due to its widespread use and 
acceptance by regulatory agencies (including the U.S. Food and Drug Administration 
(FDA) 3. This study design is supported by FDA guidelines for drugs which undergo 
substantial hepatic metabolism and for which an indication is sought for patients with HI 3.  
7.2.2 Child-Pugh Classification of Hepatic Insufficiency 
The Child classification, which should only be applied to patients with a diagnosis of hepatic 
cirrhosis, was initially used to assess the preoperative risk of patients with hepatic cirrhosis. 
The Child scale, as modified by Pugh, et al.4, has been subsequently found useful in 
classifying a patient’s level of HI for pharmacokinetic studies. The Child-Pugh scale has 
been shown to correlate with hepatic (i.e., metabolic) clearance for several compounds 3.  
In the current study, patients with chronic, stable HI with features of cirrhosis due to any 
etiology will be enrolled, and the Child-Pugh scale will be used to classify the severity of liver 
disease. Only 5 of the 6 parameters listed in Table 1 are scored. The bilirubin score in the 
table is dependent upon the type of cirrhosis (primary biliary cirrhosis versus all other 
causes). Subjects’ scores of 5 to 6, 7 to 9, and 10 to 15 on this scale are classified as 
having mild, moderate, and severe hepatic failure, respectively.  
In addition, in order to ensure that the study subjects have laboratory abnormalities 
consistent with hepatic dysfunction (e.g., reduced serum albumin, increased serum bilirubin, 
and increased international normalized ratio [INR]), at least 4 subjects with moderate HI will 
be required to have a score of at least 2 on one of the laboratory parameters on the 
Child-Pugh scale. 
CCI


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 16 
Confidential 
Table 1: 
Child-Pugh Classification of the Severity of Liver Disease 
 
Points Score for Increasing Abnormality 
Assessment 
1 
2 
3 
Encephalopathy† 
None 
1 or 2 
3 or 4 
Ascites 
Absent 
Slight 
Moderate 
Albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
INR 
<1.7 
1.7 to 2.3 
>2.3 
Bilirubin (mg/dL)—not PBC‡§ 
Bilirubin (mg/dL)—only for PBC‡§ 
<2 
<4 
2 to 3 
4 to 10 
>3 
>10 
† 
Portal-system encephalopathy is Staged 0 to 4. 
‡ 
PBC = Primary Biliary Cirrhosis. 
§ 
Select only one dependent on type of cirrhosis. 
7.2.3 Rationale for Dose Selection 
Based 
on 
human 
pharmacokinetic 
and 
pharmacodynamic 
data 
and 
pharmacokinetic/pharmacodynamic modeling for the 2 dose levels currently in clinical 
outcomes evaluation (i.e., 12 and 40 mg), doses of 40 mg have a high probability of 
achieving ≥ 75% reduction in CSF Aβ40 and doses of 12 mg have a high probability of 
achieving ≥ 50% reduction in CSF Aβ40 in elderly subjects. As 40 mg is the highest dose 
being evaluated in Phase III studies and likely the highest possible marketed dose, a single 
dose of 40 mg has been chosen for this study. 
A potential enhancement in exposure of up to 13-fold due to the effects of hepatic 
insufficiency would fall within previously studied safety and tolerability margins established 
with a 550 mg dose in a single dose study. This safety margin is deemed sufficient to 
account for a possible increase in exposure due to the moderate and mild HI of the study 
subjects. 
7.2.4 Rationale for Endpoints 
The primary endpoints for this study will include the pharmacokinetic parameters AUC0-∞ 
and Cmax which best describe the systemic exposure of MK-8931 following a single dose, 
in subjects with hepatic impairment or healthy control subjects.  
7.2.5 Rationale for Planned Exploratory Biomarker Research 
Planned Genetic Analysis 
Understanding genetic determinants of drug response and the molecular basis of disease is 
an important endeavor during medical research. This research will evaluate whether genetic 
variation within a clinical trial population correlates with response to the treatment(s) under 
evaluation and/or disease. If genetic variation is found to predict efficacy or adverse events, 
the data might inform optimal use of therapies in the patient population. Knowledge of the 
molecular basis of disease contributes to the development of novel biomarkers and the 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 17 
Confidential 
identification of new drug targets. This research contributes to understanding molecular 
basis of disease and the genetic determinants of efficacy and safety associated with the 
treatments in this study. 
7.2.6 Rationale for Future Biomedical Research 
The Sponsor will conduct Future Biomedical Research on DNA specimens consented for 
future biomedical research during this clinical trial. 
Such research is for biomarker testing to address emergent questions not described 
elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens 
from appropriately consented subjects. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to 
use such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time. The details 
of this Future Biomedical Research sub-trial are presented in Appendix 2 – Collection and 
Management of Specimens for Future Biomedical Research.  
 
 
 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 18 
Confidential 
8 
STUDY OBJECTIVES, ESTIMATIONS AND ENDPOINTS 
8.1 
Objectives and Estimations 
8.1.1 Primary 
Part 1: 
Objective:  To compare the plasma pharmacokinetics (e.g., AUC0-∞, AUC0-last, 
AUC0-24hr, Cmax, C24hr, apparent terminal t½, and Tmax, as applicable) of MK-8931, 
following administration of a single oral dose of 40 mg MK-8931 to subjects with moderate 
HI to that of healthy matched control subjects. 
Estimation:  The plasma pharmacokinetics (AUC0-∞ and Cmax) of MK-8931 following a 
single oral dose of MK-8931 to subjects with moderate HI will be estimated and compared to 
those in healthy matched control subjects. 
Part 2 (Optional): 
Objective:  To compare the plasma pharmacokinetics (e.g., AUC0-∞, AUC0-last, 
AUC0-24hr, Cmax, C24hr, apparent terminal t½, and Tmax, as applicable) of MK-8931, 
following administration of a single oral dose of 40 mg MK-8931 to subjects with mild HI to 
that of healthy matched control subjects. 
Estimation:  The plasma pharmacokinetics (AUC0-∞ and Cmax) of MK-8931 following a 
single oral dose of MK-8931 to subjects with mild HI will be estimated and compared to 
those in healthy matched control subjects. 
8.1.2 Secondary 
Part 1: 
Objective:  To evaluate the safety and tolerability of MK-8931 following administration of a 
single oral dose in subjects with moderate HI. 
Part 2 (Optional): 
Objective:  To evaluate the safety and tolerability of MK-8931 following administration of a 
single oral dose in subjects with mild HI. 
8.1.3 Planned Exploratory Biomarker (Parts 1 and 2) 
Objective:  To explore the relationship between genetic variation and response to the 
treatment(s) administered, and mechanisms of disease. Variation across the human 
genome may be analyzed for association with clinical data collected in this study. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 19 
Confidential 
8.2 
Analysis Endpoints 
Pharmacokinetics: 
The primary pharmacokinetic endpoints are AUC0-∞ and Cmax for MK-8931 in subjects with 
HI versus healthy matched subjects. 
The pharmacokinetic parameters AUC0-last, AUC0-24hr, C24hr, Tmax, CL/F, Vz/F, and 
apparent terminal t½, as appropriate, for MK-8931 will also be computed. 
Safety: 
Safety endpoints will include all types of adverse events, physical examinations, vital signs 
(heart rate and blood pressure), 12-lead ECGs, and clinical laboratory tests (hematology, 
serum chemistry, and urinalysis). 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 20 
Confidential 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a 2-part, non-randomized, open-label, single-dose study to evaluate the 
pharmacokinetics of MK-8931, in subjects with moderate (Part 1) and mild (Part 2) HI 
compared to those in healthy matched control subjects. 
Up to 32, adult, male and female subjects will be enrolled. 
Screening of subjects will occur within 28 days prior to dosing.  
Part 1 will be initiated with subjects with moderate HI. Healthy control subjects will be 
enrolled following completion of enrollment of all subjects with moderate HI (Part 1). Each 
healthy control subject will be matched to the mean body mass index (BMI; ± 10%) and age 
(± 15 years) of the subjects with moderate HI. The number of healthy subjects of each 
gender will match that of the moderate HI subjects (±1). Following completion of the clinical 
portion, a safety and pharmacokinetic analysis will be performed in order to support the 
decision to continue the study to Part 2. 
If a decision is made to continue with Part 2, subjects with mild HI will be enrolled. If any of 
the healthy control subjects from Part 1 do not also meet the matching criteria for the mild HI 
in Part 2, additional healthy control subjects will be enrolled in Part 2 to acquire data from a 
total of 8 healthy subjects that match the mean BMI (± 10%) and age (± 15 years) of mild HI 
(Part 2). The gender of the additional healthy subject(s) will be selected to ensure the 
number of healthy subjects of each gender will match that of the mild HI subjects (±1). The 
comparison between mild HI and healthy control subjects will include only the healthy 
controls who meet the matching criteria for mild HI. 
On Day 1 of either part, a single oral dose of MK-8931 will be administered followed by 
pharmacokinetic sampling for 120 hours. Blood samples for the potential assessment of 
protein binding of MK-8931 will be collected. 
Safety will be monitored throughout the study by repeated clinical and laboratory 
evaluations. 
Subjects may be replaced at the discretion of the Sponsor. 
9.1.1 Confinement, Return Visits and Follow-up 
Subjects will be housed from Day -1 at the time indicated by the CRU until after the 
120-hour blood draw and/or study procedures. At the Investigator’s discretion, subjects may 
be released from the CRU prior to Day 6; if so, subjects will then be asked to return to the 
CRU for subsequent study procedures. At all times, a subject may be required to remain at 
the CRU for longer at the discretion of the Investigator. 
Subjects (including subjects who terminate the study early) will return to the CRU 
approximately 14 days after study drug administration for follow-up procedures, and to 
determine if any adverse events have occurred since the last study visit. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 21 
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9.1.2 Study Duration 
The duration of the study from screening to follow-up is approximately 6 weeks. 
9.2 
Selection of Study Population 
9.2.1 Inclusion Criteria 
9.2.1.1 Subjects with Hepatic Insufficiency 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study, unless otherwise specified: 
1. Adult male or female subjects, 45-85 years of age, inclusive, at screening. 
2. BMI ≥ 19 and ≤ 40 kg/m2, at screening. 
3. Continuous non-smokers or light smokers (< 10 cigarettes/day or the equivalent). 
Subjects must agree to consume no more than 10 cigarettes or equivalent/day from the 
time of screening and throughout the period of sample collection. 
4. Baseline health is judged to be stable based on medical history (except for the hepatic 
insufficiency condition), physical examination, vital signs, ECGs, and laboratory safety 
tests. Subjects who do not qualify based on a reversible condition or mild intercurrent 
illness may be re-screened after the underlying condition is resolved. 
5. Subject has a diagnosis of chronic (> 6 months), stable (no acute episodes of illness 
within the previous 2 months due to deterioration in hepatic function) HI with features of 
cirrhosis due to any etiology. 
6. Part 1 only:  Subject’s score on the Child-Pugh scale must range from 7 to 9 (moderate 
HI) at screening. At least 4 subjects must have a score of 2 or higher on at least one of 
the laboratory parameters (i.e., albumin, INR, and/or bilirubin) at screening on the 
Child-Pugh scale. 
7. Part 2 only:  Subject’s score on the Child-Pugh scale must range from 5 to 6 (mild HI) at 
screening. 
8. Subjects must be completely informed of the unknown risks of pregnancy and agree not 
to become pregnant or father a child during the time they are participating in this study. 
9. For a female of childbearing potential:  either be sexually inactive (abstinent) for 14 days 
prior to dosing and throughout the study or be using one of the following acceptable birth 
control methods: 
a. intrauterine device in place for at least 3 months prior to dosing and use a physical 
barrier method (e.g., condom, diaphragm) and spermicide throughout the study. 
b. double physical barrier methods (e.g., condom and diaphragm) with spermicide for at 
least 14 days prior to dosing and throughout the study. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 22 
Confidential 
c. surgical sterilization of the partner (vasectomy for 4 months minimum) and use a 
physical barrier method (e.g., condom, diaphragm) and spermicide throughout the 
study. 
d. hormonal contraceptives for at least 3 months prior to dosing of the study and use a 
physical barrier method (e.g., condom, diaphragm) and spermicide throughout the 
study. 
Female subjects who claim to be sexually inactive, but become sexually active during 
the course of the study must agree to use a double physical barrier method (e.g., 
condom and diaphragm) with spermicide from the time of the start of sexual activity 
through completion of the study or if having a surgically sterilized partner (vasectomy for 
4 months minimum) must agree to use a physical barrier method (e.g., condom, 
diaphragm) and spermicide through completion of the study. 
In addition, female subjects of childbearing potential will be advised to remain sexually 
inactive or to keep the same birth control method for at least 14 days following dosing. 
10. Females of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
• 
hysteroscopic sterilization; 
• 
bilateral tubal ligation or bilateral salpingectomy; 
• 
hysterectomy; 
• 
bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to dosing and have 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status 
as per Investigator or designee’s judgment. 
11. Non-vasectomized male subjects must agree to use a condom with spermicide or 
abstain from sexual intercourse from dosing until 90 days after dosing. No restrictions 
are required for vasectomized males provided their vasectomy has been performed 
4 months or more prior to dosing. Males who have been vasectomized less than 
4 months prior to dosing must follow the same restrictions as non-vasectomized males. 
12. Male subjects must agree not to donate sperm from dosing until 90 days after dosing. 
13. Understands the study procedures in informed consent forms (ICFs), be willing and able 
to comply with the protocol, and provides written informed consent for the trial, including 
for Future Biomedical Research. Future Biomedical Research participation is voluntary 
and is not required in order to participate in the trial. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 23 
Confidential 
9.2.1.2 Healthy Control Subjects 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study, unless otherwise specified: 
1. Healthy adult male or female subjects, 45-85 years of age, inclusive, at screening. For 
healthy subjects enrolled in Part 1, age must be within ± 15 years of the mean age of 
subjects with moderate HI (Part 1). For any additional healthy subject enrolled in Part 2, 
age must be within ± 15 years of the mean age of subjects with mild HI (Part 2). A 
similar number of males and females (±1) will be enrolled in the HI and healthy groups. 
The gender of the additional healthy subject(s) enrolled in Part 2 will be selected to 
ensure the number of healthy subjects of each gender will match that of the mild HI 
subjects (±1). 
2. BMI ≥ 19 and ≤ 40 kg/m2 at screening. For healthy subjects enrolled in Part 1, BMI must 
be within ± 10% of the mean BMI of the subjects with moderate HI (Part 1). For any 
additional healthy subject enrolled in Part 2, BMI must be within ± 10% of the mean BMI 
of subjects with mild HI (Part 2). 
3. Continuous non-smokers or light smokers (< 10 cigarettes/day or the equivalent). 
Subjects must agree to consume no more than 10 cigarettes or equivalent/day from the 
time of screening and throughout the period of sample collection. 
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs, or ECGs, as deemed by the Investigator. 
5. Subjects must be completely informed of the unknown risks of pregnancy and agree not 
to become pregnant or father a child during the time they are participating in this study  
6. For a female of childbearing potential:  either be sexually inactive (abstinent) for 14 days 
prior to dosing and throughout the study or be using one of the following acceptable birth 
control methods: 
a. intrauterine device in place for at least 3 months prior to dosing and use a physical 
barrier method (e.g., condom, diaphragm) and spermicide throughout the study. 
b. double physical barrier methods (e.g., condom and diaphragm) with spermicide for at 
least 14 days prior to dosing and throughout the study. 
c. surgical sterilization of the partner (vasectomy for 4 months minimum) and use a 
physical barrier method (e.g., condom, diaphragm) and spermicide throughout the 
study. 
d. hormonal contraceptives for at least 3 months prior to dosing of the study and use a 
physical barrier method (e.g., condom, diaphragm) and spermicide throughout the 
study. 
Female subjects who claim to be sexually inactive, but become sexually active during 
the course of the study must agree to use a double physical barrier method (e.g., 
condom and diaphragm) with spermicide from the time of the start of sexual activity 
through completion of the study or if having a surgically sterilized partner (vasectomy for 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 24 
Confidential 
4 months minimum) must agree to use a physical barrier method (e.g., condom, 
diaphragm) and spermicide through completion of the study. 
In addition, female subjects of childbearing potential will be advised to remain sexually 
inactive or to keep the same birth control method for at least 14 days following dosing. 
7. Females of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
• 
hysteroscopic sterilization; 
• 
bilateral tubal ligation or bilateral salpingectomy; 
• 
hysterectomy; 
• 
bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to dosing and have FSH 
serum levels consistent with postmenopausal status as per Investigator or designee’s 
judgment. 
8. Non-vasectomized male subjects must agree to use a condom with spermicide or 
abstain from sexual intercourse from dosing until 90 days after dosing. No restrictions 
are required for vasectomized males provided their vasectomy has been performed 
4 months or more prior to dosing. Males who have been vasectomized less than 
4 months prior to dosing must follow the same restrictions as non-vasectomized males. 
9. Male subjects must agree not to donate sperm from dosing until 90 days after dosing. 
10. Understands the study procedures in ICFs, be willing and able to comply with the 
protocol, and provides written informed consent for the trial, including for Future 
Biomedical Research. Future Biomedical Research participation is voluntary and is not 
required in order to participate in the trial. 
9.2.2 Exclusion Criteria 
9.2.2.1 Subjects with Hepatic Insufficiency 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. Subject is mentally or legally incapacitated or has significant emotional problems at the 
time of the screening visit or expected during the conduct of the study. 
2. History or presence of clinically significant medical or psychiatric condition or disease in 
the opinion of the Investigator.  
3. History of any illness that, in the opinion of the Investigator, might confound the results of 
the study or poses an additional risk to the subject by their participation in the study. 
4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.  


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 25 
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5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or 
related compounds. 
6. Female subjects who are pregnant or lactating. 
7. Positive results for the urine drug and/or alcohol screen at screening or check-in, unless 
the positive drug screen is due to prescription drug use and is approved by the 
Investigator and the Sponsor Medical Monitor. 
8. Positive results at screening for human immunodeficiency virus (HIV) or hepatitis B 
surface antigen (HBsAg) or hepatitis C virus (HCV) (i.e., HCV antibody positive, HCV 
RNA positive) with decompensated liver disease. 
9. Seated blood pressure is less than 90/40 mmHg or greater than 180/105 mmHg at 
screening. 
10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. 
11. QTcF interval is > 480 msec or has ECG findings deemed abnormal with clinical 
significance by the Investigator or designee at screening. 
12. Abnormal hemoglobin level deemed clinically significant by the Investigator at screening. 
13. Unable to refrain from or anticipates the use of any medication or substance (including 
prescription or over-the-counter, vitamin supplements, natural or herbal supplements) as 
indicated in Section  9.3.1 for the prohibited time period. 
14. Has been on a diet incompatible with the CRU-provided standard meals/snacks, in the 
opinion of the Investigator, within the 28 days prior to dosing of study drug, and 
throughout the study. 
15. Donation of blood or had significant blood loss within 56 days prior to dosing of study 
drug. 
16. Plasma donation within 28 days prior to dosing of study drug. 
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or Sponsor staff directly involved with this study. 
18. Participation in another clinical trial within 28 days prior to dosing. The 4-week window 
will be derived from the date of the last dosing in the previous study to Day 1 of the 
current study. 
19. Subject who dosed in one part (e.g., Part 1) will not be enrolled in the other part (e.g., 
Part 2). 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 26 
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9.2.2.2 Healthy Control Subjects 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. Subject is mentally or legally incapacitated or has significant emotional problems at the 
time of the screening visit or expected during the conduct of the study. 
2. History or presence of clinically significant medical or psychiatric condition or disease in 
the opinion of the Investigator.  
3. History of any illness that, in the opinion of the Investigator, might confound the results of 
the study or poses an additional risk to the subject by their participation in the study. 
4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.  
5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or 
related compounds. 
6. Female subjects who are pregnant or lactating. 
7. Positive results for the urine drug and/or urine or breath alcohol screen at screening or 
check-in. 
8. Positive results at screening for HIV, HBsAg, or HCV (i.e., HCV antibody positive, HCV 
RNA positive). 
9. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at 
screening. 
10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. 
11. QTcF interval is > 480 msec or has ECG findings deemed abnormal with clinical 
significance by the Investigator or designee at screening. 
12. Abnormal hemoglobin level deemed clinically significant by the Investigator at screening. 
13. Unable to refrain from or anticipates the use of any medication or substance (including 
prescription or over-the-counter, vitamin supplements, natural or herbal supplements) as 
indicated in Section  9.3.1 for the prohibited time period. 
14. Has been on a diet incompatible with the CRU-provided standard meals/snacks, in the 
opinion of the Investigator, within the 28 days prior to dosing of study drug, and 
throughout the study. 
15. Donation of blood or had significant blood loss within 56 days prior to dosing of study 
drug. 
16. Plasma donation within 28 days prior to dosing of study drug. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
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17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or Sponsor staff directly involved with this study. 
18. Participation in another clinical trial within 28 days prior to dosing. The 4-week window 
will be derived from the date of the last dosing in the previous study to Day 1 of the 
current study. 
9.2.3 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, a subject 
may be withdrawn by the Investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons. 
Specific details regarding discontinuation or withdrawal procedures, including specific details 
regarding withdrawal from Future Biomedical Research, are provided in Section  9.2.3.1. 
Discontinuation is “permanent”. Once a subject is discontinued, he/she shall not be allowed 
to enroll again. 
Subjects may be replaced at the discretion of the Sponsor. 
A subject must be discontinued from the study for any of the following reasons: 
• 
The subject withdraws consent. 
• 
The subject has a confirmed positive serum pregnancy test. 
• 
The subject has a medical condition or personal circumstance which, in the opinion 
of the Investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol. 
A subject may be discontinued from the study for any of the following reasons: 
• 
Adverse events. 
• 
Difficulties in blood collection. 
• 
Protocol violation. 
9.2.3.1 Withdrawal/Discontinuation 
The Investigator or designee must notify the Sponsor when a subject has been 
discontinued/withdrawn from the study. If a subject discontinues for any reason at any time 
during the course of the study, the procedures scheduled at early termination (as outlined in 
Section  6) will be performed. Furthermore, the subject will be asked to return to the clinic for 
a follow-up (approximately 14 days after dosing of study drug), to determine if any adverse 
events have occurred since the last visit. Any adverse events which are present at the time 
of discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section  10.1.6. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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9.2.3.1.1 Withdrawal from Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research. Subjects may 
withdraw consent at any time by contacting the Principal Investigator for the main trial. If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (
 Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal. Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results. 
No new analyses would be generated after the request is received.  
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
9.3 
Study Restrictions 
9.3.1 Prohibitions and Concomitant Therapy 
Consumption of foods and beverages containing the following substances will be prohibited 
as indicated: 
• 
Xanthines/Caffeine:  24 hours before dosing until the last pharmacokinetic sample 
collection; 
• 
Alcohol:  48 hours before dosing until the last pharmacokinetic sample collection; 
• 
Grapefruit/Seville orange:  14 days before dosing until the last pharmacokinetic 
sample collection. 
Concurrent therapy with any medication during the course of the study including both 
prescription and non-prescription drugs must first be discussed with the Investigator and 
Sponsor Clinical Monitor prior to dosing, unless appropriate medical care necessitates that 
therapy should begin before the Investigator and Sponsor Clinical Monitor can be consulted. 
Hormonal contraceptives and hormone replacement therapy are not prohibited. During the 
study, acetaminophen (up to 2 g per 24 hours) may be administered at the discretion of the 
Investigator or designee. 
Appropriate sources will be consulted by the Investigator or designee to confirm lack of 
pharmacokinetic/pharmacodynamic interaction with the drug. 
If deviations occur, the Investigator in consultation with the Sponsor Clinical Monitor will 
decide on a case-by-case basis. 
All medications taken by subjects during the course of the study will be recorded. 
PPD


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Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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Subjects with HI: 
Subjects who are taking medications for stable diseases for approximately 2 weeks (or 
5 half-lives of the compound, whichever is longer) prior to dosing will be allowed to 
participate in the study at the discretion of the Investigator and following consultation with 
the Sponsor Clinical Monitor. If a subject is prescribed prohibited medication, upon 
discussion between the Sponsor and the Investigator, the Investigator may substitute the 
previously prescribed medication to an allowed one for the purpose of this study. 
In addition, certain prescription medications used to treat manifestations of hepatic disease 
or medications needed to treat stable diseases (e.g., ACE inhibitors, angiotensin II receptor 
antagonists, beta-blockers) will be allowed during the study following consultation with the 
Sponsor Clinical Monitor and the Investigator, provided the subjects are on a stable regimen 
for approximately 2 weeks (or 5 half-lives of the compound, whichever is longer) prior to 
study drug administration and is able to withhold the use within 4 hours prior to 
administration of the study drug. 
Diuretics will be restricted for 4 hours prior to dosing until 4 hours post dosing. Subjects on 
diuretics must be on a stable dose for at least 2 weeks prior to study drug administration, to 
participate in this study. 
Iron supplements or other metal cations; or multivitamins containing iron or zinc will be 
restricted for the 6 hours prior to and after dosing as they may potentially affect absorption 
of the study drugs. 
Lactulose will be restricted for the 6 hours prior to and after dosing as it may potentially 
affect absorption of the study drugs. 
Healthy Control Subjects: 
Any 
medication 
or 
substance 
(including 
prescription 
or 
over-the-counter 
(e.g., 
acetaminophen), vitamin supplements, natural or herbal supplements) which cannot be 
discontinued at least 14 days prior to dosing and throughout the study are prohibited. 
 
 
 
 
 
CCI
CCI


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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be deemed acceptable following consultation with the 
Sponsor Clinical Monitor and the Investigator. 
Subjects who are taking medications for stable diseases for approximately 1 month (or 
5 half-lives of the compound, whichever is longer) prior to dosing, will be allowed to 
participate in the study at the discretion of the Investigator and following consultation with 
the Sponsor Clinical Monitor. If a subject is prescribed prohibited medication, upon 
discussion between the Sponsor and the Investigator, the Investigator may substitute the 
previously prescribed medication to an allowed one for the purpose of this study. 
9.3.2 Meals 
Water (except water provided with dosing) will be restricted 1 hour prior to and 1 hour after 
study drug administration, but will be allowed ad libitum at all other times. Other fluids may 
be given as part of the standard meals and/or snacks, but will be restricted at all other times 
throughout the confinement period. 
Subjects will fast overnight for at least 10 hours prior to study drug administration. Subjects 
will continue the fast for at least 4 hours postdose. Standard meals will be provided at 
approximately 4 and 9 hours postdose, and at appropriate time thereafter. A snack will also 
be provided at approximately 12 hours postdose, and at appropriate time thereafter. When 
confined in the CRU, subjects will fast from all food and drink except water between meals 
and snacks. 
Each meal and/or snacks served at the CRU will be standardized and will be similar in 
caloric content and composition. 
9.3.3 Activity 
Following dosing, subjects will remain seated or semi-reclined for the first 4 hours. Subjects 
will then resume normal activity. During the first 4 hours postdose, subjects may be allowed 
to rise for brief periods under supervision (e.g., in order to use the toilet facilities). 
However, should adverse events occur at any time, subjects may be placed in an 
appropriate position or will be permitted to lie down on their right side.  
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion 
of the study. 
Depending on the CRU rules and regulations, subjects may be prohibited from smoking 
during their confinement or during portions of their confinement. 
CCI


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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9.4 
Treatments 
9.4.1 Treatments Administered 
MK-8931 will be supplied as 40 mg tablets. 
Each subject will receive a single oral dose of 40 mg MK-8931 (1 x 40 mg tablet), at Hour 0, 
on Day 1 in a fasted state.  
All study drugs will be administered with approximately 240 mL of water, according to the 
allocation schedule. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject and for each study period, as per the allocation schedule. 
Subjects will be instructed not to crush, split, or chew the study drug. 
The exact clock time of dosing will be recorded. 
9.4.2 Method of Assigning Subjects to Treatment Groups 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be 
assigned a unique allocation identification number prior to dosing, different from the 
screening number, and will receive the corresponding product, according to the allocation 
scheme generated at Celerion.  
Subjects will receive the treatment on one occasion.  
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., allocation number 0101 will replace allocation number 0001). 
9.4.3 Blinding 
This is an open-label study. 
9.4.4 Treatment Compliance  
A qualified designee will be responsible for monitoring the administration of timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the 
subjects have swallowed the study drug. Once a subject has finished the water, the qualified 
designee will use a flashlight and a tongue depressor to check the subject’s mouth. 
Subjects’ hands will also be verified to ensure that the study drug was ingested. 
9.4.5 Study 
Design 
or 
Procedure 
Modifications 
Permitted 
within 
Protocol 
Parameters  
This is a Phase I assessment of MK-8931 in humans, and the pharmacokinetic, 
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 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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Phase I clinical trials. Modifications to the clinical or laboratory procedures may be required 
to achieve the scientific goals of the trial objectives and/or to ensure appropriate safety 
monitoring of the trial subjects. 
The timing of procedures for assessment of safety procedures (e.g., vital signs, ECG, safety, 
laboratory tests, etc.) currently outlined in the protocol may be modified during the study 
based on newly available safety, tolerability, pharmacokinetic or pharmacodynamic data 
(e.g., to obtain data closer to the time of peak plasma concentrations). Additional laboratory 
safety tests may be added to blood samples previously drawn to obtain additional safety 
information (e.g., adding creatinine kinase to chemistry panel that was already drawn). 
These changes will not increase the number of study procedures for a given patient/subject 
during his/her participation in the entire trial. 
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the trial objectives must be detailed by in 
a Protocol Clarification Letter and forwarded to the Investigator for retention. The Protocol 
Clarification Letter may be forwarded to the Institutional Review Board (IRB) at the discretion 
of the Investigator. 
 
 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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10 STUDY PROCEDURES 
The Study Events Flow Chart (Section  6) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. 
Additional evaluations/testing may be deemed necessary by the Investigator and/or the 
Sponsor for reasons related to subject safety. 
For this study, the blood collection for MK-8931 is the critical parameter and 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, but can be performed 
prior or after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
10.1 Safety Assessment 
10.1.1 Screening 
Within 28 days prior to dosing, medical history and demographic data, including name, sex, 
age, race, ethnicity, body weight (kg), height (cm), and BMI (kg/m2) will be recorded. Each 
subject will have a physical examination, vital sign measurements (heart rate, blood 
pressure, temperature, and respiratory rate), 12-lead ECG and the laboratory tests of 
hematological, hepatic and renal function, and additional tests as noted in Section  10.1.5. 
10.1.2 Physical Examination 
A physical examination will be performed as per Study Events Flow Chart (Section  6). 
Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the Investigator or designee. 
10.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate, 
will be measured as outlined in the Study Events Flow Chart (Section  6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and heart 
rate measurements will be performed with subjects in a seated position for at least 1 minute, 
except when they are supine or semi-reclined because of study procedures and/or adverse 
events (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
Blood pressure and heart rate will be measured within 24 hours prior to Day 1 dosing for the 
predose time point. When scheduled postdose, vital signs will be performed within 
approximately 10 minutes of the scheduled time point. 
10.1.4 ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section  6). 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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ECGs will be performed with subjects in a supine position for at least 5 minutes. All ECG 
tracings will be reviewed by the Study Physician or his/her designee. 
ECGs will be measured within 24 hours prior to Day 1 dosing for the predose time point. 
When scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point. 
A subject will be withdrawn from the study by the Study Physician or his/her designee if, in 
their medical judgment, ECG findings are present which make continued study participation 
not in the subject’s best interest. 
10.1.5 Laboratory Tests 
All tests listed below will be performed as per Study Events Flow Chart (Section 6). In 
addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the Investigator. 
Hematology 
 
Serum Chemistry* 
• 
Hemoglobin 
• 
Hematocrit  
• 
Total and differential leukocyte 
count 
• 
Red blood cell count 
• 
Platelet count 
 
 
• 
Blood urea nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase (AST)  
• 
Alanine aminotransferase (ALT) 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Glucose (fasting) 
• 
Creatinine** 
 
Urinalysis 
 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein*** 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood*** 
• 
Nitrite*** 
• 
Urobilinogen 
• 
Leukocyte esterase*** 
 
• 
HIV test 
• 
HBsAg 
• 
HCV (antibodies & RNA) 
• 
Urine drug screen 
 Opiates 
 Amphetamines  
 Barbiturates  
 Benzodiazepines 
 Cocaine 
 Cannabinoids 
• 
Urine or breathalyzer alcohol screen 
• 
Serum pregnancy test (for females 
only) 
• 
FSH (for postmenopausal females 
only) 
• 
Prothrombin INR (HI patients only) 
 
* 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropout or 
rechecks, subjects may not have fasted for 8 hours before the serum chemistry sample is taken.  
** At screening, creatinine clearance will be calculated using Cockcroft-Gault formula. 
*** If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination (red blood cell, white blood cell, bacteria, casts, and, epithelial cells) will be performed. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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10.1.6 Assessing and Recording Adverse Events  
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product or 
protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change 
in frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. 
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent, or protocol-specified procedure whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use. 
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse, and from withdrawal. 
For allocated subjects only, all adverse events that occur after the consent form is signed 
but before enrollment must be reported by Investigator if they are the result of a protocol 
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment, or a procedure. From the time of enrollment through 
14 days following cessation of treatment, all adverse events must be reported by the 
Investigator. Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets. The reporting timeframe for adverse events meeting any serious 
criteria is described in Section  10.1.6.3.1. The Investigator will make every attempt to follow 
all subjects with non-serious adverse events for outcome.  
Paper reporting procedures can be found in the Investigator Trial File Binder (or equivalent). 
10.1.6.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor  
The subject has taken (accidentally or intentionally) any drug administered as part of the 
protocol and exceeding the dose as prescribed by the protocol. It is up to the Investigator or 
the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor. 
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product 
or vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is 
taken without any associated clinical symptoms or abnormal laboratory results, the overdose 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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is reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported by the 
Investigator within 24 hours to the Sponsor either by electronic media or paper. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent). 
10.1.6.2 Reporting of Pregnancy and Lactation to the Sponsor 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of Investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before enrollment 
must be reported by the Investigator if they cause the subject to be excluded from the trial, 
or are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of enrollment through 14 days following 
cessation of Sponsor’s product must be reported by the Investigator. All reported 
pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious 
events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent). 
Pregnant partners of male subjects will not be followed. 
10.1.6.3 Immediate Reporting of Adverse Events 
10.1.6.3.1 Serious Adverse Events  
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that has the following outcome: 
• 
Death 
• 
Immediately life threatening 
• 
Persistent or significant disability/incapacity 
• 
Inpatient hospitalization or prolongation of hospitalization 
• 
Congenital anomaly/birth defect 
• 
Other important medical event 
Note:  In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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as serious adverse events to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes. 
• 
Cancer 
• 
Overdose 
Refer to Table 2 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until enrollment, any serious 
adverse event, or follow up to a serious adverse event, including death due to any cause, 
that occurs to any subject must be reported within 24 hours to the Sponsor if it causes the 
subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at enrollment through 14 days following cessation of 
treatment, any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause, whether or not related to the Sponsor's product, must be reported 
within 24 hours to the Sponsor either by electronic media or paper. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent). 
Additionally, any serious adverse event, considered by an Investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
Investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome. 
10.1.6.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as ECI and must be 
reported to the Sponsor. 
For the time period beginning when the consent form is signed until enrollment, any ECI, or 
follow up to an ECI, that occurs to any subject must be reported within 24 hours to the 
Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at enrollment through 14 days following cessation of 
treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s product, 
must be reported within 24 hours to the Sponsor, either by electronic media or paper. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent). 
Events of clinical interest for this trial include: 
• 
an overdose of Sponsor's product, as defined in Section  10.1.6.1 that is not associated 
with clinical symptoms or abnormal laboratory results.  


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
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• 
For healthy control subjects:, an elevated AST or ALT laboratory value that is greater 
than or equal to three times (3X) the upper limit of normal (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 upon 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 trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder or equivalent. 
For healthy control subjects, it may also be appropriate to conduct additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood tests 
including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria 
noted above. In these cases, the decision to proceed with additional evaluation will be 
made through consultation between the study investigators and the Sponsor Clinical 
Director. However, abnormalities of liver blood tests that do not meet the criteria noted 
above are not ECIs for this trial. 
• 
For subjects with HI: 
AST and ALT: 
 In subjects with baseline AST or ALT <2 x ULN – AST or ALT ≥5 x ULN; 
 In subjects with baseline AST or ALT ≥2 x ULN but <5 x ULN – AST or ALT >3 x the 
baseline level; 
 In subjects with baseline AST or ALT ≥5 x ULN – AST or ALT >2 x the baseline level 
or any AST or ALT value >20 x ULN. 
Total bilirubin: 
 In subjects with baseline total bilirubin <1.5 mg/dL – total bilirubin >2.0 mg/dL; 
 In subjects with baseline total bilirubin ≥1.5 mg/dL but ≤3.0 mg/dL – total bilirubin 
≥2 x the baseline level; 
 In subjects with baseline total bilirubin >3.0 mg/dL – total bilirubin ≥2 x baseline level 
or any total bilirubin value >10 mg/dL. 
*Note:  The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology. 
10.1.6.4 Evaluating Adverse Events 
An Investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 2. The Investigator’s assessment of causality is required for 
each adverse event. Refer to Table 2 or instructions in evaluating adverse events. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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Table 2: 
Evaluating Adverse Events 
Maximum 
Intensity 
(Severity) 
Mild 
awareness of sign or symptom, but easily tolerated (for pediatric trials, 
awareness of symptom, but easily tolerated) 
Moderate 
discomfort enough to cause interference with usual activity (for pediatric 
trials, definitely acting like something is wrong) 
Severe 
incapacitating with inability to work or do usual activity (for pediatric trials, 
extremely distressed or unable to do usual activities) 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that: 
None 
†Death; or 
†Immediately life threatening; or places the subject, in the view of the Investigator, at 
immediate risk of death from the event as it occurred [Note:  This does not include an adverse 
event that, had it occurred in a more severe form, might have caused death.]; or 
†Persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions); or 
†Inpatient hospitalization or prolongation of 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 [including 
hospitalization for an elective procedure] for a preexisting condition which has not worsened 
does not constitute a serious adverse event.); or 
†Congenital anomaly/birth defect (in offspring of subject taking the product regardless of 
time to diagnosis); or 
Cancer; or 
Overdose (whether accidental or intentional). Any adverse event associated with an overdose 
is considered a serious adverse event. An overdose that is not associated with an adverse 
event is considered a non-serious event of clinical interest and must be reported within 
24 hours. 
Other important medical event that may not result in death, not be life threatening, or not 
require hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed previously (designated above by 
a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the 
appropriate length of time and units. 
Action taken  
The action taken is in reference to the either the Sponsor’s Product or the Interacting Drug. 
Did the adverse event cause the Sponsor's product or the Interacting Drug to be: 
None 
Reduced 
Interrupted 
Discontinued 
Increased  
Not Applicable 
Unknown 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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Relationship 
to Sponsor's 
Product 
Did the Sponsor's product cause the adverse event? The determination of the likelihood that 
the Sponsor's product caused the adverse event will be provided by an Investigator who is a 
qualified physician. The Investigator’s signed/dated initials on the source document or 
worksheet that supports the causality noted on the adverse event form, ensures that a 
medically qualified assessment of causality was done. This initialled document must be 
retained for the required regulatory time frame. The criteria below are intended as reference 
guidelines to assist the Investigator in assessing the likelihood of a relationship between the 
test drug and the adverse event based upon the available information. 
Relationship 
to Sponsor's 
Product 
(continued) 
The following components are to be used to assess the relationship between the 
Sponsor's product and the adverse event; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's 
product caused the adverse event: 
Exposure 
Is there evidence that the subject was actually exposed to the Sponsor's 
product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
Time Course 
Did the adverse event follow in a reasonable temporal sequence from 
administration of the Sponsor's product?  
Is the time of onset of the adverse event compatible with a drug-induced 
effect (applies to trials with investigational medicinal product)? 
Likely Cause 
Is the adverse event 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? 
If yes, did the adverse event 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 adverse event resulted in 
death or permanent disability; (2) the adverse event resolved/improved 
despite continuation of the Sponsor's product; (3) the trial is a single-dose 
drug trial; or (4) Sponsor's product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to the Sponsor's product in this trial? 
If yes, did the adverse event 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 adverse event resulted 
in death or permanent disability, or (2) the trial is a single-dose drug trial; or 
(3) Sponsor's product(s) is/are used only one time.) 
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT 
WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE 
SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S 
PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE U.S. CLINICAL MONITOR AND THE INSTITUTIONAL 
REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the adverse event consistent with 
previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an Investigator who is 
a qualified physician according to his/her best clinical judgment, including consideration of the above elements. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 41 
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Record one of the following: 
Use the following scale of criteria as guidance (not all criteria must be 
present to be indicative of a Sponsor's product relationship). 
Related (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 adverse event onset relative to the administration of the 
Sponsor's product is reasonable. The adverse event is more likely explained 
by the Sponsor's product than by another cause. 
Not Related (there is not a 
reasonable possibility of 
Sponsor's product 
relationship) 
Subject did not receive the Sponsor's product OR temporal sequence of the 
adverse event onset relative to administration of the Sponsor's product is not 
reasonable OR there is another obvious cause of the adverse event. (Also 
entered for a subject with overdose without an associated adverse event.) 
10.1.6.5 Sponsor Responsibility for Reporting Adverse Events  
All adverse events will be reported to regulatory authorities, IRB or independent ethics 
committees (IECs), and Investigators in accordance with all applicable global laws and 
regulations. 
10.2 Pharmacokinetic Assessment 
10.2.1 Blood Sampling and Processing 
For all subjects, blood samples for the determination of MK-8931 plasma concentration and 
protein binding (optional) will be collected and processed according to Appendix 4 and 
Appendix 5, respectively, at scheduled time points as delineated in the Study Events Flow 
Chart (Section  6). 
The allowable deviation window is as follows: 
Table 3: 
Time Deviation Window Allowed for Blood Sampling 
Sample collection time 
Allowed deviation 
0.0 – 8.0 hour 
≤± 2 minutes 
>8.0 – 24.0 hour 
≤± 5 minutes 
>24.0 – 72.0 hour 
≤± 10 minutes 
>72.0 – 120.0 hour 
≤± 15 minutes 
10.3 Planned Genetic Analysis Sample Collection 
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
are provided in Appendix 3. 
10.4 Future Biomedical Research Samples 
The following specimens are to be obtained as part of Future Biomedical Research:  
• 
DNA for future research. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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10.5 Blood Volume Drawn for Study Assessments 
Table 4: 
Blood Volume During the Study 
Sample Type 
Number of 
Time Points 
Approximate 
Volume per 
Time Point * 
(mL) 
Approximate Sample 
Volume Over Course 
of Study 
(mL) 
Screening laboratory safety tests 
(including hematology, serum chemistry, 
and serology), FSH (for postmenopausal 
female subjects only) and serum 
pregnancy (for female subjects only). 
1 
12.5 
12.5 
Screening PT/INR (for HI patients only) 
1 
4.5 
4.5 
Blood for Planned Genetic Analysis 
1 
8.5 
8.5 
On-study hematology and serum 
chemistry (includes serum pregnancy 
when scheduled at the same time) 
2 
12.5 
25 ** 
Blood for MK-8931 concentrations 
14 
4 
56 
Blood for MK-8931 protein binding 
3 
10 
30 
Total Blood Volume for Subjects with Hepatic Insufficiency (mL)→ 
136.5 **, § 
Total Blood Volume for Healthy Subjects (mL)→ 
132 **, § 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** An additional hematology and serum chemistry test will be performed in the event of early 
termination; therefore an additional 12.5 mL may be collected. 
§ If additional pharmacokinetic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. 
 
 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 43 
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11 DATA ANALYSIS 
11.1 Pharmacokinetic Parameters 
Pharmacokinetic parameters for plasma MK-8931 will be calculated as follows: 
AUC0-last: 
Area under the concentration versus time curve, from 0 to the 
time of the last quantifiable (above LLOQ) sample. 
AUC0-∞: 
Area under the concentration versus time curve from 0 to infinity 
after single dosing. 
AUC0-24hr: 
Area under the concentration versus time curve, from 0 to 
24 hours after dosing. 
C24hr: 
Plasma concentration at 24 hours. 
CL/F: 
Apparent clearance after extravascular administration. 
Cmax: 
Maximum 
observed 
plasma 
concentration 
after 
the 
administration of a given dose. 
fu: 
Fraction of unbound drug in plasma. 
Tmax: 
Time to maximum observed plasma drug concentration. 
t½: 
(Apparent) terminal half-life. 
Vz/F: 
Apparent volume of distribution during the terminal phase after 
extravascular administration. 
No value for AUC0-∞, CL/F, Vz/F, or apparent terminal t½ will be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
Additional pharmacokinetic parameters may also be calculated for MK-8931 plasma protein 
binding in terms of unbound concentrations (e.g., Cmax_u, AUC0-∞_u, CLu/F). 
11.2 Statistical Methods 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Pharmacology Sciences department at Celerion. 
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report (CSR). 
Additional statistical analyses, other than those described in this section, may be performed 
if deemed appropriate. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 44 
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11.2.1 Determination of Sample Size 
The precision estimates presented below are based on a between subject log scale 
standard deviation estimate for MK-8931 AUC0-∞ and Cmax of 0.267 and 0.269, 
respectively, as observed in MK-8931 Protocol 023, the only study in which the preliminary 
market formulation has been administered and rich pharmacokinetic data are available. 
AUC0-∞:  With a sample size of 8 subjects with moderate hepatic insufficiency or N=8 with 
mild hepatic insufficiency (if Part 2 is conducted) and 8 subjects in the healthy control group, 
the half width of the 90% confidence interval for the AUC0-∞ geometric mean ratio (GMR; 
HI/healthy) on the log scale will be 0.24. The lower and upper 90% confidence limits for the 
GMR will be given by OBS/1.27 and OBS*1.27, where OBS is the observed GMR. Thus, if 
the observed AUC0-∞ GMR is 1.50, the 90% confidence interval would be [1.18, 1.91]. 
Cmax:  With a sample size of 8 subjects with moderate hepatic insufficiency or N=8 with 
mild hepatic insufficiency (if Part 2 is conducted) and 8 subjects in the healthy control group, 
the half width of the 90% confidence interval for the Cmax GMR (HI/healthy) on the log 
scale will be 0.24. The lower and upper 90% confidence limits for the GMR will be given by 
OBS/1.27 and OBS*1.27, where OBS is the observed GMR. Thus, if the observed Cmax 
GMR is 1.50, the 90% confidence interval would be [1.18, 1.91]. 
11.2.2 Subjects to Analyze 
The decision as to which plasma samples collected will be assayed for evaluation of 
pharmacokinetics 
will 
be 
collaboratively 
determined 
by 
the 
Departments 
of 
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism and the appropriate 
department within Early-Stage Development. If indicated, these samples may also be 
assayed and/or pooled for assay in an exploratory manner for metabolites. 
The following populations are defined for the analysis and reporting of data. All subjects will 
be reported, and their data analyzed, according to the treatment they actually received. 
All Subjects as Treated:  All subjects who received at least one dose of the investigational 
drug. This population will be used for assessments of safety and tolerability. 
Per-Protocol:  The set of data generated by the subset of subjects who comply with the 
protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance covers such considerations as 
exposure to treatment, availability of measurements and absence of major protocol 
deviations. Any subjects or data values excluded from analysis will be identified, along with 
their reason for exclusion, in the CSR. At the end of the study, all subjects who are 
compliant with the study procedure as aforementioned and have available data will be 
included in the primary analysis dataset. This population will be used for the 
pharmacokinetic analyses. 
11.2.3 Descriptive Statistics 
Individual values will be listed for each plasma pharmacokinetic parameter by population, 
and the following (non-model-based) descriptive statistics will be provided:  N (number of 
subjects with non-missing data), arithmetic mean, standard deviation, arithmetic percent 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 45 
Confidential 
coefficient of variation (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 ln-scale). For Tmax, only 
median, minimum, and maximum will be provided. 
11.2.4 Analysis Overview 
Pharmacokinetics 
Part 1:  
Individual AUC0-∞ values of MK-8931 after single-dose administration of 40 mg MK-8931 to 
subjects with moderate HI and healthy matched control subjects enrolled in Part 1 will be 
ln-transformed and evaluated with an ANCOVA model. The ANCOVA model will contain a 
categorical factor for population (subjects with moderate HI, healthy matched control 
subjects) and gender, and continuous covariates age and BMI. Gender will be included only 
if there are at least three males and three females from each population. A 90% confidence 
interval for the AUC0-∞ difference in least-squares means (subjects with moderate HI - 
healthy matched control subjects) will be computed from the model. These confidence limits 
will then be exponentiated to obtain a confidence interval for the GMR of AUC0-∞ (subjects 
with moderate HI / healthy matched control subjects). 
The pharmacokinetic condition to initiate Part 2 of the study will be met if the point estimate 
for the AUC0-∞ ratio of geometric means (subjects with moderate HI / healthy matched 
control subjects) exceeds 1.5. 
AUC0-last, AUC0-24hr, Cmax, and C24hr, will be analyzed in a similar fashion as AUC0-∞. 
Part 2:  
If Part 2 is conducted, the pharmacokinetic parameters of MK-8931 after single-dose 
administration of 40 mg MK-8931 to subjects with mild HI and healthy control subjects 
matched to subjects with mild HI (from Part 1 and/or Part 2, as applicable) will be analyzed 
in a similar fashion as the pharmacokinetic parameters in Part 1. 
Parts 1 and 2: 
Plots of the individual values of AUC0-∞, AUC0-last, AUC0-24hr, Cmax, and C24hr for each 
population will be provided. 
11.2.5 Other Analyses 
The relationship between MK-8931 pharmacokinetics and hepatic insufficiency may be 
examined in an exploratory manner via a scatter plot of MK-8931 AUC0-∞ versus the 
Child-Pugh score, including the data from subjects with moderate HI and, if conducted, 
subjects with mild HI, and healthy subjects as reference. 
Relationships between MK-8931 AUC0-∞ and the baseline laboratory components of the 
Child-Pugh score (i.e., bilirubin, albumin levels, and prothrombin time) may also be 
assessed graphically. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 46 
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11.3 Safety Evaluation 
The safety and tolerability of MK-8931 will be evaluated by clinical assessment of adverse 
events and other safety measurements. Summary statistics for the laboratory safety tests, 
ECGs, and/or vital signs may also be computed and provided, as deemed clinically 
appropriate. 
 
 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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12 STUDY ADMINISTRATION 
12.1 Ethics 
12.1.1 Institutional Review Board 
This protocol will be reviewed by an IRB and the study will not start until the IRB has 
approved the protocol or a modification thereof. The IRB is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The IRB is with the International Conference on 
Harmonization (ICH) compliant and may be reached at: 
 
 
 
Tel.:  
 or 
 
Fax:  
 
12.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, Good Clinical Practices (GCP), 21 CFR Parts 50, 56, and 312, the ethical 
principles set forth in the Declaration of Helsinki, and the ICH harmonized tripartite guideline 
regarding GCP (E6 Consolidated Guidance, April 1996). 
12.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and 
date an ICF summarizing the discussion prior to screening, and will be assured that they 
may withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their ICF. 
The initial ICF, any subsequent revised written informed consent form and any written 
information provided to the subject must receive the IRB approval/favorable opinion in 
advance of use. The subject should be informed in a timely manner if new information 
becomes available that may be relevant to the subject’s willingness to continue participation 
in the trial. The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the subject’s 
dated signature. 
The informed consent will adhere to IRB/Ethics Research Committee (ERC) requirements, 
applicable laws and regulations and Sponsor requirements. 
PPD
PPD
PPD
PPD


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 48 
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12.1.4 Consent and Collection of Specimens for Future Biomedical Research 
The Investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial. A copy of the 
informed consent will be given to the subject. 
12.2 Termination of the Study 
Celerion, the Investigator, and/or Merck reserve the right to terminate the study in the 
interest of subject welfare. 
12.2.1 Clinical Criteria for Early Trial Termination 
There are no pre-specified criteria for terminating the trial early. 
12.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant 
to the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance and quality control systems to ensure that 
the trial is conducted, and that data are generated, documented and reported in compliance 
with the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements and local laws, rules and regulations relating to the 
conduct of the clinical study. 
The CSR will be audited by the quality assurance (QA) department and the QA audit 
certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit 
checks are then performed for appropriate databases as a validation routine using SAS® to 
check for missing data, data inconsistencies, data ranges etc. Corrections are made prior to 
database lock. 
Case Report Forms (CRFs) are printed off directly from the database. Each CRF is reviewed 
and signed by the Investigator. 
12.4 Data Management 
The Investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the Investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature. By entering 
his/her electronic signature, the Investigator confirms that all recorded data have been 
verified as accurate. 
Detailed information regarding Data Management procedures will be outlined in Celerion 
Data Management Plan. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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12.5 Direct Access to Source Data/Documents 
Celerion will ensure that the Sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). In the event 
that other trial-related monitoring should be done by other parties, they will be required to 
sign a confidentiality agreement prior to any monitoring and auditing. 
12.6 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of the study formulations to allow completion of 
this study. The lot numbers and expiration dates (where available) of the drugs supplied will 
be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the conclusion 
of the study, any unused MK-8931 drugs will be returned to the Sponsor unless otherwise 
specified by the Sponsor. If no supplies remain, this fact will be documented in the 
pharmacy product accountability records. 
12.7 Data Handling and Record Keeping 
Celerion’s Merck library CRFs will be supplied. 
12.8 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final report will be written according to the 
ICH E3 Guideline (Structure and Content of Clinical Study Reports). 
12.9 Compliance with Law, Audit, and Debarment 
By signing this protocol, the Investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP 
(e.g., International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use Good Clinical Practice:  Consolidated Guideline and 
other generally accepted standards of good clinical practice); and all applicable federal, 
state and local laws, rules and regulations relating to the conduct of the clinical trial. 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Appendix 1. 
The Investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents. 
The Investigator agrees not to seek reimbursement from subjects, their insurance providers 
or from government programs for procedures included as part of the trial reimbursed to the 
Investigator by the Sponsor. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 50 
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The Investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with GCP standards and applicable federal, state and local laws, rules and 
regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as 
required by this protocol or as otherwise required pursuant to any agreement with the 
Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the Investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The Investigator agrees to promptly take any reasonable steps that 
are requested by the Sponsor as a result of an audit to cure deficiencies in the trial 
documentation and worksheets/case report forms. 
The Investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, Investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae. By signing this protocol, 
the Investigator agrees that documentation shall be retained until at least 2 years after the 
last approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the Investigator 
when documents may be destroyed. The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the Investigator when documents no 
longer need to be retained. The Sponsor also recognizes that documents may need to be 
retained for a longer period if required by local regulatory requirements. All trial documents 
shall be made available if required by relevant regulatory authorities. The Investigator must 
consult with and obtain written approval by the Sponsor prior to destroying trial and/or 
subject files. 
ICH GCP guidelines recommend that the Investigator inform the subject’s primary physician 
about the subject’s participation in the trial if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
The Investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The Investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting 
the trial is debarred or if any proceeding for debarment is pending or, to the best of the 
Investigator’s knowledge, threatened. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
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In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC. 
According to European legislation, a Sponsor must designate an overall coordinating 
Investigator for a multi-center trial (including multinational). When more than one trial site is 
open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the Principal 
Investigators at the different trial sites in that Member State, according to national 
regulations. For a single-center trial, the Protocol CI is the Principal Investigator. In addition, 
the Sponsor must designate a principal or coordinating Investigator to review the trial report 
that summarizes the trial results and confirm that, to the best of his/her knowledge, the 
report accurately describes the conduct and results of the trial [CSR CI]. The Sponsor may 
consider one or more factors in the selection of the individual to serve as the Protocol CI 
and or CSR CI (e.g., availability of the Protocol/CSR CI during the anticipated review 
process, thorough understanding of clinical trial methods, appropriate enrollment of subject 
cohort, timely achievement of trial milestones). The Protocol CI must be a participating trial 
Investigator. 
12.10 Publication Policy 
The Sponsor will provide separate guidance on the criteria for publication of clinical trial data 
when contacted for permission to publish. 
12.11 Privacy Notice 
In order to comply with government regulations governing clinical studies, as well as 
ICH GCP 3.2.1, Merck & Co., Inc., and its corporate affiliates ("Sponsor"), is required to 
record the name and address of each IRB or IEC member that reviews and approves this 
study. The Sponsor is also required to document that each IRB or 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 (ICH GCP 8.2.8). 
 
 


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13 REFERENCES 
1 
National Institute of Health, National Institute on Aging, Alzheimer’s disease education 
and referral center, Alzheimer’s disease fact sheet [online], 2015.  
2 
Mangoni AA and Jackson SHD. Age-related changes in pharmacokinetics and 
pharmacodynamics:  basic principles and practical applications. Br J Clin Pharmacol. 
2004; 57(1):  6–14. 
3 
FDA Draft Guidance:  Pharmacokinetics in Patients With Impaired Hepatic Function:  
Study Design, Data Analysis, and Impact on Dosing and Labeling. 2003. 
4 
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
esophagus for bleeding esophageal varices. Brit J Surg 1973;60(8):646-649. 
 
 


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Appendix 1: Merck* Code of Conduct for Clinical Trials 
I. 
Introduction 
A. Purpose 
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing and reporting these trials in compliance with the 
highest ethical and scientific standards. Protection of subject safety is the overriding 
concern in the design of clinical trials. In all cases, Merck clinical trials will be 
conducted in compliance with local and/or national regulations and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki.  
B. Scope 
Such standards shall be endorsed for all clinical interventional investigations 
sponsored by Merck irrespective of the party (parties) employed for their execution 
(e.g., contract research organizations, collaborative research efforts). This Code is 
not intended to apply to trials which are observational in nature, or which are 
retrospective. Further, this Code does not apply to Investigator-initiated trials which 
are not under the control of Merck. 
II. Scientific Issues 
A. Trial Conduct 
1. Trial Design 
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven 
to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic indices of 
Merck or comparator products. Alternatively, Merck may conduct outcomes 
research trials, trials to assess or validate various endpoint measures, or trials to 
determine subject preferences, etc. 
The design (i.e., subject population, duration, statistical power) must be adequate 
to address the specific purpose of the trial. Research subjects must meet 
protocol entry criteria to be enrolled in the trial.  
2. Site Selection 
Merck selects investigative sites based on medical expertise, access to 
appropriate subjects, adequacy of facilities and staff, previous performance in 
Merck trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by Merck personnel to assess the ability to successfully conduct the 
trial. 


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3. Site Monitoring/Scientific Integrity 
Trial sites are monitored to assess compliance with the trial protocol and general 
principles of Good Clinical Practice. Merck reviews clinical data for accuracy, 
completeness and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per Merck policies and procedures, 
if fraud, misconduct or serious GCP-non-Compliance are suspected, the issues 
are promptly investigated. When necessary, the clinical site will be closed, the 
responsible regulatory authorities and ethics review committees notified and data 
disclosed accordingly.  
B. Publication and Authorship 
To the extent scientifically appropriate, Merck seeks to publish the results of trials it 
conducts. Some early phase or pilot trials are intended to be hypothesis-generating 
rather than hypothesis testing. In such cases, publication of results may not be 
appropriate since the trial may be underpowered and the analyses complicated by 
statistical issues of multiplicity. 
Merck’s policy on authorship is consistent with the requirements outlined in the 
ICH-Good Clinical Practice guidelines. In summary, authorship should reflect 
significant contribution to the design and conduct of the trial, performance or 
interpretation of the analysis, and/or writing of the manuscript. All named authors 
must be able to defend the trial results and conclusions. Merck funding of a trial will 
be acknowledged in publications.  
III. Subject Protection 
A. IRB/ERC review 
All clinical trials will be reviewed and approved by an independent IRB/ERC before 
being initiated at each site. Significant changes or revisions to the protocol will be 
approved by the IRB/ERC prior to implementation, except that changes required 
urgently to protect subject safety and well-being may be enacted in anticipation of 
IRB/ERC approval. For each site, the IRB/ERC and Merck will approve the subject 
informed consent form.  
B. Safety 
The guiding principle in decision-making in clinical trials is that subject welfare is of 
primary importance. Potential subjects will be informed of the risks and benefits of, 
as well as alternatives to, trial participation. At a minimum, trial designs will take into 
account the local standard of care. Subjects are never denied access to appropriate 
medical care based on participation in a Merck clinical trial.  
All participation in Merck clinical trials is voluntary. Subjects are enrolled only after 
providing informed consent for participation. Subjects may withdraw from a Merck 
trial at any time, without any influence on their access to, or receipt of, medical care 
that may otherwise be available to them. 


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C. Confidentiality 
Merck is committed to safeguarding subject confidentiality, to the greatest extent 
possible. Unless required by law, only the Investigator, Sponsor (or representative) 
and/or regulatory authorities will have access to confidential medical records that 
might identify the research subject by name. 
D. Genomic Research 
Genomic Research will only be conducted in accordance with informed consent 
and/or as specifically authorized by an Ethics Committee. 
IV. Financial Considerations 
A. Payments to Investigators 
Clinical trials are time- and labor-intensive. It is Merck’s policy to compensate 
Investigators (or the sponsoring institution) in a fair manner for the work performed in 
support of Merck trials. Merck does not pay incentives to enroll subjects in its trials. 
However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts. 
Merck does not pay for subject referrals. However, Merck may compensate referring 
physicians for time spent on chart review to identify potentially eligible subjects. 
B. Clinical Research Funding  
Informed consent forms will disclose that the trial is sponsored by Merck, and that 
the Investigator or sponsoring institution is being paid or provided a grant for 
performing the trial. However, the local IRB/ERC may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, publications resulting from Merck trials will indicate Merck as a source 
of funding. 
C. Funding for Travel and Other Requests 
Funding of travel by Investigators and support staff (e.g., to scientific meetings, 
Investigator meetings, etc.) will be consistent with local guidelines and practices 
including, in the U.S., those established by the American Medical Association (AMA).  
V.  Investigator Commitment 
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards. 
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of 
which is a subsidiary of Merck & Co., Inc. Merck is known as MSD outside of the United States and 
Canada. As warranted by context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc. 
 
 


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Appendix 2: 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 Research 
The specimens consented and/or collected in this trial as outlined in Section 10.4 – Future 
Biomedical Research Samples 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 drugs/vaccines may interact with 
• 
The biology of disease 
The specimen(s) may be used for future assay development and/or drug/vaccine 
development. 
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations with 
the greatest need. All specimens will be used by the Sponsor or those working for or with 
the Sponsor. 
3. Summary of Procedures for Future Biomedical Research 
a. Subjects for Enrollment 
All subjects enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research sub-trial. 
b. Informed Consent  


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Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate. Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in 
the trial flow chart. If delayed, present consent at next possible Subject Visit. 
Consent forms signed by the subject will be kept at the clinical trial site under secure 
storage for regulatory reasons. 
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. 
c. CRF Documentation for Future Biomedical Research Specimens 
Documentation of subject consent for Future Biomedical Research will be captured 
in the Case Report Forms (CRFs). Any specimens for which such an informed 
consent cannot be verified will be destroyed. 
d. Future Biomedical Research Specimen(s) 
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes. 
4. Confidential Subject Information for Future Biomedical Research  
In order to optimize the research that can be conducted with Future Biomedical 
Research specimens, it is critical to link subject' clinical information with future test 
results. In fact little or no research can be conducted without connecting the clinical trial 
data to the specimen. The clinical data allow specific analyses to be conducted. Knowing 
subject characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results. 
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.  
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site. No personal identifiers will appear on 
the specimen tube. 
5. Biorepository Specimen Usage 
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 


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will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor. 
6. Withdrawal From Future Biomedical Research  
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research. Subjects may withdraw 
consent at any time by contacting the Principal Investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(
 
Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the subject of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research trial data and results. No new analyses would be generated 
after the request is received. 
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.  
7. Retention of Specimens  
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed. 
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed 
according to Sponsor policies and procedures and this destruction will be documented in 
the biorepository database. 
8. Data Security 
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
PPD


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accomplished using network security policies and practices based on international 
standards to protect against unauthorized access. 
9. Reporting of Future Biomedical Research Data to Subjects 
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include:  Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation. 
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects. Subjects will not be identified by 
name in any published reports about this study or in any other scientific publication or 
presentation. 
10. Future Biomedical Research Study Population 
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research. 
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused. 
12. Questions 
Any questions related to the future biomedical research should be e-mailed directly to 
 
13. References 
1. National Cancer Institute:  http://www.cancer.gov/dictionary/?searchTxt=biomarker 
2. International Conference on Harmonization Guidance:  DEFINITIONS FOR 
GENOMIC 
BIOMARKERS, 
PHARMACOGENOMICS, 
PHARMACOGENETICS, 
GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
 
 
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf 
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research:  A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org 
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Appendix 3: PAXgeneTM Blood for DNA Analysis 
Clinical Biomarker Specimen Management 
 
Merck Research Laboratories  
SCP-124-00 
 
 
PAXgene™ BLOOD F OR DNA ANALYSIS 
SPECIMEN COLLECTION PROCEDURE 
 
 
SPECIMEN COLLECTION NOTES* 
 
*NOTE:  Refer to protocol flow chart or Specimen Collection Overview Chart for 
scheduled collection time points. 
 
*NOTE:  Collection of specimens from vascular access devices and heparin or saline locks 
is not recommended due to the potential for specimen contamination. This specimen should 
be collected as a peripheral blood draw. 
 
Supplies and Materials (per patient, per time point) 
 
Provided to the Institution 
• Requisition form/card 
• "PAXgene Blood DNA" labels 
• 
One 8.5 mL PAXgene™ Blood DNA collection tube (Cat#761115) 
 
Precautions 
 
* SAFETY PRECAUTION:  Contents of the PAXgene™ tube are irritating to skin. 
Wear disposable gloves, safety glasses or goggles and a laboratory coat and follow standard 
laboratory safety procedures while working with these tubes. If inhaled, supply fresh air; 
consult doctor in case of complaints. If skin contact, immediately wash with water and 
soap, and rinse thoroughly. If contents make eye contact, rinse opened eye for 15 minutes 
under running water, then consult a doctor. If swallowed, immediately call a doctor. 
 
Required Equipment 
 
• Freezer for -20oC for PAXgene™ tube storage (For storage exceptions/monthly batch 
shipments). 
 


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Clinical Biomarker Specimen Management 
 
Merck Research Laboratories  
SCP-124-00 
 
Labeling 
 
1. Place patient-specific label on the PAXgene Blood DNA tube. 
 
2. If required:  Fill out the requisition form/card appropriately (ensure that you follow 
specific processing instructions per the protocol specific Laboratory Procedure Manual). 
 
Preparation 
 
1. Ensure the patient has signed the appropriate IRB/ERC-approved consent for genetic 
specimen collection prior to collecting the specimen. 
 
2. Ensure the PAXgene™ Blood DNA collection tubes are at room temperature prior to 
collecting blood. 
 
*NOTE:  Do not use tubes after the expiration date printed on the label. 
 
3. The PAXgene™ Blood DNA collection tubes should not be the first tubes drawn 
during venipuncture. It should be the last tube collected. 
 
Specimen Collection 
 
1. Collect blood into each PAXgene™ Blood DNA collection tube via your institution's 
recommended standard procedure for venipuncture. 
 
• Ensure that the blood has stopped flowing into the tube before removing the 
tube from the holder. 
• Each tube holds approximately 8.5 mL of blood. 
• Under-filling of the tubes could result in an incorrect blood-to-additive ratio 
and may lead to poor performance (e.g. poor quality or low quantity) 
 
2. Immediately after collection, completely and gently invert the tube 10 times to mix 
uniformly. 
 
 
 
 
 
*NOTE:  After each tube is collected, it is CRITICAL to gently invert PAXgene™ 
10 times to ensure proper mixing of blood & PAXgene™ proprietary reagent. 


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Celerion Project No.:  CA13011 
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Clinical Biomarker Specimen Management 
 
Merck Research Laboratories  
SCP-124-00 
 
Specimen Processing & Handling 
 
1. Within 5-10 minutes of the blood draw, place tubes upright in a wire or hard plastic 
rack at ambient temperature (18-25°C). 
 
2. Tubes must be shipped within 24 hrs of collection to the laboratory at ambient 
temperature. 
 
Storage Exceptions (special circumstances only) 
 
If storing specimens for batch shipment:  Specimen tubes MUST be transferred to 
a -20°C freezer, in a wire or hard plastic rack in the upright position, after collection. 
Specimen tubes may be stored frozen upright at -20°C for no longer than 4 weeks at 
-20ºC. Tubes stored at -20°C must be shipped on dry ice to the Laboratory. 
 
*NOTE:  Any storage time and temperature excursions must be documented and 
communicated upon specimen shipment within the shipment inventory documents. 
 
*NOTE:  Frozen PAXgene™ Blood DNA collection tubes are subject to breakage on 
impact. To reduce the risk of breakage during handling and shipment, frozen tubes should 
be treated in the same manner as glass tubes. If freezing is required, a wire or hard plastic 
rack should be used (NO STYROFOAM) as the tubes may crack. 
 


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Clinical Biomarker Specimen Management 
 
Merck Research Laboratories  
SCP-124-00 
 
Packaging and Shipping 
 
1. It is the responsibility of the primary investigator to ensure that all staff personnel who 
will be handling, packaging, and/or shipping clinical specimens are trained and certified 
as required by National and International regulations and they ship materials in 
accordance with all current regulations relating to the handling and shipping of 
hazardous goods. 
 
2. Follow packing and shipping instructions for AMBIENT shipments. 
 
3. Contact shipping courier to obtain any required documentation/forms required for 
shipment. 
 
4. Ship to the Laboratory within 24 hr of the blood draw. 
 
5. Shipping schedule – Select overnight or priority delivery and ensure that shipments are 
received at the destination vendor Monday through Friday, except on U.S. holidays. 
Shipments can be received on Saturday with advanced notification. Contact the Vendor 
if you are uncertain about the shipping or receiving schedule. 
 
*NOTE:  For storage exceptions where ambient shipment was not possible, and 
specimens were frozen (-20°C), always ship frozen specimens on DRY ICE. 
 
Shipping Address: 
BioProcessing Solutions Alliance  
Attn:  CommStaff 
Nelson Biological Laboratories 
604 Allison Road, C120 
Piscataway, New Jersey 08854, USA 
Tel:  
 
Fax:  
 
Email:  
 
 
 
PPD
PPD
PPD


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Appendix 4: Procedures for the Collection Handling, Storage and Shipping of 
MK-8931 Pharmacokinetic Samples 
Supplies and Equipment 
1. Plastic Lavender Topped Vacutainers Containing K2EDTA as the anticoagulant:  
Capable of holding 4 mL of whole blood. (e.g., Vacutainer #367861 or Fisher #02-683-
99C) 
2. Sample Tubes:  3.6 mL NUNC Cryotube starfoot, 12.5x72mm Internal thread; screw 
cap, Polypropylene Sterile (Fisher Part # 10070731 or NUNC Part # 379189) 
Note:  These tubes (3.6 mL NUNC cryotubes) should not be substituted by other tubes 
based on the proper functioning of the automated liquid handling system. Substitution of 
tubes results in (strong) delays. 
3. Centrifuge:  Capable of rotating between 1000-3000 RCF (x g) for 10 minutes. Note that 
RCF varies according to the centrifuge rotor radius. The formula for computing RCF from 
rotation speed and centrifuge radius is RCF = 11.2r(RPM/1000)2, where r is rotor radius, 
in cm, and RPM is the rotations per minute setting of the centrifuge. A typical 
refrigerated centrifuge (GH-3.8 model from Beckman) yields 1150 RCF at 2500 RPM, for 
example. 
4. -20 ± 10°C Sample Storage Freezer 
Collection of Blood 
For specific time points of sample collection, please refer to the Study Flow Chart 
(Section 6). 
Sample Labeling 
1. Whole Blood Samples. Vacutainers containing whole blood should be labeled 
(non-barcoded) as appropriate. 
2. Plasma Samples. NUNC tubes containing plasma samples should be labeled with the 
pre-printed barcoded labels with the allocation number, day, date and time (hours 
postdose) provided by the Sponsor. Labels should be vertically attached and placed on 
the NUNC tubes toward the top of the tube in order for the level of plasma in the tube to 
be viewed. Preferably only one (1) layer of label should be placed on the tube (not 2). 
This is critical for the proper functioning of the automated liquid handling station. 
Procedure 
1. Draw approximately 4 mL whole blood into plastic (PET) vacutainer containing K2EDTA 
as the anticoagulant and invert 6 times. The vacutainer should be labeled as appropriate 
(see above). 
2. Immediately after collection, the blood containing tubes should be placed in an ice bath 
and centrifuged promptly between 1000-3000 RCF (x g) for 10 minutes. A refrigerated 
(4 to 10°C) or non-refrigerated centrifuge may be used. Note that RCF varies according 
to the centrifuge rotor radius. The formula for computing RCF from rotation speed and 


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Celerion Project No.:  CA13011 
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centrifuge radius is RCF = 11.2r (RPM/1000)2, where r is rotor radius, in cm, and RPM is 
the rotations per minute setting of the centrifuge. If the samples cannot be centrifuged 
immediately, the tubes should be kept in an ice bath and centrifuged within 30 minutes 
of collection. 
Note:  Be sure to account for rotor size variations by adjusting the revolutions per minute 
(RPM) for the specific centrifuge to yield between 1000-3000 RCF (xg) as noted in the 
Supplies and Equipment section. 
3. Immediately after separation of the whole blood, carefully transfer 1.0-2.0 mL plasma 
into a 3.6 mL NUNC cryotube identified with pre-printed barcoded labels (see above) 
and store at -20 ± 10°C until transfer to the analytical laboratory on DRY ICE. 
Note(s):  In the event that the whole blood samples cannot be processed immediately 
the samples should be kept in an ice bath. No more than 60 minutes should elapse 
between blood draw and the freezing of plasma samples. 
Sample Shipping 
Sample Preparation for Shipment 
• 
Samples are to be packaged and prepared for shipment in compliance with US 
Department of Transportation, Nuclear Regulatory Commission, International Air 
Transport Association, international, state, local, and any other applicable regulations 
• 
Sort samples by subject (all samples from one subject together) and arrange in 
sequence according to collection time. As appropriate, samples should be placed in grid 
boxes and bundled together and placed in freezer/plastic bags. Small vials vulnerable to 
leakage or damage should be placed in divided trays or boxes.  
• 
Enclose a detailed specimen inventory, sealed in a Zip-Loc™ bag (or equivalent brand), 
in the shipment box: 
Specimen Inventory Sheet/Form/Log 
The following information will be included on the specimen inventory sheet/form/log 
which will accompany the sample shipment: 
• MK number 
• Study number 
• Randomization number 
• Period 
• Nominal time 
• Specimen type 
• Date(s) of sample collection 
• Total number of samples in shipment 
• Merck barcodes (if feasible) 
• 
For frozen samples, there must be sufficient temperature maintenance material (e.g., dry 
ice, icepack) to maintain the samples in a frozen state for at least 72 hours. All 
shipments will be made in freezer boxes containing sufficient DRY ICE. 


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 66 
Confidential 
• 
It is the responsibility of the primary investigator to ensure that all staff personnel who 
will be handling, packaging, and/or shipping clinical specimens act in conformance with 
International Air Transport Association (IATA) regulations, US Department of 
Transportation, Nuclear Regulatory Commission, International Air Transport Association, 
international, state, local, and any other applicable regulations relating to the handling 
and shipping of hazardous goods. 
• 
Shipments should be sent on MONDAY or TUESDAY (unless prior approval from 
SPONSOR to ship WEDNESDAY) to assure receipt by FRIDAY. 
• 
Samples should be sent at intervals to be determined by the Sponsor and the 
investigator. Samples should be shipped using World Courier. The Shipment address is: 
• 
SAMPLES Shipping Address 
Analytical Laboratory 
Pharma Medica Research Inc. 
6100 Belgrave Road 
Mississauga, Ontario, Canada 
L5R 0B7 
Tel.:  
 
Fax:  
 
 
 
E-mail:  
 
Note:  Sample storage for this study is -20 ± 10°C. 
• 
The following papers are to accompany the shipment: 
o Airway Bill 
o Specimen Inventory 
• 
Notify recipient noted above, Early Clinical Scientist (ECS), and Clinical Research 
Associate (CRA) by FAX or email, immediately after the samples leave your premises. 
Provide the following information in the FAX or email: 
- MK/protocol number 
- Randomization number  
- Name of courier or transport company. 
- Name of contact at shipment point of origin 
- Time and date the shipment left your premises. 
- A copy of the Airway Bill. 
• 
Upon arrival, the shipment will be unpacked, and the contents documented. The 
individual responsible at the shipment point of origin will be notified as to sample 
disposition. 
These procedures may be altered with an administrative letter from the Sponsor. 
 
 
PPD
PPD
PPD
PPD


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 67 
Confidential 
Appendix 5: Sample Handling Instructions for MK-8931 Protein Binding 
In Vitro Protein Binding Plasma Assay — Sample Collection, Handling, Labeling, 
Storage, and Shipment 
Blood for In Vitro Protein Binding 
1. Collection of Blood 
For specific time points of sample collection, please refer to the Study Flow Chart 
(Section 6). 
2. Sample Labeling 
Spray-dried EDTA VACUTAINER tubes should be labeled with allocation number, 
period, day, date, and actual time (hours postdose). Bar-coded labels will also be 
provided by Sponsor for plasma samples. 
3. Procedures 
a. Collect 10 mL of whole blood in a K2EDTA (lavender-top) tube or equivalent, either 
by venipuncture or saline-lock. 
b. Centrifuge for 15 minutes at 3000 rpm at 4°C, remove the plasma and transfer to 
3.6-cc NUNC cryotubes or equivalent (2 aliquots per subject). If centrifugation 
cannot be performed immediately, the blood-containing tubes should be placed in an 
ice bath. 
c. All plasma samples should be immediately placed into a -80±15°C or lower freezer 
and stored frozen at -80±15°C or lower until transfer to Merck on DRY ICE. 
Blood should be centrifuged and all plasma separated and frozen within 30 minutes 
from the time the blood is drawn. The entire process from collection to separation of 
the plasma must be done as carefully as possible to minimize hemolysis of red blood 
cells and release of proteases, which can complicate sample analysis. 
4. Shipping Procedures for In Vitro Protein Binding Plasma (Archive) 
All shipments will be made in freezer boxes containing sufficient DRY ICE and labeled 
as HUMAN SAMPLES. Ship tube(s) in a leak-proof plastic bag. 
Please include a sample inventory sheet with each shipment. 
Call or fax the Sample Receipt Department at Merck Research Laboratories when the 
shipment 
has 
been 
made 
and 
give 
the 
appropriate 
airbill 
number. 
Fax:  
 Tel.:  
 
Shipment should be sent on MONDAY or TUESDAY to assure receipt by Friday. 
PPD
PPD


MK-8931 
Merck Protocol No.:  MK-8931-016-01 
Hepatic Insufficiency Study Protocol 
Celerion Project No.:  CA13011 
Merck 
US IND No:  110,186 
 
CA13011_(MK-8931-016-01)_Final_Protocol_Amendment_1_05Jan2017 
Page 68 
Confidential 
Ship for next-day delivery to: 
 
 
MRL, Division of Merck & Co., Inc. 
770 Sumneytown Pike 
Building No. 75B, LAB 1210 
West Point, Pennsylvania 19486, USA 
 
Note:  Sample storage for this study is -80±15°C or lower. 
These procedures may be altered with an administrative letter from the Sponsor. 
 
PPD