Clinical trial NCT03108924
Conditions: Renal Insufficiency
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-04-14; Completion date: 2017-09-13
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial aims to evaluate the plasma pharmacokinetics of gefapixant (MK-7264) administered to participants with varying degrees of renal insufficiency (RI) compared to healthy matched controls; and to investigate the extent of MK-7264 removal by hemodialysis (HD) in participants with end stage renal disease (ESRD), following administration of a single 50 mg dose of gefapixant.

Detailed description:

Arms: arm 1: Participants with moderate renal insufficiency (RI) are treated with a single 50 mg dose of gefapixant arm 2: Participants with severe RI are treated with a single 50 mg dose of gefapixant arm 3: Healthy, participants matched for age and body weight are treated with a single 50 mg dose of gefapixant arm 4: Participants with end stage renal disease (ESRD) requiring hemodialysis (HD), are treated in Period 1 with a single 50 mg dose of gefapixant immediately after the scheduled HD, followed in Period 2 with a single 50 mg dose of gefapixant two hours prior to HD. Between the Periods 1 and 2 MK-7264 dose administrations there was approximately a 7-day washout period with 3 dialysis sessions.
Interventions: intervention 1: Gefapixant
Intervention descriptions: intervention 1: After an overnight fast participants receive a single oral dose of 50 mg gefapixant, in one 50 mg tablet.

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03108924  
Document Date: 
09-Jun-2017
An Open-Label, Single-Dose Study to Investigate the Influence of 
Renal Insufficiency on the Pharmacokinetics of MK-7264


 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 1 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Celerion Project No.:  CA21631 
 
Merck Protocol No.:  MK-7264-026-03 
 
US IND No.:  123007 
 
 
An Open-Label, Single-Dose Study to Investigate the Influence of Renal Insufficiency on the 
Pharmacokinetics of MK-7264 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 3 
CONFIDENTIAL 
intervals for plasma PK parameters are relative to dosing (Hour 0). 
Thus AUC[0.5-4]Ca, AUC[0.5-4]Cv dialysate PK parameters were 
changed to AUC[2.5-6]Ca, AUC[2.5-6]Cv and all relevant sections to 
reflect this change were updated. 
Typographical and grammatical corrections, as well as formatting 
changes, were made throughout the protocol. 
16 May 2017 
by 
 
Final Protocol, Amendment 2 
The protocol was amended to correct an error in the calculation of the 
total blood volume drawn from subjects in Part 2 as listed in Table 3 
Blood Volume Drawn During the Study in Part 2.  
In Period 2 of Part 2 of the study, some blood samples for MK-7264 
are scheduled to be collected during hemodialysis (HD). As stated in 
Section 5 Synopsis, Section 6.2 Part 2: Subjects with ESRD, 
Section 9.1 Overall Study Design and Plan, and Section 10.1.5 
Hemodialysis (ESRD Subjects Only), the blood samples taken during 
HD will be collected from both the pre-dialyzer and post-dialyzer 
blood lines; therefore 2 blood samples per time point will be collected 
during HD. In Amendment 1 of this protocol, only 1 sample per time 
point during HD was accounted for in Table 3 Blood Volume Drawn 
During the Study in Part 2. To correct this mistake in Table 3, the 
number of time points for Blood for MK-7264 was corrected from 40 
to 49 and the total blood volume collected from each subject in Part 2 
was corrected from 216 mL to 243 mL. 
Additionally, in Section 6.2 Part 2: Subjects with ESRD, footnote 
“m” was added to the 6-hour time point for Blood for MK-7264 
Pharmacokinetics to clarify that blood samples (pre-dialyzer and 
post-dialyzer) will be collected immediately after HD is stopped. An 
“X” was also added to the 6-hour time point for Dialysate for 
MK-7264 Pharmacokinetics and footnote “n” was updated to clarify 
that a dialysate sample will be collected immediately after HD is 
stopped. Lastly, footnote “o” was updated and the “X” in the 
Hemodialysis row was extended until the 6-hour column to clarify 
that HD will be approximately 4 hours in duration as correctly 
indicated in Section 10.1.5 Hemodialysis (ESRD Subjects Only). 
Typographical corrections were also made throughout the protocol. 
04 May 2017 
by 
 
Final Protocol, Amendment 1 
The protocol was amended to document the addition of Part 2 to the 
study to assess pharmacokinetics of MK-7264 in subjects with end 
stage renal disease (ESRD) requiring hemodialysis (HD). Updates 
were applied throughout the protocol. 
Typographical and grammatical corrections, as well as formatting 
changes, were made throughout the protocol. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 4 
CONFIDENTIAL 
22 Mar 2017 
by 
 
Final Protocol 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 5 
CONFIDENTIAL 
 
2 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES 
An Open-Label, Single-Dose Study to Investigate the Influence of Renal Insufficiency on the 
Pharmacokinetics of MK-7264 
 
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: 
 
Kwan-Hong Chris Min, MD, PhD 
Tel.:  
 
E-mail:  
 
 
 
 
 
 
Signature 
 
Date 
PRINCIPAL INVESTIGATORS 
AND CLINICALS 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 6 
CONFIDENTIAL 
 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
Protocol Author 
 
Scientist, Protocol Design & Development 
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:  
 
 
 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 7 
CONFIDENTIAL 
 
4 
TABLE OF CONTENTS 
1 
PROTOCOL REVISION HISTORY .......................................................................................... 2 
2 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ...................................... 5 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY ............................................................. 6 
4 
TABLE OF CONTENTS .............................................................................................................. 7 
5 
SYNOPSIS .................................................................................................................................... 11 
6 
STUDY EVENTS FLOW CHART ............................................................................................ 15 
6.1 
Part 1: Healthy Subjects and Subjects with Severe and Moderate RI ................................. 15 
6.2 
Part 2: Subjects with ESRD ................................................................................................. 17 
7 
BACKGROUND AND RATIONALE ....................................................................................... 20 
7.1 
Background ......................................................................................................................... 20 
7.2 
Rationale .............................................................................................................................. 20 
7.2.1 
Rationale for this Study and Study Design ......................................................... 20 
7.2.2 
Rationale for the Dose Selection and Dose Regimen ......................................... 21 
7.2.3 
Rationale for Endpoints ...................................................................................... 21 
7.2.4 
Rationale for Planned Exploratory Biomarker Research .................................... 22 
7.2.5 
Rationale for Future Biomedical Research ......................................................... 22 
8 
STUDY OBJECTIVES, ESTIMATION, AND ENDPOINTS ................................................. 23 
8.1 
Objectives and Estimation ................................................................................................... 23 
8.1.1 
Primary ............................................................................................................... 23 
8.1.2 
Secondary (Both Parts) ....................................................................................... 23 
8.1.3 
Exploratory ......................................................................................................... 23 
8.1.4 
Planned Exploratory Biomarker (Both Parts) ..................................................... 23 
8.2 
Analysis Endpoints .............................................................................................................. 24 
9 
INVESTIGATIONAL PLAN ..................................................................................................... 25 
9.1 
Overall Study Design and Plan ............................................................................................ 25 
9.1.1 
Confinement, Return Visit, and Follow-up ........................................................ 26 
9.1.2 
Study Duration.................................................................................................... 26 
9.2 
Selection of Study Population ............................................................................................. 27 
9.2.1 
Inclusion Criteria ................................................................................................ 27 
9.2.1.1 
Subjects with Moderate or Severe Renal Insufficiency or with 
ESRD ..................................................................................................... 27 
9.2.1.2 
Subjects with Moderate or Severe Renal Insufficiency Only ................ 28 
9.2.1.3 
Subjects with ESRD Requiring Hemodialysis Only ............................. 28 
9.2.1.4 
Healthy Subjects .................................................................................... 28 
9.2.2 
Exclusion Criteria ............................................................................................... 30 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 8 
CONFIDENTIAL 
9.2.2.1 
Subjects with Moderate or Severe Renal Insufficiency or with 
ESRD ..................................................................................................... 30 
9.2.2.2 
Healthy Subjects .................................................................................... 31 
9.2.3 
Subject Withdrawal/Discontinuation Criteria .................................................... 32 
9.2.3.1 
Withdrawal/Discontinuation .................................................................. 33 
9.2.3.1.1 
Withdrawal from Future Biomedical Research ........................ 33 
9.3 
Study Restrictions ................................................................................................................ 33 
9.3.1 
Prohibitions and Concomitant Therapy .............................................................. 33 
9.3.2 
Meals .................................................................................................................. 35 
9.3.3 
Activity ............................................................................................................... 35 
9.4 
Treatments ........................................................................................................................... 36 
9.4.1 
Treatments Administered ................................................................................... 36 
9.4.2 
Method of Assigning Subjects to Treatment Groups ......................................... 36 
9.4.3 
Blinding .............................................................................................................. 36 
9.4.4 
Treatment Compliance ....................................................................................... 36 
9.4.5 
Study Design or Procedure Modifications Permitted within Protocol 
Parameters .......................................................................................................... 36 
10 STUDY PROCEDURES ............................................................................................................. 37 
10.1 Safety Assessment ............................................................................................................... 37 
10.1.1 
Screening ............................................................................................................ 37 
10.1.2 
Physical Examination ......................................................................................... 37 
10.1.3 
Vital Signs .......................................................................................................... 37 
10.1.4 
ECG Monitoring ................................................................................................. 38 
10.1.5 
Hemodialysis (ESRD Subjects Only) ................................................................. 38 
10.1.6 
Laboratory Tests ................................................................................................. 39 
10.1.7 
Assessing and Recording Adverse Events .......................................................... 40 
10.1.7.1 Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor ........................................................................ 40 
10.1.7.2 Reporting of Pregnancy and Lactation to the Sponsor .......................... 41 
10.1.7.3 Immediate Reporting of Adverse Events............................................... 41 
10.1.7.3.1 
Serious Adverse Events ............................................................ 41 
10.1.7.3.2 
Events of Clinical Interest ........................................................ 42 
10.1.7.4 Evaluating Adverse Events .................................................................... 43 
10.1.7.5 Sponsor Responsibility for Reporting Adverse Events ......................... 46 
10.2 Pharmacokinetic Assessment .............................................................................................. 46 
10.2.1 
Blood Sampling and Processing ......................................................................... 46 
10.2.2 
Urine Collection (Part 1 only) ............................................................................ 46 
10.2.3 
Dialysate Collection ........................................................................................... 47 
10.3 Planned Genetic Analysis Sample Collection ..................................................................... 47 
10.4 Future Biomedical Research Samples ................................................................................. 47 
10.5 Blood Volume Drawn for Study Assessments .................................................................... 47 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 10 
CONFIDENTIAL 
LIST OF APPENDICES 
Appendix 1: Merck* Code of Conduct for Clinical Trials .......................................................... 62 
Appendix 2: Collection and Management of Specimens for Future Biomedical Research ........ 65 
Appendix 3: PAXgeneTM Blood for DNA Analysis .................................................................... 69 
 
LIST OF TABLES 
Table 1: 
Evaluating Adverse Events..................................................................................... 44 
Table 2: 
Blood Volume Drawn During the Study in Part 1.................................................. 47 
Table 3 
Blood Volume Drawn During the Study in Part 2.................................................. 48 
Table 4: 
Estimated Precision Calculations ........................................................................... 51 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 11 
CONFIDENTIAL 
 
5 
SYNOPSIS 
Compound: 
MK-7264 
Clinical Indication: 
Cough 
Study Phase and Type: 
Phase I – Interventional 
Study Objectives and 
Estimation: 
Primary: 
Both Parts: 
Objective:  To evaluate the plasma pharmacokinetics of MK-7264 
administered to subjects with varying degrees of renal insufficiency 
(RI) compared to healthy matched control subjects. 
Estimation:  In subjects with moderate and severe RI, and subjects 
with ESRD, pharmacokinetic parameters (AUC0-∞, AUC0-last, 
Cmax, CL/F, and CLr, as appropriate) of MK-7264 following 
administration of a single 50 mg dose will be estimated and compared 
to those observed in healthy matched control subjects. 
Part 2 Only: 
Objective:  To investigate the extent of MK-7264 removal by 
hemodialysis.  
Estimation:  The extent to which MK-7264 is removed from plasma by 
hemodialysis will be estimated following administration of a single 
50 mg dose of MK-7264 in subjects with ESRD requiring 
hemodialysis. 
Secondary (Both Parts): 
Objective:  To evaluate the safety and tolerability of MK-7264 in 
subjects with moderate and severe RI (Part 1) and in subjects with 
ESRD on hemodialysis (Part 2). 
Exploratory: 
Objective 1 
(both 
parts): 
 
To 
estimate 
and 
compare 
the 
pharmacokinetic parameters (AUC0-12, AUC0-24, AUC0-48, Ae0-24, 
Ae0-48, Tmax, Vz/F, apparent terminal t½, and Fe, as applicable) 
between subjects with various degrees of RI and healthy matched 
control subjects. 
Objective 2 (both parts):  Analyze the potential relationship between 
appropriate MK-7264 pharmacokinetic parameters and renal function. 
Objective 3 (Part 2 only):  To estimate pharmacokinetic parameters 
(AUCD, AUC[2.5-6]Ca, AUC[2.5-6]Cv, CLD,plasma, CLD,dialysate, 
AD, and AD,total) for MK-7264 in subjects with ESRD following 
dosing, as appropriate. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 12 
CONFIDENTIAL 
Planned Exploratory Biomarker (Both Parts):  
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 an open-label, 2-part, single dose study. In Part 1, the 
pharmacokinetics of MK-7264 will be evaluated in subjects with 
moderate and severe RI compared to healthy matched control subjects. 
In Part 2, the pharmacokinetics of MK-7264 will be evaluated in 
subjects with ESRD requiring HD under dialysis and non-dialysis 
conditions. Parts 1 and 2 of the study may be conducted concurrently. 
Assignment to a renal function group will be as follows: 
Group 
N 
eGFR (mL/min/1.73m2)* 
Part 1 
Severe Insufficiency 
6 
<30 **, not on dialysis 
Moderate Insufficiency 
6 
30 – 59 *** 
Healthy Matched Control 
6 
≥90**** 
Part 2 
ESRD requiring HD 
6 
requiring HD 
* Estimated glomerular filtration rate (eGFR) based on Modification of 
Diet in Renal Disease (MDRD) equation at screening. Baseline eGFR will 
be obtained twice during the screening period, and the mean of the two 
values will be used for group assignment. The second baseline eGFR 
sample may be obtained at the time of check-in. 
** Reasonable efforts will be made to enroll at least 2 subjects with eGFR 
values of < 20 mL/min/1.73m2  
*** Reasonable efforts will be made to enroll at least 2 subjects with 
eGFR values of 30 - 45 mL/min/1.73m2 
**** Healthy control subjects are within ± 10 years of the mean age and 
within ± 10 kg (where the weight is rounded to the nearest kg) of the mean 
weight for the pooled severe RI, moderate RI, and ESRD groups. For 
healthy subjects a creatinine clearance computed over a 24 hour urine 
collection for subjects that do not qualify with ≥90 eGFR may be done for 
confirmation purposes.  
Part 1: 
On Day 1, a single oral dose of MK-7264 will be administered 
followed by pharmacokinetic sampling for 72 hours. Urine samples 
will be collected for 48 hours postdose, if possible. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 13 
CONFIDENTIAL 
Part 2: 
Subjects with ESRD requiring HD will receive a single dose of 
MK-7264 on two occasions.  
On Day 1 of Period 1, subjects with ESRD requiring HD will receive a 
single oral dose of MK-7264 immediately following their scheduled 
HD, followed by pharmacokinetic sampling for 72 hours. Subjects will 
initiate the next HD immediately following the 72-hour blood draw on 
Day 4. If the next scheduled HD must be initiated before 72 hours 
postdose, a sample for MK-7264 analysis will be collected prior to 
HD. Urine samples will be collected for 48 hours postdose, if possible. 
On Day 1 of Period 2, subjects with ESRD requiring HD will receive a 
single oral dose of MK-7264 approximately 2 hours prior to their 
scheduled HD followed by pharmacokinetic sampling for 72 hours. 
The HD session will initiate immediately following the 2-hour blood 
draw. During this dialysis session, pre- and post-dialyzer plasma 
samples will be collected every 30 minutes and dialysate samples will 
be collected pre-dialysis, post-dialysis, and for 1 minute every 30 
minutes during HD for MK-7264 analysis. Urine samples will be 
collected for 48 hours postdose, if possible. 
There will be a washout period of approximately 7 days (with 
3 dialysis sessions) between MK-7264 dosing in Periods 1 and 2. 
Both Parts: 
The clinic will contact all subjects (including those who terminate the 
study early) approximately 14 days after the last study drug 
administration to determine if any adverse events have occurred since 
last visit. 
Blinding: 
This is an open-label study. 
Number of Subjects: 
Twenty-four (24), adult, male and female subjects between 18 and 
80 years of age (inclusive) will be enrolled; 6 subjects with ESRD 
requiring HD, 6 subjects with severe RI, 6 subjects with moderate RI, 
and 6 healthy matched control subjects. 
Once subjects with severe and moderate RI and subjects with ESRD 
are enrolled, the healthy matched control subjects will be enrolled. 
Each healthy control subject will be matched to the mean age 
(±10 years) and weight (±10 kg, where the weight is rounded to the 
nearest kg) of subjects with RI. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 14 
CONFIDENTIAL 
Dosage, Dosage Form, 
Route, and Dose Regimen: 
Part 1: 
Subjects will receive a single oral dose of 50 mg MK-7264 (1 x 50 mg 
tablet) at Hour 0 on Day 1. 
Part 2: 
Subjects will receive a single oral dose of 50 mg MK-7264 (1 x 50 mg 
tablet) at Hour 0 on Day 1 in Period 1, immediately following the 
scheduled HD, and at Hour 0 on Day 1 in Period 2, approximately 2 
hours prior to initiation of the scheduled HD. 
Both Parts: 
MK-7264 will be administered following an overnight fast, with 
approximately 240 mL of water. 
Key Assessments: 
Pharmacokinetics: 
The following pharmacokinetic parameters will be calculated for 
MK-7264 in plasma, as appropriate:  AUC0-∞, AUC0-last, AUC0-12, 
AUC0-24, AUC0-48, Cmax, Tmax, apparent terminal t½, CL/F, and 
Vz/F.  
For subjects with ESRD (Part 2 only), the following PK parameters 
will also be calculated for MK-7264 in plasma following dosing, as 
appropriate:  AUCD, AUC(2.5-6)Ca, AUC(2.5-6)Cv, CLD,plasma, 
CLD,dialysate, AD, and AD,total.  
The following pharmacokinetic parameters will be calculated for 
MK-7264 in urine (Part 1 and Part 2), as appropriate:  Ae0-24, Ae0-48, 
Fe, and CLr. 
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. 
 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 16 
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. 
The clinic will contact all subjects (including subjects who terminate early) approximately 14 days after the study drug administration to determine if any adverse 
events have occurred since the last study visit.  
d. Subjects will be admitted to the CRU on Day -2 or Day -1, at the time indicated by the CRU. 
e. 
The 16-hour time point following dosing on Day 1 will be either on Day 1 or Day 2, depending on the time of dosing on Day 1. 
f. 
A symptom-driven physical examination may be performed at other times, at the Investigator’s discretion. 
g. To be performed on Day 4 or prior to early termination from the study. 
h. Baseline eGFR will be obtained twice (at least 72 hours apart as part of subject screening) and averaged. The second baseline eGFR sample may be obtained at 
the time of check-in. 
i. 
To be performed within 24 hours prior to dosing. 
j. 
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. 
k. Urine collection intervals are: pre-dose (spot collection), 0 - 12 hours, 12 - 24 hours post-dose, and 24 -48 hours. For subjects with renal insufficiency, urine 
samples will be collected whenever possible, as they may not be able to produce urine at each interval. For subjects who are anuric, urine samples for urinalysis 
will not be collected. 
l. 
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. 
Abbreviations:  C-I = Check-in, CRU = Clinical research unit, DNA = deoxyribonucleic acid, eGFR = Estimated glomerular filtration rate, FBR = Future Biomedical Research, 
FSH = Follicle-stimulating hormone, FU = Follow-Up, HIV = Human immunodeficiency virus, IRB/IEC = Institutional review board/independent ethics committee, P = Predose, 
PK = Pharmacokinetic.  
 
 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 19 
CONFIDENTIAL 
h. 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. 
i. 
To be administered immediately following scheduled HD.  
j. 
If the next scheduled HD must be initiated before 72 hours postdose, a sample for MK-7264 analysis will be collected prior to HD. 
k. Urine collection intervals are: pre-dose (spot collection), 0 - 12 hours, 12 - 24 hours post-dose, and 24 -48 hours. Urine samples will be collected whenever 
possible, as some subjects with ESRD may not be able to produce urine at each interval. For subjects who are anuric, urine samples for urinalysis will not be 
collected. 
l. 
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. 
m. During HD, blood samples for MK-7264 will be collected from both the pre-dialyzer and post-dialyzer blood lines in addition to peripheral PK blood draw; 
thus 3 samples per time point during HD will be taken. A blood sample (a pre-dialyzer and post-dialyzer) will also be obtained immediately before the HD is 
stopped, if this time point does not coincide with a time point that is already scheduled. 
n. Dialysate samples for determination of MK-7264 will be obtained pre-dialysis, post-dialysis (immediately before the HD is stopped), and for 1 minute every 
half hour during HD.  
o. The HD session will be initiated immediately following the 2-hour postdose blood draw and the HD period will be approximately 4 hours in duration.  
p. To be performed on Day 4 of Period 2 or prior to early termination from the study. 
q. The clinic will contact all subjects (including subjects who terminate early) approximately 14 days after the last study drug administration to determine if any 
adverse events have occurred since the last study visit. 
Abbreviations:  C-I = Check-in, CRU = Clinical research unit, DNA = deoxyribonucleic acid, FBR = Future Biomedical Research, FSH = Follicle-stimulating hormone, 
FU = Follow-Up, HD = Hemodialysis, HIV = Human immunodeficiency virus, IRB/IEC = Institutional review board/independent ethics committee, P = Predose, PK = Pharmacokinetic.  
 
 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 20 
CONFIDENTIAL 
7 
BACKGROUND AND RATIONALE 
7.1 
Background 
P2X3 receptors are ligand-gated ion channels that respond to adenosine triphosphate (ATP) and are 
almost exclusively localized on C-fiber sensory neurons, including those that innervate the upper and 
lower airways. ATP is released by damaged, stressed, and inflamed tissues. ATP and P2X3 
containing receptors have been shown to be involved in airways sensitization and their involvement 
provides a rationale for P2X3 antagonism in the treatment of chronic cough. 
MK-7264, a selective P2X3 receptor antagonist, is the first clinical agent targeting this receptor, and 
is being evaluated for treatment of cough. Additionally, MK-7264 has been evaluated in asthma, 
interstitial cystitis/bladder pain syndrome, and osteoarthritis pain. P2X3 antagonists may address the 
unmet medical needs for any of these indications. 
Refer to the Confidential Clinical Investigator’s Brochure (IB) for detailed background information 
on MK-7264 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 
Preliminary data indicate that MK-7264 is eliminated primarily through renal elimination with 
metabolism playing a secondary role in its elimination. Following multiple dose administration, 
approximately 60% of a 50 mg dose was excreted at steady state in healthy subjects. Thus, it is 
anticipated that the in the setting of renal impairment, alterations in the pharmacokinetics of 
MK-7264 are likely and dose adjustments may be indicated. The need for dose adjustment is a 
clinically significant issue as the incidence of renal impairment is associated with increasing age, and 
the patient population in MK-7264-012, a Phase 2b chronic cough efficacy study, had a median age 
of approximately 60, though there was a wide range of ages from 22 to 79. 
The potential impact of mild renal impairment was assessed in a previous Phase 1 multiple dose study 
in healthy and elderly adult male and female subjects, MK-7264-007, which included subjects with 
mild renal impairment. A non-population based preliminary pharmacokinetic analysis of this study 
investigated the impact of eGFR on exposures (AUC and Cmax) in elderly and non-elderly subjects 
using a linear fixed effect model. In this analysis, a subject with mild renal impairment 
(eGFR = 60 mL/min) in comparison to a subject with normal renal function (eGFR = 90 mL/min) 
would be predicted to have an increase of AUC0-t and Cmax of 19% and 11%, respectively, with a 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 21 
CONFIDENTIAL 
300 mg dose at steady state. Age and gender did not appear to have an effect on the pharmacokinetics 
of MK-7264 independent of eGFR in this analysis. 
Since MK-7264 is eliminated primarily through renal excretion, the impact of renal function on 
pharmacokinetics of MK-7264 will be extended beyond the previous experience in subjects with mild 
impairment to subjects with moderate and severe renal impairment as well as subjects with ESRD. 
The relationship between renal function (as measured by eGFR) and exposure (as measured by AUC) 
will be explored by comparing the pharmacokinetics in within-study control subjects with normal 
renal function to those with varying degrees of renal impairment. The study will also examine the 
degree to which MK-7264 is removed from plasma by hemodialysis. The safety and tolerability of 
MK-7264 when administered in subjects with renal impairment will also be assessed. The control 
subjects will be matched by age (mean within ± 10 years) and body weight (mean ± 10 kg) to the 
mean age and body weight of pooled moderate and severe renal impairment subjects, as 
recommended by the draft FDA Guidance (Guidance for Industry: Pharmacokinetics in Patients with 
Impaired Renal Function Study Design, Data Analysis, and Impact on Dosing and Labeling; issued 
March 2010)1. 
7.2.2 
Rationale for the Dose Selection and Dose Regimen 
A single dose administration regimen has been chosen for this study. Pharmacokinetic data from 
multiple dose administration at doses between 7.5 and 50 mg twice daily (BID) of MK-7264 
demonstrate accumulation of 1.4 to 1.5-fold. This accumulation was well predicted by the single-dose 
data, with no observed time-dependent non-linearities. Thus the characterization of the single dose 
pharmacokinetics of MK-7264 in subjects with renal impairment should be sufficient to define 
appropriate adjustments in dosing with chronic administration of MK-7264 in this patient population. 
Single and multiple doses of MK-7264 up to 1800 mg BID have been generally well tolerated in 
healthy subjects, with the most common dose-related AEs associated with taste disturbance 
(dysgeusia, ageusia, hypogeusia). In the rising single dose study MK-7264-001, taste disturbance 
related AEs were observed at doses of 200 mg or greater, and not at doses of 100 mg or lower. In the 
multiple dose studies, the incidence of taste related AEs at 50 mg BID of MK-7264 ranged from 58% 
to 81% of subjects. A recently completed Phase 2b study in patients with chronic cough indicated that 
a 50 mg BID dose of MK-7264 was the dose where maximum efficacy in reducing the frequency of 
awake cough was reached. 
Therefore, the dose proposed in this study will be 50 mg, which will be the highest potential dose in 
the Phase 3 program, in order to provide information regarding the effect of RI on the 
pharmacokinetics of a therapeutic dose of MK-7264. 
Given the margin between the single dose of 50 mg and the 1800 mg dose that has been generally 
well tolerated, subjects with severe and moderate renal impairment may be administered a single oral 
50 mg dose of MK-7264 in parallel in this study. 
7.2.3 
Rationale for Endpoints 
The primary objective of this study is to evaluate the pharmacokinetic profile of MK-7264 in subjects 
with impaired renal function. This study will compare the overall pharmacokinetic profile of 
MK-7264 in subjects with impaired renal function to that of healthy subjects, and this will be assessed 
by overall exposure (AUC0-∞), Cmax, CL/F and CLr. 
 
 
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04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 22 
CONFIDENTIAL 
For ESRD subjects only, CLD,plasma, CLD,dialysate, AD, and AD,total will provide a measure of 
the extent of MK-7264 removal by HD. 
7.2.4 
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 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. 
7.2.5 
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. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 23 
CONFIDENTIAL 
 
8 
STUDY OBJECTIVES, ESTIMATION, AND ENDPOINTS 
8.1 
Objectives and Estimation 
8.1.1 
Primary 
Both Parts: 
Objective:  To evaluate the plasma pharmacokinetics of MK-7264 administered to subjects with 
varying degrees of RI compared to healthy matched control subjects. 
Estimation:  In subjects with moderate and severe RI, and subjects with ESRD, pharmacokinetic 
parameters (AUC0-∞, AUC0-last, Cmax, CL/F, and CLr, as appropriate) of MK-7264 following 
administration of a single 50 mg dose will be estimated and compared to those observed in healthy 
matched control subjects. 
Part 2 Only: 
Objective:  To investigate the extent of MK-7264 removal by hemodialysis.  
Estimation:  The extent to which MK-7264 is removed from plasma by hemodialysis will be 
estimated following administration of a single 50 mg dose of MK-7264 in subjects with ESRD 
requiring hemodialysis. 
8.1.2 
Secondary (Both Parts) 
Objective:  To evaluate the safety and tolerability of MK-7264 in subjects with moderate and severe 
RI (Part 1) and in subjects with ESRD on hemodialysis (Part 2). 
8.1.3 
Exploratory 
Objective 1 (both parts):  To estimate and compare the pharmacokinetic parameters (AUC0-12, 
AUC0-24, AUC0-48, Ae0-24, Ae0-48, Tmax, Vz/F, apparent terminal t½, and Fe, as applicable) 
between subjects with various degrees of RI and healthy matched control subjects. 
Objective 2 (both parts):  Analyze the potential relationship between appropriate MK-7264 
pharmacokinetic parameters and renal function. 
Objective 3 (Part 2 only):  To estimate pharmacokinetic parameters (AUCD, AUC[2.5-6]Ca, 
AUC[2.5-6]Cv, CLD,plasma, CLD,dialysate, AD, AD,total) for MK-7264 in subjects with ESRD 
following dosing, as appropriate.  
8.1.4 
Planned Exploratory Biomarker (Both Parts) 
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. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 24 
CONFIDENTIAL 
8.2 
Analysis Endpoints 
Pharmacokinetics: 
Part 1 
The primary pharmacokinetic endpoints will include AUC0-∞, AUC0-last, Cmax, and CL/F in 
plasma and CLr in urine, as appropriate, for MK-7264 in subjects with RI versus healthy matched 
subjects. 
The pharmacokinetic parameters AUC0-12, AUC0-24, AUC0-48, Tmax, apparent terminal t½, and 
Vz/F in plasma, and Ae0-24, Ae0-48, and Fe in urine, as appropriate, for MK-7264 will also be 
computed. 
Part 2 
The primary pharmacokinetic endpoints will include AUC0-∞, AUC0-last, Cmax, CL/F, AUCD, 
AUC(2.5-6)Ca, and AUC(2.5-6)Cv, as appropriate, for MK-7264 in subjects with ESRD in plasma 
following the HD dosing versus non-HD dosing. 
The following pharmacokinetic parameters will also be calculated for MK-7264 in plasma following 
the HD and non-HD dosing, as appropriate: AUC0-12, AUC0-24, AUC0-48, Tmax, apparent 
terminal t½, Vz/F, CLD,plasma, CLD,dialysate, AD, and AD,total. 
Safety: 
Safety endpoints will include adverse events, physical examinations, vital signs, 12-lead ECGs, and 
clinical laboratory tests. 
 
 
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04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 25 
CONFIDENTIAL 
 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is an open-label, 2-part, single dose study. In Part 1, the pharmacokinetics of MK-7264 will be 
evaluated in subjects with moderate and severe RI compared to healthy matched control subjects. In 
Part 2, the pharmacokinetics of MK-7264 will be evaluated in subjects with ESRD requiring HD 
under dialysis and non-dialysis conditions. Parts 1 and 2 of the study may be conducted concurrently. 
Twenty-four (24), adult, male and female subjects between 18 and 80 years of age (inclusive) will be 
enrolled; 6 subjects with ESRD requiring HD, 6 subjects with severe RI, 6 subjects with moderate RI, 
and 6 healthy matched control subjects. 
Once subjects with ESRD and subjects with severe and moderate RI are enrolled, the healthy matched 
control subjects will be enrolled. Each healthy control subject will be matched to the mean age 
(±10 years) and weight (±10 kg, where the weight is rounded to the nearest kg) of subjects with RI. 
Screening of subjects will occur within 28 days prior to the first dose. 
Assignment to a renal function group will be as follows: 
Group 
N 
eGFR (mL/min/1.73m2)* 
Part 1 
Severe Insufficiency 
6 
<30 **, not on dialysis 
Moderate Insufficiency 
6 
30 – 59 *** 
Healthy Matched Control 
6 
≥90**** 
Part 2 
ESRD requiring HD 
6 
requiring HD 
* eGFR based on MDRD equation at screening. Baseline eGFR will be obtained twice during the screening 
period, and the mean of the two values will be used for group assignment. The second baseline eGFR 
sample may be obtained at the time of check-in.  
** Reasonable efforts will be made to enroll at least 2 subjects with eGFR values of < 20 mL/min/1.73m2  
*** Reasonable efforts will be made to enroll at least 2 subjects with eGFR values of 
30 - 45 mL/min/1.73m2 
**** Healthy control subjects are within ±10 years of the mean age and within ± 10 kg (where the weight is 
rounded to the nearest kg) of the mean weight for the pooled severe RI, moderate RI, and ESRD groups. For 
healthy subjects a creatinine clearance computed over a 24 hour urine collection for subjects that do not 
qualify with ≥90 eGFR may be done for confirmation purposes. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 26 
CONFIDENTIAL 
Part 1 
On Day 1, a single oral dose of MK-7264 will be administered followed by pharmacokinetic 
sampling for 72 hours. Urine samples will be collected for 48 hours postdose, if possible. 
Part 2: 
Subjects with ESRD requiring HD will receive a single dose of MK-7264 on two occasions.  
On Day 1 of Period 1, subjects with ESRD requiring HD will receive a single oral dose of MK-7264 
immediately following their scheduled HD, followed by pharmacokinetic sampling for 72 hours. 
Subjects will initiate the next HD immediately following the 72-hour blood draw on Day 4. If the 
next scheduled HD must be initiated before 72 hours postdose, a sample for MK-7264 analysis will 
be collected prior to HD. Urine samples will be collected for 48 hours postdose, if possible. 
On Day 1 of Period 2, subjects with ESRD requiring HD will receive a single oral dose of MK-7264 
approximately 2 hours prior to their scheduled HD followed by pharmacokinetic sampling for 
72 hours. The HD session will initiate immediately following the 2-hour blood draw. During this 
dialysis session, pre- and post-dialyzer plasma samples will be collected every 30 minutes during HD 
and dialysate samples will be collected pre-dialysis, post-dialysis, and for 1 minute every 30 minutes 
during HD for MK-7264 analysis. Urine samples will be collected for 48 hours postdose, if possible. 
There will be a washout period of approximately 7 days (with 3 dialysis sessions) between MK-7264 
dosing in Periods 1 and 2. 
Both Parts: 
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 Visit, and Follow-up 
In each part and in each period, subjects will be housed from Day -2 or Day – 1 at the time indicated 
by the CRU, until after the 72-hour blood draw. At all times, a subject may be required to remain at 
the CRU for longer at the discretion of the Investigator. 
The clinic will contact all subjects (including those who terminate the study early) approximately 
14 days after the last study drug administration to determine if any adverse events have occurred 
since the last study visit. 
9.1.2 
Study Duration 
The duration of Part 1 of the study from screening to Day 4 is approximately 4.5 weeks. The duration 
of Part 1 of the study from screening to follow-up is approximately 6 weeks.  
The duration of Part 2 of the study from screening to Day 4 of Period 2 is approximately 5.5 weeks. 
The duration of Part 2 of the study from screening to follow-up is approximately 7 weeks. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 27 
CONFIDENTIAL 
9.2 
Selection of Study Population 
9.2.1 
Inclusion Criteria 
9.2.1.1 
Subjects with Moderate or Severe Renal Insufficiency or with ESRD  
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 subject, 18-80 years of age, inclusive, at screening. 
2. Subject is a non-smoker or moderate smoker (≤ 20 cigarettes/day or the equivalent). Subject must 
agree to consume no more than 10 cigarettes or equivalent/day from the time of screening and 
throughout the period of sample collection. 
3. Subject has a body mass index (BMI) ≥ 18.5 and ≤ 40.0 kg/m2, at screening. 
4. Females be non-pregnant, non-breast feeding and: 
a. If with reproductive potential: subject must demonstrate a serum β-human chorionic 
gonadotropin (β –hCG) level consistent with the nongravid state at screening and agree to use 
(and/or have their partner use) two (2) acceptable methods of birth control beginning at 
screening, throughout the study and until 2 weeks after the last dosing of study drug. 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide and contraceptive sponge) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
b. If postmenopausal:  subject is without menses for at least 1 year and have a documented 
follicle stimulating hormone (FSH) level in the postmenopausal range at screening, 
c. If surgically sterile:  subject is status post hysterectomy, oophorectomy, or tubal ligation.  
NOTE: These procedures must be confirmed with medical records. In the absence of 
documentation, hysterectomy may be confirmed by pelvic exam or if necessary by 
ultrasound; oophorectomy may be confirmed by hormone levels, particularly FSH in the 
postmenopausal range, but tubal ligation subjects without records should be excluded. 
Information must be captured appropriately within the site's source documents. 
5. A subject understands the study procedures in the informed consent forms (ICFs), is willing and 
able to comply with the protocol, and provides written informed consent for the trial. Future 
Biomedical Research participation is voluntary and is not required in order to participate in the 
trial. 
 
 
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04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 28 
CONFIDENTIAL 
9.2.1.2 
Subjects with Moderate or Severe Renal Insufficiency Only 
6. With the exception of RI, subject is judged to be in good health based on medical history, 
physical examination, vital signs, and laboratory safety tests. Subject has no clinically significant 
ECG abnormality, as deemed by the Investigator. Subjects who do not qualify based on a 
reversible condition or mild intercurrent illness may be re-screened after the underlying condition 
is resolved. 
7. Subject has baseline eGFR <30 mL/min/1.73m2 and is not on dialysis (severe RI) or  
30 – 59 mL/min/1.73m2 (moderate RI) based on eGFR equation from MDRD at screening as 
defined as follows (for females multiply result by 0.742, if African American multiply result by 
1.212):  
The MDRD equation is: 
eGFR = 175 x (Scr,std)-1 154 x (Age)-0 203 
Scr, std:  serum creatinine (mg/dL) measured with a standardized assay. 
Baseline eGFR will be obtained twice (at least 72 hours apart as part of subject screening) and the 
mean of the two values will be used. The second baseline eGFR sample may be obtained at the 
time of check-in. 
Reasonable efforts will be made to enroll at least 2 subjects with eGFR values of 
< 20 mL/min/1.73m2 (severe RI group) and at least 2 subjects with eGFR values of 
30 - 45 mL/min/1.73m2 (moderate RI group). 
9.2.1.3 
Subjects with ESRD Requiring Hemodialysis Only 
6. Baseline health is judged to be stable based on medical history, laboratory profiles, vital signs, or 
ECGs at screening, as deemed by the Investigator. 
7. Subject has ESRD maintained on stable regiment of thrice-weekly HD for at least 3 months prior 
to first dosing. 
9.2.1.4 
Healthy 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, 18-80 years of age, inclusive, at screening. Age must be 
within ± 10 years of the mean age of subjects with RI.  
2. Subject is a non-smoker or moderate smoker (≤ 20 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. 
3. Subject has a BMI ≥ 18.5 and ≤ 40.0 kg/m2, at screening. Subject must be within ± 10 kg of the 
mean weight (where the weight is rounded to the nearest kg) of the mean weight of subjects with 
RI. 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 29 
CONFIDENTIAL 
4. Subject is medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs, or ECGs, as deemed by the Investigator. 
5. Females must be non-pregnant, non-breastfeeding and: 
a. If with reproductive potential: subject must demonstrate a serum β –hCG level consistent 
with the nongravid state at screening and agree to use (and/or have their partner use) two (2) 
acceptable methods of birth control beginning at screening, throughout the study and until 
2 weeks after dosing of study drug. Combination method (requires use of two of the 
following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide and contraceptive sponge) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
b. If postmenopausal:  subject is without menses for at least 1 year and have a documented 
follicle stimulating hormone (FSH) level in the postmenopausal range at screening, 
c. If surgically sterile:  subject is status post hysterectomy, oophorectomy, or tubal ligation.  
NOTE: These procedures must be confirmed with medical records. In the absence of 
documentation, hysterectomy may be confirmed by pelvic exam or if necessary by 
ultrasound; oophorectomy may be confirmed by hormone levels, particularly FSH in the 
postmenopausal range, but tubal ligation subjects without records should be excluded. 
Information must be captured appropriately within the site's source documents. 
6. Subject has baseline eGFR ≥ 90 mL/min/1.73 m2 based on eGFR equation from MDRD at 
screening, defined as follows (for females multiply result by 0.742, if African American multiply 
result by 1.212)*: 
eGFR = 175 x (Scr,std)-1 154 x (Age)-0 203 
Scr, std:  serum creatinine (mg/dL) measured with a standardized assay. 
Baseline eGFR will be obtained twice (at least 72 hours apart as part of subject screening), and 
the mean of the two values will be used. The second baseline eGFR sample may be obtained at 
the time of check-in. A creatinine clearance computed over a 24-hour urine collection for subjects 
that do not qualify with ≥ 90 eGFR may be done for confirmation purposes. 
7. Subject understands the study procedures in the ICFs, is willing and able to comply with the 
protocol, and provides written informed consent for the trial. Future Biomedical Research 
participation is voluntary and is not required in order to participate in the trial. 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 30 
CONFIDENTIAL 
9.2.2 
Exclusion Criteria 
9.2.2.1 
Subjects with Moderate or Severe Renal Insufficiency or with ESRD 
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. Subject has a history or presence of clinically significant medical or psychiatric condition or 
disease in the opinion of the Investigator.  
3. Subject has a 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. Subject has a history or presence of alcoholism or drug abuse within the past 6 months prior to 
first dosing. 
5. Subject has a history or presence of hypersensitivity or idiosyncratic reaction to the study drug or 
related compounds (including sulfonamides). 
6. Subject has a history or presence of: 
• 
renal artery stenosis; 
• 
major risk factors for renal/urinary calculi, as judged by Investigator. 
7. Subject (with exception of subject with ESRD) has rapidly fluctuating renal function as 
determined by historical measurements. Rapidly fluctuating renal function is defined as > 20% 
difference between two measurements of eGFR taken at least 72 hour apart as part of subject 
screening may be enrolled after consultation with Sponsor if additional evidence can be provided 
to support stable renal function. 
8. Subject with ESRD has required frequent emergent HD (≥3) within a year prior to first dosing. 
9. A female subject who is pregnant, or who is lactating. 
10. Subject has positive results for the urine or saliva drug and/or urine or breath alcohol screen at 
screening or check-in, unless the positive drug screen is due to prescription drug use that is 
approved by the Investigator and Sponsor’s Clinical Monitor. 
11. Subject has positive results at screening for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), or hepatitis C virus (HCV). 
12. Subject has positive macroscopic hematuria or crystalluria at screening or check-in, as deemed 
clinically significant by Investigator. 
13. Subject is 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. 
 
 
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04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 31 
CONFIDENTIAL 
14. Subject has been on a diet incompatible with the on-study diet, in the opinion of the Investigator, 
within the 28 days prior to first dosing, and throughout the study. 
15. Subject has donated blood or had significant blood loss within 56 days prior to first dosing. 
16. Subject has donated plasma within 7 days prior to the first dosing. 
17. Subject is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is a member of the investigational site or sponsor staff member directly involved with 
this trial. 
18. Subject has taken MK-7264 at any time prior to first dosing on the current study. 
19. Subject participated in another clinical trial within 28 days prior to first dosing. The 4-week 
window will be derived from the date of dosing in the previous study to Day 1 of the current 
study. All visits and procedures from any previous study must be completed before screening for 
any given subject. 
9.2.2.2 
Healthy 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. Subject has a history or presence of clinically significant medical or psychiatric condition or 
disease in the opinion of the Investigator.  
3. Subject has a 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. Subject has a history or presence of alcoholism or drug abuse within the past 2 years prior to 
dosing. 
5. Subject has a history or presence of hypersensitivity or idiosyncratic reaction to the study drug or 
related compounds (including sulfonamides). 
6. Subject has a history or presence of: 
• 
renal artery stenosis; 
• 
major risk factors for renal/urinary calculi (current or history within the past 5 years of 
renal/urinary calculi or conditions, which predispose to renal/urinary calculi); 
7. A female subject who is pregnant, or who is lactating. 
8. Subject has positive results for the urine or saliva drug and/or urine or breath alcohol screen at 
screening or check-in. Unless the positive drug screen is due to prescription drug use that is 
approved by the Investigator and Sponsor’s Clinical Monitor. 
9. Subject has positive results at screening for HIV, HBsAg, or HCV. 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 32 
CONFIDENTIAL 
10. Subject has positive macroscopic hematuria or crystalluria at screening or check-in, as deemed 
clinically significant by Investigator. 
11. Subject is 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. 
12. Subject has been on a diet incompatible with the on-study diet, in the opinion of the Investigator, 
within the 28 days prior to dosing, and throughout the study. 
13. Subject has donated blood or had significant blood loss within 56 days prior to dosing. 
14. Subject has donated plasma within 7 days prior to the dosing. 
15. Subject is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is a member of the investigational site or sponsor staff member directly involved with 
this study. 
16. Subject has taken MK-7264 at any time prior to dosing on the current study. 
17. Subject participated in another clinical trial within 28 days prior to dosing. The 4 week window 
will be derived from the date of dosing in the previous study to Day 1 of the current study. All 
visits and procedures from any previous study must be completed before screening for any given 
subject. 
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. 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 33 
CONFIDENTIAL 
A subject may be discontinued from the study for any of the following reasons: 
• 
Adverse events. 
• 
Difficulties in blood collection. 
• 
Protocol violation (other than those listed above). 
• 
If a subject vomits within 3 hours after dosing, i.e., a period of time equal to two times the 
Tmax of MK-7264, he/she may be withdrawn from the study. The clinical report will include 
reasons for subject withdrawals as well as details relevant to the subject’s withdrawal. 
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 clinic will contact all subjects (including those who terminate the 
study early) approximately 14 days after the last study drug administration to determine if any 
adverse events have occurred since 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 10.1.7 
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 in Part 1 and each period in Part2 until the last 
pharmacokinetic sample collection; 
 
 
04PQ5D
PPD
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 34 
CONFIDENTIAL 
• 
Alcohol: 48 hours before dosing in Part 1 and each period in Part2 until the last 
pharmacokinetic sample collection; 
• 
Grapefruit/Seville orange: 14 days before dosing in Part 1 and first dose in Part2 until the last 
pharmacokinetic sample collection. 
Subjects who are taking medications for stable diseases for ~2 weeks for subjects with RI (including 
ESRD) and ~1 month for healthy subjects prior to first 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. 
Concurrent therapy with any medication during the course of the protocol 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. During the study, acetaminophen (up to 
2 g per 24 hours) may be administered at the discretion of the Investigator. 
Appropriate sources will be consulted by the Investigator or designee to confirm lack of 
pharmacokinetic/pharmacodynamic interaction with the study drug. If deviations occur, the 
Investigator will decide on a case-by-case basis whether the subject may continue participation in the 
study based on the time the study drug was administered and its pharmacology.  
All medications taken by subjects during the course of the study will be recorded. 
For Renal Impaired Subjects: 
All prescription or non-prescription medications (including St. John’s wort) that are strong inhibitors 
or strong inducers of P-gp transporters will be prohibited. These transporter inhibitors and inducers 
will not be allowed for at least 14 days and 28 days respectively prior to first dosing and throughout 
the study. Medications of particular concern include, but are not limited to azole antifungals 
(ketoconazole, itraconazole), macrolide antibiotics (erythromycin, clarithromycin), HIV protease 
inhibitors, nefazodone, rifampin, dexamethasone, troglitazone, barbiturates, and any drug or 
supplement (e.g., St. John’s wort) that inhibits or induces P-gp transporters. Weak P-gp inhibitors or 
inducers may be deemed acceptable following consultation with the Sponsor Clinical Monitor and the 
Investigator. 
Subjects who are taking certain prescription medications to treat manifestations of renal disease or 
medications needed to treat stable diseases (e.g., angiotensin converting enzyme inhibitors, 
angiotensin II receptor antagonists, beta-blockers, diuretics) will be allowed to participate in the study 
at the discretion of the Investigator and following consultation with the Sponsor Clinical Monitor. 
Subjects must be on a stable regimen for at least 2 weeks (or 5 half-lives of the study drug, whichever 
is longer) prior to first study drug administration and is able to withhold the use within 4 hours prior 
to administration of the study drug.  
Any medication (including over-the-counter) that would significantly alter eGFR, which, by the 
determination of the Investigator, might interfere with the study (e.g., cimetidine) must be 
discontinued at least 2 weeks (or 5 half-lives of the compound, whichever is longer) prior to first 
dosing of study drug.  
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 35 
CONFIDENTIAL 
Phosphate binders containing aluminum, calcium, or lanthanum salts; iron supplements or other metal 
cations;H2-receptor antagonists (H2RAs [except cimetidine]); or multivitamins containing iron or 
zinc must be withheld at least 8 hours prior to dosing and at least 4 hours post dosing.  
For Healthy Subjects: 
Any medication or substance (including prescription or over-the-counter, vitamin supplements, 
natural or herbal supplements) which cannot be discontinued at least 14 days prior to dosing and 
throughout the study are prohibited. All prescription or non-prescription medications (including St. 
John’s wort) that are strong inhibitors or strong inducers of P-gp transporters will be prohibited for at 
least 14 days and 28 days respectively prior to dosing and throughout the study. Certain medications 
may be deemed acceptable following consultation with the Sponsor Clinical Monitor and the 
Investigator. Appropriate sources will be consulted by the Investigator or designee to confirm lack of 
potential pharmacokinetic/pharmacodynamic interaction with study drug. 
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.  
On all days that subjects are confined in the CRU, standard meals will be provided at approximately 
4 and 9 hours postdose, and at appropriate times thereafter. Snacks will be offered at appropriate 
times. 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 
Subjects will remain ambulatory or seated upright for the first 4 hours following study drug 
administration, except when they are supine or semi-reclined for study procedures. 
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.  
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 36 
CONFIDENTIAL 
9.4 
Treatments 
9.4.1 
Treatments Administered 
Part 1: 
Subjects will receive a single oral dose of 50 mg MK-7264 (1 x 50 mg tablet) at Hour 0 on Day 1. 
Part 2: 
Period 1:  Subjects will receive a single oral dose of 50 mg MK-7264 (1 x 50 mg tablet) at Hour 0 on 
Day 1 immediately following their scheduled HD.  
Period 2: Subjects will receive a single oral dose of 50 mg MK-7264 (1 x 50 mg tablet) at Hour 0 on 
Day 1, approximately 2 hours prior to their scheduled HD. 
Both Parts: 
MK-7264 will be administered following an overnight fast, with approximately 240 mL of water. 
Subjects will be instructed not to crush, split, or chew the study drug. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each subject. 
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 receive the dose of MK-7264. 
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 the timed oral dose. 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  
The dose and administration of the trial study drug to any subject may not be modified. If necessary a 
subject must be discontinued for the reasons described in Section 9.2.3 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 37 
CONFIDENTIAL 
 
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-7264 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 10.1.6. 
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.  
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 38 
CONFIDENTIAL 
10.1.4 ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart (Section 6). 
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 Hemodialysis (ESRD Subjects Only) 
ESRD subjects only will receive HD as per their regular schedule. Dosing in Period 1 will occur 
immediately following completion of a normally scheduled HD and dosing in Period 2 will occur 
approximately 2 hours prior to the normally scheduled HD as per the Study Events Flow Chart 
(Section 6).  
In Period 2, the HD period will be approximately 4 hours for all subjects. Blood samples collected 
during HD will be collected from both the pre-dialyzer and post-dialyzer blood lines.  
The blood flow, dialysate flow, and the make and model of the dialyzer will be recorded. 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 39 
CONFIDENTIAL 
10.1.6 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 
• 
Urine or saliva drug screen 
 Opiates 
 Amphetamines 
 Barbiturates 
 Benzodiazepines 
 Cocaine 
 Cannabinoids 
• 
Urine or breath alcohol screen 
• 
Serum pregnancy test  
(for females only) 
• 
FSH (for postmenopausal females 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, eGFR will be calculated based on MDRD for renal classification 
assignment. Baseline eGFR will be obtained twice and the mean of the two values 
will be used for group assignment in Part 1 of the study. 
*** 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. 
¥ 
Any unexplained drug-related hematuria or evidence of triphosphate crystals should 
be referred to a nephrologist 
 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 40 
CONFIDENTIAL 
10.1.7 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  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 
allocation 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 treatment, or a 
procedure. From the time of allocation 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 10.1.7.3.1. The Investigator will make every attempt to follow 
all subjects with non-serious adverse events for outcome. Any unexplained drug-related hematuria or 
evidence of triphosphate crystals should be referred to a nephrologist. 
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent). 
10.1.7.1 
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 is reported as a 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 41 
CONFIDENTIAL 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with or without an adverse event must be reported by the Investigator within 
24 hours to the Sponsor either by electronic media or paper. Electronic reporting procedures can be 
found in the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent). 
10.1.7.2 
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 allocation 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, treatment or a procedure. Pregnancies and lactations that occur from the time of 
allocation through 14 days following cessation of Sponsor’s product must be reported by the 
Investigator. All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious 
events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media or paper. 
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent). 
10.1.7.3 
Immediate Reporting of Adverse Events 
10.1.7.3.1 
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 as serious adverse 
events to meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes. 
 
 
04PQ5D
 
 
04WT3N


MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 42 
CONFIDENTIAL 
• 
Cancer 
• 
Overdose 
Refer to Table 1 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment allocation, 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, treatment or a procedure. 
For the time period beginning at treatment allocation through 14 days following cessation of 
treatment, any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause, whether or not related to the Sponsor's product, must be reported within 24 hours to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in the EDC 
data entry guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder 
(or equivalent). 
Additionally, any serious adverse event, considered by an Investigator who is a qualified physician to 
be related to the Sponsor's product that is brought to the attention of the Investigator at any time 
outside of the time period specified in the previous paragraph also must be reported immediately to 
the Sponsor. 
All subjects with serious adverse events must be followed up for outcome. 
10.1.7.3.2 
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 treatment allocation, 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,  treatment or a 
procedure. 
For the time period beginning at treatment allocation 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. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be found in 
the Investigator Trial File Binder (or equivalent). 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 43 
CONFIDENTIAL 
Events of clinical interest for this trial include: 
• 
an overdose of Sponsor's product, as defined in Section 10.1.7.1 that is not associated with 
clinical symptoms or abnormal laboratory results.  
• 
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. 
10.1.7.4 
Evaluating Adverse Events 
An Investigator who is a qualified physician will evaluate all adverse events with respect to the 
elements outlined in Table 1. The Investigator’s assessment of causality is required for each adverse 
event. Refer to Table 1 or instructions in evaluating adverse events. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 44 
CONFIDENTIAL 
Table 1: 
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: 
†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 ECI 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 †). 
None 
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 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 45 
CONFIDENTIAL 
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. 
 
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. 
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. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 46 
CONFIDENTIAL 
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.) 
10.1.7.5 
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 i.e., per ICH 
Topic E6 (R1) Guidelines for Good Clinical Practice. 
10.2 Pharmacokinetic Assessment 
10.2.1 Blood Sampling and Processing 
For all subjects, blood samples for the determination of MK-7264 will be collected at scheduled time 
points as delineated in the Study Events Flow Chart (Section 6). 
Instructions for blood sampling, collection, processing, and sample shipment for MK-7264 will be 
provided separately. 
Blood collections outside the following windows will be considered deviations: 
Hour 
Deviation window 
 0.0 to 0.5 hour 
± 2 minutes 
> 0.5 to 2.0 hour 
± 2 minutes 
> 2.0 to 8.0 hour 
± 2 minutes 
> 8.0 to 24 hour 
± 5 minutes 
> 24.0 hour 
± 10 minutes 
10.2.2 Urine Collection (Part 1 only) 
Prior to the predose sample, each subject will be instructed as to urine collection methods.  
Urine samples for determination of MK-7264 concentrations will be collected at selected intervals as 
delineated in the Study Events Flow Chart (Section 6). For subjects with moderate and severe RI, and 
subjects with ESRD, urine samples will be collected whenever possible, as they may not be able to 
produce urine at each interval. For subjects who are anuric, urine samples for urinalysis will not be 
collected. 
On Day 1, a spot collection will be obtained prior to dosing for the pre-dose sample. Subjects will be 
asked again to empty their bladder within approximately 15 minutes prior to dosing, and no urine will 
be collected at this time unless it is needed for the pre-dose sample. Only one predose urine sample 
will be collected on Day 1. 
After administration of MK-7264, during the entire postdose in-house observation period, all urine 
will be collected completely. Urine portions will be pooled per subject within any planned collection 
interval. Just prior to the end of each sampling interval, subjects will be encouraged to void their 
bladder again to complete the collection. If they do void at any time during the collection interval, the 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 47 
CONFIDENTIAL 
time should be documented. Should this be the case, subjects need to attempt to void again at the end 
of the collection period, as scheduled. However, should subjects be unable to void, this will be 
documented as well. 
Urine will be refrigerated during the collection intervals. The weight of an empty urine collection 
container and total weight of urine collected during each timed interval will be recorded. 
10.2.3 Dialysate Collection 
For ESRD subjects only, dialysate samples will be collected at scheduled time points as delineated in 
the Study Events Flow Chart (Section 6).  
Instructions for dialysate sampling, collection, processing, and sample shipment for MK-7264 will be 
provided separately. 
10.3 Planned Genetic Analysis Sample Collection 
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples will be 
provided in the 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 
10.5 Blood Volume Drawn for Study Assessments 
Table 2: 
Blood Volume Drawn During the Study in Part 1 
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, serology), FSH 
(for postmenopausal female subjects only) and 
serum pregnancy (for female subjects only). 
1 
12.5 
12.5 
Blood for Planned Genetic Analysis 
1 
8.5 
8.5 
On-study hematology and serum chemistry 
(this includes serum pregnancy for female 
subjects only when scheduled at the same 
time) 
3 
12.5 
37.5 
Blood for MK-7264 
15 
3 
45 
Total Blood Volume (mL)→ 
103.5§ 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
§ If additional safety, or pharmacokinetic, analysis is necessary or if larger collection tubes are required to 
obtain sufficient plasma/serum for analysis, additional blood may be obtained (up to a maximum of 50 mL). 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 48 
CONFIDENTIAL 
Table 3 
Blood Volume Drawn During the Study in Part 2 
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, serology), FSH 
(for postmenopausal female subjects only) and 
serum pregnancy (for female subjects only). 
1 
12.5 
12.5 
Blood for Planned Genetic Analysis 
1 
8.5 
8.5 
On-study hematology and serum chemistry 
(this includes serum pregnancy for female 
subjects only when scheduled at the same 
time) 
6 
12.5 
75 
Blood for MK-7264 
58 
3 
174 
Total Blood Volume (mL)→ 
270§ 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
§ If additional safety, or pharmacokinetic, analysis is necessary or if larger collection tubes are required to 
obtain sufficient plasma/serum for analysis, additional blood may be obtained (up to a maximum of 50 mL). 
 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 49 
CONFIDENTIAL 
 
11 DATA ANALYSIS 
11.1 Pharmacokinetic Parameters 
11.1.1 Plasma 
For all subjects, pharmacokinetic parameters for plasma MK-7264 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 dosing. 
AUC0-12: 
Area under the concentration versus time curve, from 0 to 12 hours after 
dosing. 
AUC0-24: 
Area under the concentration versus time curve, from 0 to 24 hours after 
dosing. 
AUC0-48: 
Area under the concentration versus time curve, from 0 to 48 hours after 
dosing. 
CL/F: 
Apparent clearance after extravascular administration. 
Cmax: 
Maximum observed plasma concentration after the administration of a given 
dose. 
Tmax: 
Time to maximum observed plasma drug concentration. 
t½: 
(Apparent) terminal half-life. 
Vz/F: 
Apparent volume of distribution during the terminal phase 
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. 
No pharmacokinetic parameters will be calculated for subjects with 2 or fewer consecutive time 
points with detectable concentrations. 
Individual and mean plasma concentration time curves (both linear and log-linear) will be included in 
the final report. 
11.1.2 Urine (Part 1 and Part 2) 
For subjects with moderate or severe renal impairment, subjects with ESRD, and for matched healthy 
subjects, pharmacokinetic parameters for urine MK-7264 will be calculated as follows: 
Ae0-24: 
Total amount of drug excreted unchanged in the urine over the period of 24 hours, 
obtained by adding the amounts excreted over each collection interval. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 50 
CONFIDENTIAL 
Ae0-48: 
Total amount of drug excreted unchanged in the urine over the period of 48 hours, 
obtained by adding the amounts excreted over each collection interval. 
CLr: 
Renal clearance calculated as Ae(t’-t”)/AUC(t’-t”) where t’-t” is the longest interval 
of time during which Ae and AUC are both obtained.  
Fe: 
Fraction of MK-7264 excretion during each collection interval. Obtained by dividing 
the amount of MK-7264 excreted in each collection interval by the dose. 
11.1.3 Hemodialysis: Dialysate and Plasma 
For subjects with ESRD only, pharmacokinetic parameters for plasma MK-7264 will be calculated as 
follows based on concentration in plasma samples from the pre-dialyzer line during the dialysis 
period (Ca) and on concentration in plasma samples from the post-dialyzer line during the dialysis 
period (Cv): 
AUCD: 
Plasma AUC values determined from Ca versus time profile during the 
dialysis period (2-6 hours) using ‘linear up, log down’ calculation 
method option in WinNonlin. 
AUC(2.5-6)Ca: 
Plasma AUC values determined from Ca versus time profile during the 
dialysis period from 2.5 hour to 6 hours using ‘linear up, log down’ 
calculation method option in WinNonlin. 
AUC(2.5-6)Cv: 
Plasma AUC values determined from Cv versus time profile during the 
dialysis period from 2.5 hour to 6 hours using ‘linear up, log down’ 
calculation method option in WinNonlin. 
CLD,plasma: 
Dialysis clearance based on plasma, calculated as Q x R x 
[AUC(2.5-6)Ca – AUC(2.5-6)Cv)/ AUC(2.5-6)Ca, where Q is the flow 
rate of blood through the dialyzer, and R is the ratio of blood drug 
concentration to plasma drug concentration 
For subjects with ESRD only, pharmacokinetic parameters for dialysate MK-7264 will be calculated 
as follows: 
CD: 
Concentration in dialysate samples. 
AD: 
Amount of drug recovered from each dialysate collection, calculated as:  
CD x dialysate volume 
rr: 
Rate of drug removal, calculated as:  (CD x dialysate flow rate) 
AD, total: 
Cumulative amount of drug recovered from the dialysate will be  
obtained by integrating the rr versus time profile over the dialysis session 
duration, using actual times relative to the start time of dialysis. 
CLD,dialysate: 
HD clearance based on dialysate, calculated as: AD,total/AUCD. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 51 
CONFIDENTIAL 
11.2 Statistical Methods 
The statistical analysis of the data obtained from this study will be the responsibility of the Data 
Management and Biometrics 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. 
11.2.1 Determination of Sample Size 
The sample size selected for each population to evaluate the effect of renal impairment on the PK of 
MK-7264 was not chosen to satisfy any a priori statistical requirement. This sample size (N= 6 per 
group) has historically been shown to be sufficient for studies of this type and should provide 
adequate data to support the planned analyses. Nevertheless, estimates of the expected precision of 
the estimates, based on these sample sizes are presented below. 
The precision of the estimated ratios of geometric means (severe renal impairment / normal renal 
function) of pharmacokinetic parameters obtained from this study can be assessed by calculating the 
half-width of the 90% confidence intervals expected for the given sample size and assumed 
variability. The between-subject geometric coefficient of variation (GCV) for MK-7264 AUC0-12, 
after administration of 50 mg MK-7264 observed in healthy subjects in a previous study (PN 022) is 
15%. Since the between subject variability in severe renal subjects has historically been seen to be 
2-3 folds higher in many studies, the geometric CV obtained from healthy were inflated by a factor of 
2 for severe renal subjects and was used for the following calculations. Assuming a sample size of 
6 subjects per population and observed pooled between-subject standard deviation of 0.21 for 
AUC0-12 on the natural log scale, then the half width of the 90% confidence intervals of GMRs for 
MK-7264 AUC0-12 on the log scale will be 0.22 The lower and upper 90% confidence limits for the 
true GMRs will be given by OBS/1.25 and OBS*1.25 for AUC0-12, respectively, where OBS is the 
observed GMR. Thus, for example, if the observed GMR for AUC0-12 was 1.50, then the 90% 
confidence intervals for the GMR would be 1.20 to 1.87. 
Table 4: 
Estimated Precision Calculations 
Parameter 
N 
(per group) 
Half width 
(log scale) 
Observed GMR 
90% confidence interval 
for Observed GMR 
AUC0-12 
6 
0.22 
1.50 
(1.20, 1.87) 
Cmax 
6 
0.24 
1.50 
(1.18, 1.91) 
Note: GCV for AUC0-12 and Cmax on Day 1 from PN 22 for 50 mg bid dose were 15% and 16%, 
respectively 
 
11.2.2 Subjects to Analyze 
The decision as to which plasma samples collected will be assayed for evaluation of 
pharmacokinetics/pharmacodynamics will be collaboratively determined by the Departments of 
Quantitative Pharmacology and Pharmacometrics and the appropriate department within Early-Stage 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 52 
CONFIDENTIAL 
Development. If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers. 
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 violations. 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 Analysis Overview 
11.2.3.1 
Primary Analysis:  Regression Analysis   
For this analysis, all the data from Part 1 will be included. 
In addition to running the primary regression analysis below using BSA normalized eGFR as the 
measure of renal function for each subject, the analysis will also be run using BSA un-normalized 
eGFR and CLcr from C-G equation.  
Separately for each pharmacokinetic parameter, individual values of AUC0-∞, AUC0-last, Cmax, 
CL/F, and CLr will be evaluated with a linear mixed effects model containing eGFR as a continuous 
variable. The subject’s mean renal function value derived from 2 serum creatinine measurements at 
Screening will be used for the analysis. Estimates of the slope and intercept, together with 
corresponding 95% confidence intervals will be obtained. The estimated mean and corresponding 
95% confidence interval for each RI group will be predicted at the midpoint of the defined eGFR 
range for each group (45, and 22.5 for moderate, and severe, respectively). However, for the normal 
renal function group, the estimated mean and corresponding 95% confidence interval will be 
predicted at the median of the observed eGFR values. Sample SAS code is given below: 
Proc mixed data=pk ; 
model PK= eGFR / s cl DDFM=KR alpha=0.05 outpm=normres  ; 
estimate "predicted PK in severe" int 1 eGFR 22.5/alpha=0.1 cl e; 
estimate "predicted PK in moderate" int 1 eGFR 45/alpha=0.1 cl e; 
estimate "predicted PK in mild" int 1 eGFR 75/alpha=0.1 cl e; 
estimate "predicted PK in normal" int 1 eGFR xx /alpha=0.1 cl e; 
 
 
xx is median eGFR for healthy matched control subject group; 
run; 
The data will be examined for departures from the assumptions of the model. The residuals from the 
model will be examined for normality using diagnostic plots such as residuals vs predicted values and 
normal probability plots of residuals. Lack of fit will also be visually assessed. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 53 
CONFIDENTIAL 
If the model used does not fit the data adequately, other models, such as natural log transformed 
pharmacokinetic versus renal function or natural log transformed pharmacokinetic versus natural log 
transformed renal function, will be explored. Other transformations or non-linear models will also be 
considered.  
Additionally, plots of MK-7264 pharmacokinetic parameter values AUC0-∞, AUC0-last, Cmax, 
CL/F, and CLr versus eGFR along with a regression line and 95% confidence bands for regression 
line will be constructed. Different symbols will be used to identify different renal function groups. 
Additionally, separate plots of AUC0-∞ and Cmax values vs age and body weight will be provided 
Individual values will be listed for each PK parameter (AUC0-∞, AUC0-last, AUC0-12, AUC0-24, 
AUC0-48, Cmax, Tmax, CL/F, Vz/F, apparent terminal t½, Ae0-24, Ae0-48, and Fe) 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 CV (calculated as 100 
x standard deviation/arithmetic mean), median, minimum, maximum, geometric mean, and geometric 
percent CV (calculated as 100 x sqrt( exp(s2) - 1), where s2 is the observed variance on the natural 
log-scale). 
11.2.3.2 
Secondary Analysis: Categorical Analysis  
Separately for each pharmacokinetic parameter, individual values of AUC0-∞, AUC0-last, Cmax, 
CL/F, and CLr (as appropriate) will be natural log-transformed and evaluated with a linear 
fixed-effects model containing a categorical effect for population (ESRD renal impairment Period 1 
of Part 2, severe RI, moderate RI, and healthy matched control, based on BSA normalized eGFR). 
The REPEATED statement with the GROUP=Population option will be used in SAS PROC MIXED 
to estimate separate variances for each population. The Kenward and Roger adjustment will be used 
to calculate the denominator degrees of freedom for the fixed-effect (DDFM=KR). Ninety-five 
percent (95%) confidence intervals for the least squares means for each population will be 
constructed on the natural log scale and will reference the t-distribution. Exponentiating the least-
squares means and their corresponding 95% confidence intervals will yield estimates for the 
population geometric means and confidence intervals about the geometric means on the original 
scale.  Sample SAS code is given below: 
Proc mixed =data; 
CLASS Population Subject; 
MODEL lnpk = Population / DDFM=KR; 
REPEATED / GROUP=Population; 
LSMEANS Population / CL; 
run; 
To compare subjects with RI in each of the renal categories to subjects with normal renal function, a 
two sided 90% confidence interval for the true difference in means (renal impairment – normal renal 
function) will be calculated for each PK parameters (AUC0-∞, AUC0-last, Cmax, CLr, and CL/F) 
using the mean square error from the model and referencing a t-distribution. For each of the RI 
populations, these confidence limits will be exponentiated to obtain the 90% confidence interval for 
the true ratio of geometric means (renal impairment/normal renal function) for each pharmacokinetic 
parameter. 
 
 
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Renal Insufficiency Study Protocol 
 
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Figures showing individual pharmacokinetic values with GMs (95% confidence intervals) by 
population, plotted on the natural log scale, will be provided for AUC0-∞, AUC0-last, Cmax, CL/F, 
and CLr. 
Summary Statistics using BSA un-normalized eGFR:  The subjects will be re-categorized into 
different renal categories based on their BSA un-normalized eGFR and non-model based summary 
statistics by population will be provided for (AUC0-∞, AUC0-last, AUC0-12, AUC0-24, AUC0-48, 
Cmax, Tmax, CL/F, Vz/F, apparent terminal t½, Ae0-24, Ae0-48, and Fe, as applicable). 
Analysis using CLcr (C-G equation):  The subjects will be re-categorized into different renal 
categories based on their CLcr obtained from C-G equation and non-model based summary statistics 
by population will be provided for (AUC0-∞, AUC0-last, AUC0-12, AUC0-24, AUC0-48, Cmax, 
Tmax, CL/F, Vz/F, apparent terminal t½, Ae0-24, Ae0-48, and Fe, as applicable).  
11.2.3.3 
ESRD Requiring Hemodialysis (Part 2) 
To evaluate the extent to which MK-7264 is removed from plasma by hemodialysis, a linear mixed 
effect model with population (ESRD RI Period 1, ESRD Period 2) as a fixed effect will be used. An 
unstructured covariance matrix will be used to allow for unequal treatment variances and to model the 
correlation between the two treatment measurements within each subject via the REPEATED 
statement in SAS PROC MIXED. Kenward and Roger's method will be used to calculate the 
denominator degrees of freedom for the fixed effects (DDFM=KR). 
A natural log transformation will be applied to CL/F, AUC0-∞, AUC0-last, and Cmax. For each PK 
parameter, 95% confidence intervals for the least squares mean will be constructed on the natural log 
scale and will reference the t-distribution. Exponentiating the least-squares means and their 
corresponding 95% confidence intervals will yield estimates for the population geometric means and 
confidence intervals about the geometric means on the original scale.  
A two sided 90% confidence interval for the true difference in means (ESRD RI in Period 2 -ESRD 
RI in Period 1) will be calculated for each PK parameter (AUC0-∞, AUC0-last, Cmax, and CL/F) 
using the mean square error from the model and referencing a t-distribution. These confidence limits 
will be exponentiated to obtain the 90% confidence interval for the true ratio (GMR) of geometric 
means (ESRD RI in Period 2 of Part 2 / ESRD RI in Period 1 of Part 2) for each pharmacokinetic 
parameter. 
Sample SAS code is given below: 
proc mixed data=dataset; 
class population subject; 
model endpoint = population/ddfm=kr; 
repeated /type=UN subject=subject group=population; 
run; 
Plots with individual ratios overlaid with GMR and corresponding 90% CI will be provided for CL/F, 
AUC0-∞, AUClast, and Cmax 
 
 
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Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
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Individual listings and descriptive statistics for AUCD, AUC(2.5-6)Ca, AUC(2.5-6)Cv, CLD,plasma, 
CLD,dialysate, AD, and AD,total following a single-dose administration of MK-7264 will be provided 
for subjects with ESRD. 
Individual listings and descriptive summary statistics may be provided for CLr for ESRD subjects, if 
CLr could be determined in these subjects. 
11.3 Safety Evaluation 
The safety and tolerability of MK-7264 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. 
 
 
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Celerion Project No.:  CA21631 
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12 STUDY ADMINISTRATION 
12.1 Ethics 
12.1.1 Institutional Review Board 
This protocol will be reviewed by the 
 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 compliant with the International Conference on Harmonization (ICH), 
and may be reached at: 
 
 
 
 
 
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. 
 
 
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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 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. 
 
 
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Celerion Project No.:  CA21631 
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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 MK-7264 and 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-7264 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. 
The Investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
Clinical supplies will be affixed with a clinical label and in accordance with regulatory requirements.  
12.6.1 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
12.6.2 Discard/Destruction/Returns and Reconciliation 
The Investigator is responsible for keeping accurate records of the clinical supplies received from the 
Sponsor or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial. For all trial sites, the local country Sponsor personnel or designee will 
provide appropriate documentation that must be completed for drug accountability and return, or local 
discard and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is documented. 
12.7 Data Handling and Record Keeping 
Celerion’s Merck library CRFs will be supplied. 
 
 
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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 Harmonisation 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. 
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 
 
 
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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. 
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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Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
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13 REFERENCES 
1. Food and Drug Administration:  Center for Drug Evaluation and Research (CDER). Guidance 
for Industry - Pharmacokinetics in Patients with Impaired Renal Function — Study Design, 
Data Analysis, and Impact on Dosing and Labeling (March 2010). 
 
 
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Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
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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. 
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, 
 
 
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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. 
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. 
 
 
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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  
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 
 
 
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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 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. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 67 
CONFIDENTIAL 
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 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. 
 
 
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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 68 
CONFIDENTIAL 
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: 
 
DEFINITIONS 
FOR 
GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
- 
E15; 
Available 
from: 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-for-
genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-sample-
cod.html 
3. 
Industry Pharmacogenomics Working Group. 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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MK-7264 
 
Merck Protocol No.:  MK-7264-026-03 
Renal Insufficiency Study Protocol 
 
Celerion Project No.:  CA21631 
Merck 
US IND No.:  123007 
 
CA21631_(MK-7264-026-03)_Amendment3_Protocol_09Jun2017 
Page 72 
CONFIDENTIAL 
specimens were frozen (approximately -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:  
 
 
 
 
 
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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT03108924  
Document Date: 
09-Jun-2017
An Open-Label, Single-Dose Study to Investigate the Influence of 
Renal Insufficiency on the Pharmacokinetics of MK-7264


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9.7 Changes in the Conduct of the Trial 
The original protocol dated 22-Mar-2017 [16.1.1.1] was amended on 04-May-2017 
[16.1.1.2], 16-May-2017 [16.1.1.3], and 09-Jun-2017 [16.1.1.4]. Amendment 1 was 
generated to add Part 2 to the study to assess the PK of MK-7264 in subjects with ESRD 
requiring HD. Amendment 2 was generated to: 1) correct an error in the calculation of the 
total blood volume in Part 2 and to clarify that blood (pre-dialyzer and post-dialyzer) and 
dialysate samples were to be collected immediately after HD was stopped and 2) that HD 
would be approximately 4 hours in duration. Amendment 3 was generated to: 1) correct the 
blood volume drawn during the study in Part 2 to account for 3 samples per time point during 
HD; 2) to clarify that the last post-dialyzer blood sample and dialysate sample were to be 
collected immediately before HD was stopped; 3) to clarify that dialysate samples were to be 
collected pre-dialysis, post-dialysis, and for 1 minute every 30 minutes during HD for 
MK-7264 analysis; and 4) to modify the nomenclature of PK parameters calculated on 
plasma MK-7264 concentrations from the pre- and post-dialyzer lines. A protocol 
clarification letter (PCL) was issued on 06-Jun-2017 that described the changes outlined in 
Amendment 3. A second PCL was issued on 27-Jul-2017 to clarify the number of dialysis 
sessions (2) during the 7-day washout period between MK-7264 dosing in Periods 1 and 2 of 
Part 2. All 3 amendments were finalized after the initial screening date (14-Apr-2017) but 
prior to dosing of the ESRD subjects in Part 2 (28 and 29-Jul-2017). The 3 amendments 
outlined changes that were only relevant for Part 2 of the study; these amendments had no 
impact on Part 1 of the study that had already begun prior to their finalization. The PCLs 
were finalized prior to the washout period between Periods 1 and 2 of Part 2. There were no 
other changes in the conduct of the study. 
9.8 Statistical Analysis Plan 
 Statistical and Analytical Plans to Address Study Objectives 
9.8.1
Refer to Section 9.8.3. 
 Determination of Sample Size and Power to Address Study Hypotheses 
9.8.2
Refer to the protocol [16.1.1.4]. 
 Statistical/Analytical Methods and Issues 
9.8.3
Pharmacokinetics 
The plasma PK of MK-7264 administered to subjects with varying degrees of RI was 
compared to healthy matched control subjects using regression and categorical analysis. 
 
Regression Analysis (Part 1) 
Separately, individual values of AUC0-last, AUC0-∞, Cmax, CL/F, and CLr were 
ln-transformed and evaluated with a linear fixed-effects model containing eGFR as a 
continuous variable. The subject’s mean renal function value derived from 2 serum creatinine 
 
 
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measurements at screening were used for the analysis. Estimates of the slope and intercept, 
together with corresponding 95% confidence intervals (CI) were obtained. The estimated 
mean and corresponding 95% CI for each RI group were predicted at the mid-point of the 
defined eGFR range for each group (45 mL/min/1.73 m2 for moderate and 
22.5 mL/min/1.73 m2 for severe). Although subjects with mild RI were not enrolled in this 
study, the PK of MK-7264 were also predicted in this population at the eGFR of 
75 mL/min/1.73 m2 (the midpoint of the eGFR range for mild RI of 
60 - 89 mL/min/1.73 m2). For the healthy population, the estimated mean and corresponding 
95% CI were predicted at the median of the observed eGFR values. The predicted means and 
corresponding 95% CIs were exponentiated to obtain estimates on the original scale. In 
addition to running the regression analysis using BSA normalized eGFR as the measure of 
renal function for each subject, the analysis was also run using BSA non-normalized eGFR 
and CrCL from the Cockcroft-Gault (C-G) equation.  
Categorical Analysis (Part 1 and Part 2 Period 1) 
Separately, individual values of AUC0-last, AUC0-∞, Cmax, CL/F, and CLr were 
ln-transformed and evaluated with a linear fixed-effects model containing a categorical effect 
for population (ESRD Non-HD, severe RI, moderate RI, and healthy matched control, based 
on BSA normalized eGFR). The REPEATED statement with the GROUP=Population option 
was used in SAS PROC MIXED to estimate separate variances for each population. The 
Kenward-Roger adjustment was used to calculate the denominator degrees of freedom for the 
fixed-effect (DDFM=KR). Ninety-five percent (95%) CI for the least-squares means for each 
population were constructed on the ln-scale and referenced to the t-distribution. The 
least-squares means (LSM) and their corresponding 95% CI were exponentiated to yield 
estimates for the population geometric means (GM) and CI about the GM on the original 
scale. To compare subjects with RI in each of the renal categories to subjects with normal 
renal function, a two-sided 90% CI for the true difference in means (renal impairment – 
normal renal function) was calculated for each PK parameter (AUC0-last, AUC0-∞, Cmax, 
CLr, and CL/F) using the mean square error from the model and referencing a t-distribution. 
For each of the RI populations, these confidence limits were exponentiated to obtain the 
90% CI for the true GMR renal impairment/normal renal function) for each PK parameter. 
Figures showing individual PK values with GMs (95% CI) by population, were provided for 
AUC0-last, AUC0-∞, Cmax, CL/F, and CLr. 
ESRD HD vs ESRD Non-HD (Part 2) 
To evaluate the extent of MK-7264 removal by HD in Part 2, a linear mixed-effects model 
with population (ESRD Non-HD, ESRD HD) as a fixed effect was used. An unstructured 
covariance matrix was used to allow for unequal variances and to model the correlation 
between the two measurements within each subject via the REPEATED statement in SAS 
PROC MIXED. The Kenward-Roger adjustment was used to calculate the denominator 
degrees of freedom for the fixed-effects (DDFM=KR).A ln-transformation was applied to 
AUC0-last, AUC0-∞, Cmax, and CL/F. For each PK parameter, 95% CIs for the LSMs was 
constructed on the ln-scale and referenced the t-distribution. The LSMs and corresponding 
95% CIs were then exponentiated to obtain population GM and CI about the GM on the 
 
 
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original scale. A two sided 90% CI for the true difference in means (ESRD HD - ESRD 
Non-HD) was calculated for each PK parameter (AUC0-last, AUC0-∞, Cmax, and CL/F) 
using the mean square error from the model and referencing a t-distribution. These 
confidence limits were exponentiated to obtain the 90% CI for the GMR (ESRD HD / ESRD 
Non-HD) for each PK parameter. 
Other Pharmacokinetic Analyses 
Subjects with moderate and severe RI and healthy matched control subjects (based on their 
BSA normalized eGFR) were re-categorized into different renal categories based on their 
BSA non-normalized eGFR and CrCL. Non-model based summary statistics by population 
were provided for AUC0-last, AUC0-∞, Cmax, CL/F and CLr. 
Non-model-based %CV of the GM were presented for plasma MK-7264 AUC0-12, 
AUC0-24, AUC0-48, apparent terminal t½, and Vz/F for subjects with moderate and severe 
RI, ESRD Non-HD, ESRD HD, and healthy matched control subjects. Individual values were 
also listed for each PK parameter by population and non-model-based descriptive statistics 
were provided. 
Arithmetic mean (AM) concentration-time plots (with and without standard deviation [SD] 
error bars) of plasma, pre- and post-dialyzer plasma, and dialysate MK-7264 were presented 
by population on a linear-linear scale plot with an inset semi-log scale plot. The BLQ values 
were treated as 0 for the calculation of the AM (and SD, as appropriate). At the beginning of 
the profile, if < 50% of subjects had a quantifiable concentration ≥ LLOQ for a given time 
point, the AM concentration was presented as 0. At the end of the profile when 
concentrations from some subjects began to fall BLQ, the AM value was only plotted if 
≥ 50% of subjects had quantifiable concentrations ≥ LLOQ and the AM value was ≥ LLOQ. 
However, all AM values were presented in the concentration tables. A reference line for the 
LLOQ value was added to the plot, where possible, as well as a footnote indicating the AM 
concentrations at or after certain time points that were not presented since > 50% of subjects 
had values < LLOQ or the AM was < LLOQ. 
AM (with and without SD error bars) cumulative Ae-time plots of urine MK-7264 were 
presented by population on a linear-linear scale plot. BLQ urine MK-7264 concentration 
values were treated as 0 for the calculation of the Ae and respective AM (and SD, as 
appropriate). AM (with and without SD error bars) rr - time (with time corresponding to the 
midpoint of the 1-minute dialysate collection) plots of urine MK-7264 were presented on a 
linear-linear scale plot. BLQ MK-7264 concentration values were treated as 0 for the 
calculation of the rr and respective AM (and SD, as appropriate). 
Safety 
Safety and tolerability of MK-7264 was evaluated by clinical assessments, including AEs, 
vital signs, physical examination, 12-lead ECGs, and standard laboratory safety tests 
(hematology, chemistry, and urinalysis) which were obtained at pre-specified time points 
throughout the study. AEs were coded according to Version 20.0 of the Medical Dictionary 
 
 
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for Regulatory Activities (MedDRA®) as modified by Merck. Incidence of the number of 
subjects with AEs was tabulated by population. AEs related to study drug were also tabulated 
by population. AEs were listed by subject. Since no meaningful changes in individual 
laboratory safety values, ECGs, and vital signs were observed, summary statistics were not 
provided. 
9.8.3.1 Handling of Dropouts or Missing Data 
There were no subject discontinuations in this study.  
Peripheral blood samples could not be collected at 6 time points (0.25, 3, 3.5, 4.5, 5.5, and 
36 hours postdose) for 1 subject with ESRD in Part 2, Period 1, and for 1 time point 
(16 hours postdose) for the same subject in Part 2, Period 2, due to difficult venipuncture. 
Therefore, the plasma MK-7264 concentrations at these time points were treated as missing.  
Urine samples could not be collected in Periods 1 and 2 of Part 2 for the same 5 of 6 subjects 
with ESRD. Therefore, urine MK-7264 concentrations at each collection interval were 
treated as missing. 
The dialysate samples at 4 hours postdose for 1 subject and at 4.5 hours postdose for 
2 subjects were mistakenly discarded. Therefore, the dialysate MK-7264 concentrations at 
these time points were treated as missing. 
9.8.3.2 Multicenter Studies 
This study was conducted at 2 clinical sites. Data from both sites were combined for data 
summarization and analyses. Study site was not included as a factor in the statistical 
analyses. 
9.8.3.3 Multiple Comparisons/Multiplicity 
No hypotheses were tested so no multiplicity adjustment was needed for the study. 
9.9 Changes in the Planned Analyses 
One (1) subject with ESRD had 6 missing peripheral blood samples (Part 2, Period 1) due to 
difficult venipuncture. This 1 subject was excluded from the primary PK analyses presented 
in Section 11. Supplementary analysis including all 6 subjects is shown in Section 14.  
One (1) dialysate sample was missing for 3 subjects (4-hour for 1 subject; 4.5-hour for 
2 subjects) as they were mistakenly not processed and discarded; therefore, the AD and rr 
values at these time points could not be determined. In addition, a sensitivity analysis was 
performed and it was determined that the missing sample had minimal impact (≤ 1%) on the 
extent of removal of MK-7264 by HD; therefore, a decision was made to include all subjects 
in the analysis.  
 
 
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Five (5) of the 6 ESRD subjects did not produce urine; therefore, PK parameters in Periods 1 
and 2 of Part 2 could not be calculated. Although the remaining subject did produce urine, 
MK-7264 concentrations in urine were not quantifiable. 
For Part 1, the protocol classified the categorical analysis as a secondary analysis; however, 
when Part 2 was added, it was considered as a part of the primary analysis used to assess the 
primary PK objective in ESRD subjects, and was described as such in the statistical analysis 
plan.  
The protocol stated that dialysate samples would be collected pre- and post-HD, as well as 
for 1 minute every half hour during HD; however, as dialysate is a product of HD, no pre- or 
post-HD samples were obtained. 
Non-model based summary statistics by population based on BSA normalized eGFR were 
provided for both primary (AUC0-∞, AUC0-last, Cmax, CL/F, and CLr) and exploratory 
endpoints (AUC0-12, AUC0-24, AUC0-48, Tmax, Vz/F, apparent terminal t½, Ae0-12, 
Ae12-24, Ae24-48, Ae0-24, Ae0-48, Fe0-12, Fe12-24, Fe24-48, Fe0-24 and Fe0-48). 
However, non-model based summary statistics by population based BSA non-normalized 
eGFR and CrCL using C-G equation were provided only for primary AUC0-∞, AUC0-last, 
Cmax, CL/F and CLr, as some categories had few or no subjects. 
 
There were no other changes to the planned analyses of the original protocol [16.1.1.4]. 
10 TRIAL SUBJECTS AND DATA SETS ANALYZED 
Individual subject level data listings are provided in [16.2.1, 16.2.4, 16.2.5, 16.2.7, and 
16.2.8]. Individual subject case report forms [16.3] are available upon request. 
10.1 Subject Disposition 
Twenty-four (24) subjects were enrolled into the study; 6 healthy matched control subjects, 
6 subjects with moderate renal impairment, 6 subjects with severe renal impairment, and 
6 subjects with ESRD requiring HD. All 24 subjects completed the study per protocol 
[16.1.1.4, 16.2.1, 16.4]. See Table 10-1 below for the study subject disposition details. 
All subjects satisfied all inclusion and none of the exclusion criteria, with verification at 
check-in. Individual subjects’ information related to check-in and inclusion/exclusion criteria 
is presented in [16.2.5.1, 16.4]. 
 
 
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