Clinical trial NCT03295266
Conditions: Hepatic Insufficiency Antibacterial Agents
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-12-19; Completion date: 2018-03-15
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, single-dose, Phase 1 study to evaluate the pharmacokinetics (PK) of intravenous (IV) MK-3866 in participants with moderate and severe hepatic impairment (HI) compared to that of matched healthy participants. The primary purpose of this study is to understand the effect of HI on the plasma PK of MK-3866 in order to guide dosing recommendations for participants with HI. This study will also evaluate the safety and tolerability of MK-3866 in participants with moderate and severe HI.

Detailed description:

Arms: arm 1: Participants with moderate HI (estimated glomerular filtration rate \[eGFR\] of ≤60mL/min/1.73m\^2) receive a single IV dose of MK-3866 (150 mg) on Day 1. arm 2: Participants with severe HI (eGFR of ≤50 mL/min/1.73m\^2) receive a single IV dose of MK-3866 (150 mg) on Day 1. arm 3: Healthy participants receive a single IV dose of MK-3866 (150 mg) on Day 1.
Interventions: intervention 1: MK-3866
Intervention descriptions: intervention 1: Single IV infusion of MK-3866 150 mg administered over 30 minutes at Hour 0 on Day 1 of treatment period.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03295266 
Document Date: 
06-Dec-2017
An Open-Label Study to Investigate the Single-Dose 
Pharmacokinetics of MK-3866 when Administered to Subjects with 
Moderate and Severe Hepatic Impairment


Product:  MK-3866  
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Protocol/Amendment No.:  006-02  
 
 
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A. 
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, U.S.A.  
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent). 
TITLE: 
An Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-3866 when 
Administered to Subjects with Moderate and Severe Hepatic Impairment 
IND NUMBER:  133,048 
 
EudraCT NUMBER:  Not Applicable 
 
 
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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES .............................................................................................. 8 
1.0 
TRIAL SUMMARY.................................................................................................. 10 
2.0 
TRIAL DESIGN........................................................................................................ 10 
 
Trial Design ........................................................................................................... 10 
2.1
 
Trial Diagram ........................................................................................................ 12 
2.2
3.0 
OBJECTIVES & ESTIMATIONS .......................................................................... 12 
 
Primary Objectives & Estimations ..................................................................... 12 
3.1
 
Secondary Objectives & Estimations .................................................................. 13 
3.2
 
Exploratory Objectives ......................................................................................... 13 
3.3
4.0 
BACKGROUND & RATIONALE .......................................................................... 13 
 
Background ........................................................................................................... 13 
4.1
 
Rationale ................................................................................................................ 13 
4.2
 Rationale for the Trial and Selected Subject Population .................................... 13 
4.2.1
4.2.1.1 Child-Pugh Classification of Hepatic Insufficiency .................................... 14 
 Rationale for Dose Selection .............................................................................. 15 
4.2.2
 Planned Exploratory Biomarker Research .......................................................... 15 
4.2.3
4.2.3.1 Planned Genetic Analysis ............................................................................ 15 
 Future Biomedical Research ............................................................................... 16 
4.2.4
 
Benefit/Risk ........................................................................................................... 16 
4.3
5.0 
METHODOLOGY ................................................................................................... 16 
 
Entry Criteria ........................................................................................................ 16 
5.1
 Diagnosis/Condition for Entry into the Trial ...................................................... 16 
5.1.1
 Subject Inclusion Criteria.................................................................................... 16 
5.1.2
 Subject Exclusion Criteria .................................................................................. 20 
5.1.3
 
Trial Treatment ..................................................................................................... 23 
5.2
 Dose Selection .................................................................................................... 23 
5.2.1
5.2.1.1 Dose Selection (Preparation) ....................................................................... 23 
 Timing of Dose Administration .......................................................................... 23 
5.2.2
 Trial Blinding ...................................................................................................... 23 
5.2.3
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Treatment Allocation ............................................................................................ 23 
5.3
 
Stratification .......................................................................................................... 23 
5.4
 
Concomitant Medications (Allowed and Prohibited) ........................................ 24 
5.5
 
Rescue Medications & Supportive Care ............................................................. 25 
5.6
 
Diet/Activity/Other Considerations ..................................................................... 25 
5.7
 Diet ...................................................................................................................... 25 
5.7.1
 Alcohol, Caffeine, Tobacco, Activity ................................................................. 26 
5.7.1
5.7.1.1 Alcohol ......................................................................................................... 26 
5.7.1.2 Caffeine Restrictions .................................................................................... 26 
5.7.1.3 Smoking Restrictions ................................................................................... 26 
5.7.1.4 Activity Restrictions .................................................................................... 26 
 
Subject Withdrawal/Discontinuation Criteria ................................................... 26 
5.8
 Discontinuation of Treatment ............................................................................. 26 
5.8.1
 Withdrawal from the Trial .................................................................................. 27 
5.8.2
 
Subject Replacement Strategy ............................................................................. 27 
5.9
 
Beginning and End of the Trial ........................................................................... 27 
5.10
 
Clinical Criteria for Early Trial Termination ................................................... 27 
5.11
6.0 
TRIAL FLOW CHART ........................................................................................... 28 
7.0 
TRIAL PROCEDURES ........................................................................................... 34 
 
Trial Procedures ................................................................................................... 34 
7.1
 Administrative Procedures .................................................................................. 34 
7.1.1
7.1.1.1 Informed Consent......................................................................................... 34 
7.1.1.1.1 General Informed Consent .................................................................... 34 
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical 
Research ................................................................................................ 35 
7.1.1.2 Inclusion/Exclusion Criteria ........................................................................ 35 
7.1.1.3 Subject Identification Card .......................................................................... 35 
7.1.1.4 Medical History ........................................................................................... 35 
7.1.1.5 Prior and Concomitant Medications Review ............................................... 35 
7.1.1.5.1 Prior Medications .................................................................................. 35 
7.1.1.5.2 Concomitant Medications ..................................................................... 35 
7.1.1.6 Assignment of Screening Number ............................................................... 35 
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7.1.1.7 Assignment of Treatment Number............................................................... 36 
7.1.1.8 Trial Compliance ......................................................................................... 36 
 Clinical Procedures/Assessments ........................................................................ 36 
7.1.2
7.1.2.1 Body Weight and Height ............................................................................. 36 
7.1.2.2 Body Mass Index ......................................................................................... 36 
7.1.2.3 12-Lead Electrocardiogram ......................................................................... 36 
7.1.2.4 Vital Signs (Blood Pressure, Pulse Rate, Respiratory Rate, Body 
Temperature) ................................................................................................ 36 
 Laboratory Procedures/Assessments .................................................................. 37 
7.1.3
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 37 
7.1.3.2 Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 38 
7.1.3.2.1 Blood Collection for Plasma MK-3866 ................................................ 38 
7.1.3.2.2 Urine Collection for Urinary MK-3866 ................................................ 38 
7.1.3.3 Planned Genetic Analysis Sample Collection.............................................. 39 
7.1.3.4 Future Biomedical Research Samples ......................................................... 39 
 Other Procedures ................................................................................................. 39 
7.1.4
7.1.4.1 Withdrawal/Discontinuation ........................................................................ 39 
7.1.4.1.1 Withdrawal from Future Biomedical Research .................................... 39 
7.1.4.1.2 Lost to Follow-up .................................................................................. 40 
7.1.4.2 Subject Blinding/Unblinding ....................................................................... 40 
7.1.4.3 Domiciling ................................................................................................... 40 
7.1.4.4 Calibration of Critical Equipment ................................................................ 40 
 Visit Requirements .............................................................................................. 41 
7.1.5
7.1.5.1 Screening...................................................................................................... 41 
7.1.5.2 Treatment Period .......................................................................................... 41 
7.1.5.3 Discontinued Subjects Continuing to be Monitored in the Trial ................. 41 
7.1.5.4 Post-Trial...................................................................................................... 41 
7.1.5.5 Critical Procedures Based on Trial Objectives: Timing of Procedure ......... 41 
7.1.5.6 Trial Procedures Modifications Permitted within Protocol Parameters ...... 42 
 
Assessing and Recording Adverse Events .......................................................... 42 
7.2
 Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor .......................................................................................................... 43 
 Reporting of Pregnancy and Lactation to the Sponsor ....................................... 44 
7.2.2
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 Immediate Reporting of Adverse Events to the Sponsor .................................... 44 
7.2.3
7.2.3.1 Serious Adverse Events ............................................................................... 44 
7.2.3.2 Events of Clinical Interest ............................................................................ 45 
 Evaluating Adverse Events ................................................................................. 46 
7.2.4
 Sponsor Responsibility for Reporting Adverse Events ...................................... 49 
7.2.5
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 49 
 
Statistical Analysis Plan Summary ..................................................................... 49 
8.1
 Source of Variance Estimates: Precision and Sample Size................................. 49 
8.1.1
 Statistical Core Methods: .................................................................................... 49 
8.1.2
8.1.2.1 Primary PK Analysis.................................................................................... 49 
8.1.2.2 Secondary PK Analysis................................................................................ 50 
8.1.2.2.1 Objective 1 ............................................................................................ 50 
8.1.2.2.2 Objective 2 ............................................................................................ 50 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 50 
 
Investigational Product ........................................................................................ 50 
9.1
 
Packaging and Labeling Information ................................................................. 51 
9.2
 
Clinical Supplies Disclosure ................................................................................. 51 
9.3
 
Storage and Handling Requirements .................................................................. 51 
9.4
 
Discard/Destruction/Returns and Reconciliation .............................................. 51 
9.5
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 52 
 
Confidentiality ....................................................................................................... 52 
10.1
 Confidentiality of Data ....................................................................................... 52 
10.1.1
 Confidentiality of Subject Records ..................................................................... 52 
10.1.2
 Confidentiality of Investigator Information ........................................................ 52 
10.1.3
 Confidentiality of IRB/IEC Information ............................................................. 53 
10.1.4
 
Compliance with Financial Disclosure Requirements ....................................... 53 
10.2
 
Compliance with Law, Audit and Debarment ................................................... 53 
10.3
 
Compliance with Trial Registration and Results Posting Requirements ........ 55 
10.4
 
Quality Management System ............................................................................... 55 
10.5
 
Data Management ................................................................................................. 55 
10.6
 
Publications ........................................................................................................... 56 
10.7
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11.0 
LIST OF REFERENCES ......................................................................................... 57 
12.0 
APPENDICES ........................................................................................................... 58 
 
Merck Code of Conduct for Clinical Trials ........................................................ 58 
12.1
 
Collection and Management of Specimens for Future Biomedical 
12.2
Research ................................................................................................................. 60 
 
Approximate Blood Volumes Drawn by Trial Visit and by Sample Types ..... 64 
12.3
13.0 
SIGNATURES........................................................................................................... 65 
 
Sponsor's Representative ..................................................................................... 65 
13.1
 
Investigator ............................................................................................................ 65 
13.2
14.0 
APPENDIX 1 ............................................................................................................. 66 
 
Child-Pugh Scale for the Assessment of Hepatic Impairment ......................... 66 
14.1
LIST OF TABLES 
Table 1 Child-Pugh Classification of the Severity of Liver Disease ...................................... 15 
Table 2 Trial Treatment .......................................................................................................... 23 
Table 3 Trial Flow Chart – Panels A and B ............................................................................ 28 
Table 4 Trial Flow Chart – Panel C ........................................................................................ 31 
Table 5 Laboratory Tests ........................................................................................................ 37 
Table 6 Pharmacokinetic Collection Windows....................................................................... 42 
Table 7 Evaluating Adverse Events ........................................................................................ 47 
Table 8 Product Descriptions .................................................................................................. 51 
 
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LIST OF FIGURES 
           
Figure 1 Trial Diagram ........................................................................................................... 12 
 
 
 
 
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SUMMARY OF CHANGES 
 
PRIMARY REASON FOR THIS AMENDMENT: 
Section Number (s) 
Section Title (s) 
Description of Change (s) 
Rationale 
2.1 
Trial Design 
Change the trial treatment dose 
from 200 mg to 150 mg. 
Upon review of pharmacokinetic and safety 
data from MK-3866 PN002, the multiple 
ascending dose study, it was determined that 
the starting dose for subjects with hepatic 
impairment should be 150 mg.  
4.2.1 
Rationale for the Trial and Selected 
Subject Population 
4.2.2 
Rationale for Dose Selection 
5.2 
Trial Treatment, Table 2 
9.1 
Investigational Product 
 
ADDITIONAL CHANGES FOR THIS AMENDMENT: 
Minor typographical and formatting errors were corrected throughout the protocol. Additional changes are listed below. 
Section Number (s) 
Section Title (s) 
Description of Change (s) 
Rationale 
2.1 
Trial Design 
For the timing of the infusion, a 
variance of ±5 minutes was 
added. 
To provide flexibility to the total MK-3866 
infusion time of 30 minutes. 
4.2.1 
Rationale for the Trial and Selected 
Subject Population 
Add that maximum exposure is 
unlikely to exceed  2.7-fold 
higher than 150 mg. 
To provide further rationale for dose. 
5.5 
Concomitant Medication (Allowed 
and Prohibited) 
Clarify the restrictions on use of 
enzyme/transporter inhibitors 
and inducers. 
Inhibitors of OATP1B1/1B3 transporters are 
also prohibited. 
Clarify the window for 
withholding allowed 
prescription medications after 
study treatment adminitration. 
Certain allowed prescription medications must 
be withheld for 4 hours after study treatment 
administration. 
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Section Number (s) 
Section Title (s) 
Description of Change (s) 
Rationale 
6.0 
Trial Chart 
Clarify time points for 
Concomitant Medication 
Review and Adverse Events 
Monitoring. 
Assessments will be conducted throughout 
study. 
Update footnote “a” to state that 
subjects will return to the 
clinical research unit 14 days 
after the last dose for follow-up 
procedures, and to determine if 
any adverse events have 
occurred soince the last study 
visit. 
To provide details regarding the post trial 
visit. 
7.1.2.4 
Vital Signs (Blood Pressure, Pulse 
Rate, Respiratory Rate, Body 
Temperature) 
Remove the statement body 
temperature will be measured 
“with an oral or tympanic 
thermometer”. 
To not limit the clinical reseach unit’s options 
and to allow the site to follow its typical 
process for measuring body temperature. 
9.1 
Investigational Product 
Change “dosing concentration” 
to “dose”. 
To clarify that the dose to be administered will 
be 150 mg. 
 
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1.0 TRIAL SUMMARY 
 
Abbreviated Title 
MK-3866 Hepatic Impairment Study 
Sponsor Product Identifiers 
MK-3866 
Trial Phase 
1 
Clinical Indication 
Treatment of bacterial infection 
Trial Type 
Interventional 
Type of control 
Healthy matching subjects 
Route of administration 
Intravenous 
Trial Blinding 
None. This is an open-label study. 
Treatment Groups 
 
Panel A) 6 subjects with moderate hepatic impairment (HI)  
Panel B) 6 subjects with severe HI 
Panel C) At least 6 (up to 12) healthy subjects 
Number of trial subjects 
At least 18 (up to 24) 
Estimated duration of trial 
The Sponsor estimates that the trial will require approximately 
56 days from the time the first subject signs the informed consent 
form (ICF) until the last subject’s last study-related visit.  
Duration of Participation 
Each subject will participate in the trial for approximately 43 days 
from the time the subject signs the ICF through the final contact.  
After a screening phase of 28 days, each subject will receive a single 
dose of the assigned treatment. Each subject will be followed for 
14 days after receiving the study treatment. 
 
 
 
2.0 TRIAL DESIGN 
 
Trial Design 
2.1
This is an open-label, single-dose study to evaluate the pharmacokinetics (PK) of 
intravenous (IV) MK-3866 in subjects with moderate and severe hepatic impairment (HI) 
compared to that of matched healthy subjects. Subjects with moderate (Panel A) and severe 
(Panel B) HI (classified using the Child-Pugh scale) shall be enrolled in parallel, and each 
Panel shall enroll a minimum of 2 subjects of each gender.  
Enrollment of healthy matching control subjects (Panel C) shall commence following the 
completion of enrollment of either Panel A or B, whichever is completed first.  Each healthy 
control subject will be matched to the mean body mass index (BMI; ±10%) and age 
(±15 years) of the subjects in the first HI Panel to complete enrollment. A total of 6 healthy 
subjects shall be enrolled into Panel C at this stage, and there should be a minimum of 2 
subjects of each gender.  
Following the completion of enrollment of the second HI panel, the matching characteristics 
(age and BMI) of the already-enrolled healthy subjects in Panel C will be compared against 
the mean values of the HI panel that is completed second. If any of the subjects already 
enrolled in Panel C do not also meet the matching criteria for the second completed HI panel, 
additional healthy subjects will be enrolled into Panel C in order to provide 6 healthy control 
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subjects who match the mean BMI (±10%) and age (±15 years) of the subjects in the second 
HI panel. The gender of the additional healthy subject(s) will be selected to ensure that there 
is a minimum of 2 subjects of each gender in the group of subjects within Panel C who match 
with the second HI panel. On the basis of this study design Panel C may ultimately include 
more than 6 subjects, but no more than 12. Although enrollment efforts into Panels A and B 
will commence at the same time, it is expected to take longer to enroll subjects into Panel B. 
The PK comparisons between each hepatically impaired Panel (A and B) and healthy 
controls (Panel C) will include only control subjects who meet the matching criteria for the 
respective HI panel. 
Subjects in Panels A, B and C will receive a single IV dose of 150 mg MK-3866 (30 minute 
infusion, ± 5 minutes). Plasma PK assessments will be performed at pre-specified time points 
up to 72 hours post-dose for moderate and severe HI and up to 48 hours postdose for the 
healthy match control group.  
Safety will be monitored throughout by repeated clinical and laboratory evaluations and the 
post-trial visit will occur approximately 14 days after administration of study drug. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
Because this is a Phase I assessment of MK-3866 in humans, the PK, pharmacodynamic (PD) 
and safety profiles of the compound are still being elucidated. This protocol is therefore 
written with some flexibility to accommodate the inherent dynamic nature of Phase I clinical 
trials. Please refer to Section 7.1.5 – Visit Requirements for examples of modifications 
permitted within the protocol parameters. 
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Trial Diagram 
2.2
Figure 1 Trial Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRU = Clinical research unit; HI = hepatic impairment; hrs = hours; IV = intravenous; PK = pharmacokinetic 
3.0 OBJECTIVES & ESTIMATIONS 
 
Primary Objectives & Estimations 
3.1
Objective (1):  To compare the plasma PK of MK-3866 following a single intravenous (IV) 
dose in subjects with moderate hepatic insufficiency (HI) to that of healthy matched control 
subjects, including area under the concentration-time curve (AUC) from time 0 hours to 
infinity (AUC0-inf),  AUC from time 0 hours to the last quantifiable concentration 
(AUC0-last), concentration at the end of infusion (Ceoi), time of maximum concentration 
(Tmax), terminal elimination half-life (t1/2), clearance (CL), and volume of distribution (Vz). 
Estimation (1): The AUC0-inf following a single IV dose of MK-3866 administered to 
subjects with moderate HI will be estimated and compared to the AUC0-inf when 
administered to healthy matched control subjects. 
Recruitment/Screening/Consent (up to 28 days) 
 
Day -2/Day -1: Admission to CRU 
Day 1: Single IV dose administration of MK-3866 
Panels A and B  (moderate and 
severe HI): 
Urine PK sampling through  
24 hrs postdose 
Plasma PK sampling through 
72 hrs postdose 
Panel C (healthy control): 
Urine PK sampling through  
24 hrs postdose 
Plasma PK sampling 
through  48 hrs postdose 
Exit CRU following 72-hr PK blood 
draw and completion of discharge 
procedures (Day 4) 
Exit CRU following 48-hr PK blood 
draw and completion of discharge 
procedures (Day 3) 
Day 15: Follow up visit 
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Objective (2):  To compare the plasma PK (e.g., AUC0-inf, AUC0-last, Ceoi, Tmax, t1/2, 
CL, Vz) of MK-3866 following a single IV dose in subjects with severe hepatic insufficiency 
(HI) to that of healthy matched control subjects. 
Estimation (2): The AUC0-inf following a single IV dose of MK-3866 administered to 
subjects with severe HI will be estimated and compared to the AUC0-inf when administered 
to healthy matched control subjects. 
 
Secondary Objectives & Estimations 
3.2
Objective (1):  To compare the urine PK (e.g., fraction of the dose excreted unchanged in 
urine [fe], renal clearance [CLR]) of MK-3866 following a single IV dose of MK-3866 in 
subjects with varying degrees of HI to those of healthy matched control subjects. 
Estimation (1): The CLR and fe of a single IV dose of MK-3866 in subjects with varying 
degrees of HI will be estimated and compared to those estimated in healthy matched control 
subjects. 
Objective (2): To evaluate the safety and tolerability of MK-3866 in subjects with moderate 
and severe HI. 
 
Exploratory Objectives 
3.3
Objective (1): 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. 
4.0 BACKGROUND & RATIONALE 
 
Background 
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3866. 
 
Rationale 
4.2
 Rationale for the Trial and Selected Subject Population 
4.2.1
MK-3866,
 is being developed for use 
 
 
 
ram-negative bacteria. MK-3866 has recently completed dosing the 
first-in-human (FIH) single ascending dose study (PN001).   
The primary purpose of this study is to understand the effect of HI on the plasma PK of 
MK-3866 in order to guide dosing recommendations for patients with HI. As a proportion of 
patients with serious Gram-negative infections have baseline HI, it is important to evaluate 
the impact of HI on the plasma PK of MK-3866. This study will also evaluate the safety and 
tolerability of MK-3866 in subjects with moderate and severe HI. 
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Renal clearance is expected to be the major elimination pathway for MK-3866, as 
approximately 65% of MK-3866 is excreted in the urine following a single IV dose.  Based 
on preclinical animal studies, hepatic elimination is anticipated to be a significant elimination 
pathway for MK-3866 as well and is expected to account for the remainder of the non-renal 
elimination of MK-3866, approximately 35%.  MK-3866 is also a substrate for the liver 
specific transporters human organic anion transporting polypeptide (OATP) 1B1/SLCO1B1 
(OATP1B1) and OATP1B3. Conducting a dedicated hepatic study for MK-3866 is in line 
with regulatory guidance which suggests a dedicated hepatic study be conducted for 
compounds in which hepatic elimination exceeds 20%.   
In the FIH study of MK-3866 in healthy subjects, while single and divided doses of up to 
2000 mg were generally well-tolerated, nausea was observed with an increased frequency at 
single doses above 800 mg. In each case, nausea was transient and its onset appeared to 
coincide temporally with the peak plasma concentration (although the relationship between 
PK and the development of nausea is currently under investigation).  
It is predicted that the potential effect of HI on single-dose PK will be to reduce the 
clearance, thereby increasing the terminal half-life and AUC of MK-3866. It is assumed that 
there is generally a linear relationship between the effect on t1/2 and AUC. Based on PN001, 
approximately 35% of MK-3866 may be hepatically eliminated; exposure increases with 
severe HI are anticipated to be approximately 1.5-fold. However, it is difficult to provide 
estimates for hepatic impairment; there is no single accepted measure to use in order to 
determine PK estimations for varying degrees of liver impairment. In consideration of both 
the PK and the tolerability of MK-3866 in subjects with HI, the dose of study drug in this 
trial was selected so that the exposure in all subjects should not exceed 800 mg in healthy 
subjects (AUC0-inf of 272 µM*hr and Ceoi of 97 µM), and is unlikely to exceed the 
exposure at 400 mg  (2.7-fold higher than the 150 mg dose) in healthy subjects (AUC0-inf of 
147 µM*hr and Ceoi of 52 µM).  On the basis of these predicted exposures from a single 
150 mg dose of MK-3866 in subjects with either moderate or severe HI, both panels can be 
recruited in parallel without posing a risk to subject safety. 
 Child-Pugh Classification of Hepatic Insufficiency 
4.2.1.1
The Child classification, which should only be applied to patients with a diagnosis of hepatic 
cirrhosis, was initially used to assess the preoperative risk of patients with hepatic cirrhosis. 
The Child scale, as modified by Pugh, has been subsequently found useful in classifying a 
patient’s level of HI for PK studies. The Child-Pugh scale (see Appendix 1) has been shown 
to correlate with hepatic (i.e., metabolic) clearance for several compounds. 
In the current study, patients with chronic, stable HI with features of cirrhosis due to any 
etiology will be enrolled, and the Child-Pugh scale will be used to classify the severity of 
liver disease. The bilirubin score in the table is dependent upon the type of cirrhosis (primary 
biliary cirrhosis versus all other causes). Subjects’ scores of 5 to 6, 7 to 9, and 10 to 15 on 
this scale are classified as having mild, moderate, and severe hepatic failure, respectively. 
In addition, in order to ensure that the study subjects have laboratory abnormalities consistent 
with hepatic dysfunction (e.g., reduced serum albumin, increased serum bilirubin, and 
increased international normalized ratio [INR]), at least three subjects with moderate HI will 
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be required to have a score of at least 2 on one of the laboratory parameters on the Child-
Pugh scale. 
Table 1 Child-Pugh Classification of the Severity of Liver Disease 
Scoring 
Points Score for Increasing Abnormality 
Assessment 
1 
2 
3 
Encephalopathy† 
None 
1 or 2 
3 or 4 
Ascites 
Absent 
Slight 
Moderate 
Albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
INR 
<1.7 
1.7 to 2.3 
>2.3 
Bilirubin (mg/dL)—not PBC‡§ 
Bilirubin (mg/dL)—only for PBC‡§ 
<2 
<4 
2 to 3 
4 to 10 
>3 
>10 
† Portal-system encephalopathy is Staged 0 to 4. 
‡ PBC = Primary Biliary Cirrhosis. 
§ Select only one dependent on type of cirrhosis. 
Interpretation 
Points 
Child-Pugh Class 
5-6 
A (mild hepatic impairment) 
7-9 
B (moderate hepatic impairment) 
10-15 
C (severe hepatic impairment) 
 
 Rationale for Dose Selection 
4.2.2
MK-3866 is currently undergoing evaluation in preclinical studies and in clinical trials with 
healthy subjects; therefore the planned clinical dose has not yet been established, but is 
presently projected to be approximately 300 mg.  For safety, the well-tolerated dose of 
150 mg will be administered to subjects with moderate and severe HI, and the control panel 
of healthy subjects matched to the moderate and severe HI panels. 
 Planned Exploratory Biomarker Research 
4.2.3
 Planned Genetic Analysis 
4.2.3.1
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 
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of disease and the genetic determinants of efficacy and safety associated with the treatments 
in this study. 
 Future Biomedical Research 
4.2.4
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 Section 12.2 – Collection and 
Management of Specimens for Future Biomedical Research. 
 
Benefit/Risk 
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine. 
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents. 
5.0 METHODOLOGY 
 
Entry Criteria 
5.1
 Diagnosis/Condition for Entry into the Trial 
5.1.1
Panel A: Subjects with moderate HI. 
Panel B: Subjects with severe HI. 
Panel C: Healthy subjects. 
 Subject Inclusion Criteria 
5.1.2
Subjects with HI 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in 
the study, unless otherwise specified. 
1. Is an adult male or female, 18-75 years of age, inclusive, at screening. 
2. Has a BMI ≥19 and ≤40 kg/m2, at screening. 
3. Is a continuous non-smoker prior to screening and enrollment. 
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4. Baseline health is judged to be stable based on medical history (except for the HI 
condition), physical examination, vital signs, ECGs, and laboratory safety tests. 
Subjects who do not qualify based on a reversible condition or mild intercurrent 
illness may be rescreened after the underlying condition is resolved. 
5. Has a diagnosis of chronic (>6 months), stable (no acute episodes of illness within the 
previous 2 months due to deterioration in hepatic function) HI with features of 
cirrhosis (confirmed by medical history). 
6. Panel A only: Has a score on the Child-Pugh scale from 7 to 9 (moderate HI) at 
screening. At least 3 subjects must have a score of 2 or higher on at least one of the 
laboratory parameters (i.e., albumin, INR, and/or bilirubin) at screening on the 
Child-Pugh scale. 
7. Panel B only: Has a score on the Child-Pugh scale from 10 to 15 (severe HI) at 
screening. 
8. Is completely informed of the unknown risks of pregnancy and agrees not to become 
pregnant or father a child during the time they are participating in this study. 
9. Has adequate peripheral venous access, as determined by the investigator, at the 
Screening visit. 
10. For a female of childbearing potential: is either sexually inactive (abstinent) for 
14 days prior to dosing and throughout the study or is using one of the following 
acceptable birth control methods: 
• Intrauterine device in place for at least 3 months prior to dosing and use a 
physical barrier method (e.g., condom, diaphragm) and spermicide throughout 
the study. 
• Double physical barrier methods (e.g., condom and diaphragm) with 
spermicide for at least 14 days prior to dosing and throughout the study. 
• Surgical sterilization of the partner (vasectomy for 4 months minimum) and 
use a physical barrier method (e.g., condom, diaphragm) and spermicide 
throughout the study. 
• Hormonal contraceptives for at least 3 months prior to dosing of the study and 
use a physical barrier method (e.g., condom, diaphragm) and spermicide 
throughout the study. 
11. Female subjects who claim to be sexually inactive, but become sexually active during 
the course of the study must agree to use a double physical barrier method (e.g., 
condom and diaphragm) with spermicide from the time of the start of sexual activity 
through completion of the study or if having a surgically sterilized partner (vasectomy 
for 4 months minimum) must agree to use a physical barrier method (e.g., condom, 
diaphragm) and spermicide through completion of the study. 
12. In addition, female subjects of childbearing potential will be advised to remain 
sexually inactive or to keep the same birth control method for at least 14 days 
following dosing. 
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13. Females of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy; 
• bilateral oophorectomy; 
• or be postmenopausal with amenorrhea for at least 1 year prior to dosing and 
have follicle-stimulating hormone (FSH) serum levels consistent with 
postmenopausal status as per Investigator or designee’s judgment. 
14. Non-vasectomized male subjects must agree to use a condom with spermicide or 
abstain from sexual intercourse from dosing until 90 days after dosing. No restrictions 
are required for vasectomized males provided their vasectomy has been performed 
4 months or more prior to dosing. Males who have been vasectomized less than 
4 months prior to dosing must follow the same restrictions as non-vasectomized 
males. 
15. Male subjects must agree not to donate sperm from dosing until 90 days after dosing. 
16. Understands the study procedures in informed consent forms (ICFs), be willing and 
able to comply with the protocol, and provides written informed consent for the trial. 
The subject may also provide consent for Future Biomedical Research. However, the 
subject may participate in the main trial without participating in Future Biomedical 
Research. 
Healthy control subjects 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in 
the study, unless otherwise specified. 
1. Is a healthy adult male or female, 18-75 years of age, inclusive, at screening. Age 
must be within ±15 years of the mean age of subjects in the first HI panel to complete 
enrollment (either Panel A or B). For any additional healthy subjects, age must be 
within ±15 years of the mean age of subjects in the second HI panel to complete 
enrollment. A similar number of males and females (±1) will be enrolled in the HI 
and healthy groups. The gender of the additional healthy subject(s) enrolled will be 
selected to ensure the number of healthy subjects of each gender will match that of 
the subjects enrolled in each HI panel (±1). 
2. Has a BMI ≥19 and ≤40 kg/m2 at screening. BMI must be within ±10% of the mean 
BMI of the subjects in the first HI panel to complete enrollment (either Panel A or B). 
For any additional healthy subject enrolled, BMI must be within ±10% of the mean 
BMI of subjects in the second HI panel to complete enrollment. 
3. Is a continuous non-smoker. 
4. Is medically healthy with no clinically significant medical history, physical 
examination, laboratory profiles, vital signs, or ECGs, as deemed by the Investigator. 
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5. Is completely informed of the unknown risks of pregnancy and agrees not to become 
pregnant or father a child during the time they are participating in this study. 
6. For a female of childbearing potential: is either sexually inactive (abstinent) for 
14 days prior to dosing and throughout the study or is using one of the following 
acceptable birth control methods: 
• Intrauterine device in place for at least 3 months prior to dosing and use a 
physical barrier method (e.g., condom, diaphragm) and spermicide throughout 
the study. 
• Double physical barrier methods (e.g., condom and diaphragm) with 
spermicide for at least 14 days prior to dosing and throughout the study. 
• Surgical sterilization of the partner (vasectomy for 4 months minimum) and 
use a physical barrier method (e.g., condom, diaphragm) and spermicide 
throughout the study. 
• Hormonal contraceptives for at least 3 months prior to dosing of the study and 
use a physical barrier method (e.g., condom, diaphragm) and spermicide 
throughout the study. 
7. Female subjects who claim to be sexually inactive, but become sexually active during 
the course of the study must agree to use a double physical barrier method (e.g., 
condom and diaphragm) with spermicide from the time of the start of sexual activity 
through completion of the study or if having a surgically sterilized partner (vasectomy 
for 4 months minimum) must agree to use a physical barrier method (e.g., condom, 
diaphragm) and spermicide through completion of the study.  
8. In addition, female subjects of childbearing potential will be advised to remain 
sexually inactive or to keep the same birth control method for at least 14 days 
following dosing. 
9. Females of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy;  
• bilateral oophorectomy; 
• or be postmenopausal with amenorrhea for at least 1 year prior to dosing and 
have FSH serum levels consistent with postmenopausal status as per 
Investigator or designee’s judgment. 
10. Non-vasectomized male subjects must agree to use a condom with spermicide or 
abstain from sexual intercourse from dosing until 90 days after dosing. No restrictions 
are required for vasectomized males provided their vasectomy has been performed 
4 months or more prior to dosing. Males who have been vasectomized less than 
4 months prior to dosing must follow the same restrictions as non-vasectomized 
males. 
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11. Male subjects must agree not to donate sperm from dosing until 90 days after dosing. 
12. Understands the study procedures in ICFs, be willing and able to comply with the 
protocol, and provides written informed consent for the trial, including for Future 
Biomedical Research. Future Biomedical Research participation is voluntary and is 
not required in order to participate in the trial. 
 Subject Exclusion Criteria 
5.1.3
Subjects with HI 
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. Has a history or presence of clinically significant medical or psychiatric condition or 
disease other than hepatic impairment in the opinion of the Investigator might 
confound the results of the study or poses an additional risk to the patient by their 
participation in the study. Remote history of cholecystectomy that is not an active 
issue may be included at the discretion of the investigator. 
3. Has a clinically significant history of cancer. Remote history with full cure or limited 
disease with complete resection (cure) may be included at the discretion of the 
investigator. 
4. Has a history of drug or alcohol abuse within the past 6 months prior to dosing. 
5. Consumes more than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day, within 6 months of screening. Subjects that consume 
4 glasses of alcoholic beverages per day may be enrolled at the discretion of the 
investigator. 
6. Consumes excessive amounts, defined as more than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-drinks, or 
other caffeinated beverages per day. 
7. Has a history of a liver transplant. 
8. Has a history or presence of hypersensitivity or idiosyncratic reaction to the study 
drugs or related compounds. 
9. Has moderate or severe renal insufficiency (estimated glomerular filtration rate 
[eGFR]  of ≤60 mL/min/1.73 m2 for moderate HI subjects or ≤50 mL/min/1.73 m2 for 
severe HI subjects, calculated according to the Modification of Diet in Renal Disease 
[MDRD] study equation). 
10. Is a female patient who is pregnant or lactating. 
11. Has positive results for the urine or breath alcohol screen and/or urine drug screen at 
screening or check-in, unless the positive drug screen is due to prescription drug use 
and is approved by the Investigator and the Sponsor Medical Monitor. 
12. Has positive results at screening for human immunodeficiency virus (HIV). 
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13. Subjects with active hepatitis C virus (HCV) infection (defined as detectable HCV 
RNA) or hepatitis B virus (HBV) infection (defined as HBsAg positive). Patients 
with prior/inactive HCV infection (defined as undetectable HCV RNA) or past HBV 
infection (defined as HBsAg negative and HBsAb positive) may be enrolled. Subjects 
with detectable HCV RNA but with stable alanine transaminase (ALT) and aspartate 
transaminase (AST) values, no elevation in either ALT or AST greater than 2-fold the 
upper limit of normal (ULN) for at least 3 months, may be enrolled with the joint 
agreement of the sponsor and principal investigator after review of their historical 
ALT and AST values. 
14. 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) listed in Section 5.5 for the prohibited time period. 
15. Has taken amiodarone at any time in their life. 
16. Has seated heart rate is equal to or lower than 44 bpm or higher than 100 bpm at 
screening. 
17. Has seated blood pressure is less than 90/40 mmHg or greater than 180/105 mmHg at 
screening. 
18. Has PR interval >240 msec or QRS >140 msec at screening. 
19. Has QTcF interval >490 msec or deemed clinically abnormal by the Investigator at 
screening. 
20. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator, within the 28 days prior to the dose of study drugs, and throughout the 
study. 
21. Has donated blood >500 mL or had significant blood loss within 56 days prior to the 
dose of study drugs. 
22. Has donated plasma within 7 days prior to the dose of study drugs. 
23. Is working at or has an immediate family member (spouse or children) who works at 
the investigational site or is a Sponsor staff directly involved with this trial. 
24. Dosed in another clinical trial within 28 days prior to dosing of study drugs. The 28-
day window will be derived from the date of the last dosing in the previous study to 
Day 1 of the current study. 
25. Subject who dosed in one part (e.g., Panel 1) will not be enrolled in the other part 
(e.g., Panel 2). 
Healthy control subjects 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. 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. Has a history or presence of clinically significant medical or psychiatric condition or 
disease in the opinion of the Investigator might confound the results of the study or 
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poses an additional risk to the patient by their participation in the study. Remote 
history of cholecystectomy that is not an active issue may be included at the 
discretion of the investigator. 
3. 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. Has a history or presence of alcoholism or drug abuse within the past 2 years prior to 
dosing. 
5. Has a history or presence of hypersensitivity or idiosyncratic reaction to the study 
drugs or related compounds. 
6. Has moderate or severe renal insufficiency (eGFR ≤60 mL/min/1.73 m2 calculated 
according to the Modification of Diet in Renal Disease study equation). 
7. Has positive macroscopic urine protein at screening and check-in (trace protein by 
dipstick will be allowed). 
8. Is a female subject who is pregnant or lactating. 
9. Has positive results for the urine or breath alcohol screen and/or urine drug screen at 
screening or check-in, unless the positive drug screen is due to prescription drug use 
and is approved by the Investigator and the Sponsor Medical Monitor. 
10. Has positive results at screening for HIV, HBsAg, or HCV. 
11. 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) listed in Section 5.5 for the prohibited time period. 
12. Has taken amiodarone at any time in their life. 
13. Has seated heart rate is equal to or lower than 44 bpm or higher than 100 bpm at 
screening. 
14. Has seated blood pressure is less than 90/40 mmHg or greater than 150/90 mmHg at 
screening. 
15. Has PR interval >200 msec, QRS >110 msec at screening. 
16. Has QTcF interval >450 msec or deemed clinically abnormal by the Investigator at 
screening. 
17. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator, within the 28 days prior to the dose of study drugs, and throughout the 
study. 
18. Has donated blood >500 mL or had significant blood loss within 56 days prior to the 
dose of study drugs. 
19. Has donated plasma within 7 days prior to the dose of study drugs. 
20. Is working at or has an immediate family member (spouse or children) who works at 
the investigational site or is a Sponsor staff directly involved with this trial. 
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21. Dosing in another clinical trial within 28 days prior to dosing of study drugs. The 
28-day window will be derived from the date of the last dosing in the previous study 
to Day 1 of the current study. 
 
Trial Treatment 
5.2
The treatment to be used in this trial is outlined below in Table 2. 
Table 2 Trial Treatment 
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Panel 
Use 
MK-3866 
150 mg 
Single dose 
Intravenous 
A  
Experimental 
MK-3866 
150 mg 
Single dose 
Intravenous 
B 
Experimental 
MK-3866 
150 mg 
Single dose 
Intravenous 
C 
Experimental 
 
Trial treatment should begin on the day of treatment allocation or as close as possible to the 
date on which the subject is allocated. 
All supplies indicated in Table 2 above will be provided centrally by the Sponsor. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
 Dose Selection 
5.2.1
 Dose Selection (Preparation) 
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject. 
 Timing of Dose Administration 
5.2.2
MK-3866 for IV administraton will be prepared and dosed per the instructions outlined in the 
Study Operation Manual. 
 Trial Blinding  
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
Treatment Allocation 
5.3
Subjects participating in this trial will be allocated by non-random assignment. 
 
Stratification 
5.4
Treatment allocation will be stratified according to the following factors: 
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1. Panel A: At least 3 subjects will have a score of 2 or higher on at least one of the 
laboratory parameters (i.e., albumin, INR, and/or bilirubin) at screening on the 
Child-Pugh scale. At least 2 subjects of each gender will be enrolled. 
2. Panel B: At least 2 subjects of each gender will be enrolled. 
3. Panel C: Healthy control subjects in Panel C will be matched to the mean BMI (±10%) 
and age (±15 years) of the HI subjects in Panels A and B. Refer to Section 2.1 for further 
details. 
 
Concomitant Medications (Allowed and Prohibited) 
5.5
Concomitant therapies will be prohibited as indicated in the exclusion criteria (Section 5.1.3).  
If a subject does not discontinue all prior medications within 14 days or 5 half-lives of  
starting the trial, he/she may be included in the study if the investigator can rationalize that 
the specific use of a prior medication is not clinically relevant within the context of the trial. 
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. 
Hormonal contraceptives and hormone replacement therapy are not prohibited. Ibuprofen (up 
to 1.2 g per 24 hour period) may be permitted during the study.  
Appropriate sources will be consulted by the Investigator or designee to confirm lack of 
PK/PD interaction with drug.  
If deviations occur, the Investigator in consultation with the Sponsor Clinical Monitor will 
decide on a case-by-case basis. 
All medications taken by subjects during the course of the study will be recorded. 
Subjects who are taking medications for stable diseases for approximately 2 weeks for 
subjects with HI and approximately 1 month for healthy subjects prior to dosing will be 
allowed to participate in the study at the discretion of the Investigator and following 
consultation with the Sponsor Clinical Monitor. If a subject is prescribed prohibited 
medication, upon discussion between the Sponsor and the Investigator, the Investigator may 
substitute the previously prescribed medication to an allowed one for the purpose of this 
study.  
All prescription or non-prescription medications (including St. John’s Wort) that are strong 
inhibitors or strong inducers of CYP3A enzymes or P-gp transporters will be prohibited. 
Inhibitors of OATP1B1/1B3 transporters are also prohibited. CYP3A and P-gp 
enzyme/transporter inhibitors and inducers will not be allowed for at least 14 days  and 
OATP1B1/1B3 inhibitors will not be allowed for at least 28 days prior to first dosing and 
throughout the study. Medications of particular concerns are HIV protease inhibitors, statins, 
antiarrhythmic agents, medications associated with QT prolongation, hepatotoxic drugs, 
investigational agents, and systemic corticosteroids.  Weak CYP3A, and/or P-gp inhibitors or 
CYP3A and/or P-gp inducers may be deemed acceptable following consultation with the 
Sponsor Clinical Monitor and the Investigator. 
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. 
Diuretics will be prohibited within 4 hours prior to dosing and within 4 hours post dosing. 
Subjects on diuretics must be on a stable dose for at least 2 weeks prior to study drug 
administration, to participate in this study. 
Certain prescription medications used to treat manifestations of hepatic disease or 
medications needed to treat stable diseases (e.g., ACE inhibitors, angiotensin II receptor 
antagonists, beta-blockers) will be allowed during the study provided the subjects are on a 
stable regimen for approximately 2 weeks (or 5 half-lives of the compound, whichever is 
longer) prior to study drug administration and is able to withhold the use within 4 hours prior 
to and 4 hours post administration of the study drug. 
 
Rescue Medications & Supportive Care 
5.6
No rescue or supportive medications are specified to be used in this trial. 
 
Diet/Activity/Other Considerations 
5.7
 Diet 
5.7.1
Subjects will refrain from consumption Seville oranges and grapefruits, or any juice or other 
product that contains Seville oranges or grapefruits, beginning approximately 2 weeks 
(14 days) prior to administration of the initial dose of trial drug, throughout the trial and until 
the posttrial visit.   
Subject also will refrain from consumption of all juices 24 hours prior to and after 
administration of each dose of trial drug on PK days.  All fruits except for Seville oranges 
and grapefruits are allowed on all days of the trial. 
Water 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 for at least 1 hour prior to dosing and will continue the fast for at least 
1 hour after the end of the infusion. 
On all days that subjects are confined in the CRU, standard meals and snacks will be 
provided 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 snack served at the CRU will be standardized, and will be similar in caloric 
content and composition. 
 
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 Alcohol, Caffeine, Tobacco, Activity 
5.7.1
 Alcohol 
5.7.1.1
Subjects are prohibited from consumption of alcohol from 48 hours prior to Day 1 dosing 
until the completion of the end-of-study postdose procedures. 
 Caffeine Restrictions 
5.7.1.2
Subject must not consume coffee, tea, cola, energy-drinks, or other caffeinated beverages or 
foods containing caffeine or xanthine from 24 hours prior to the first dose of study 
medication until after the post-trial visit. 
 Smoking Restrictions 
5.7.1.3
Smoking is not permitted during the trial. 
 Activity Restrictions 
5.7.1.4
Subjects will avoid unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the pre-trial (screening) visit until administration of the initial dose of 
trial drug, throughout the trial and until the post-trial visit. 
 
Subject Withdrawal/Discontinuation Criteria 
5.8
 Discontinuation of Treatment 
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial. 
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment 
prior to completion of the treatment period will still continue to participate in the trial as 
specified 
in 
Section 
6.0 
- 
Trial 
Flow 
Chart 
and 
Section 
7.1.4.1 
– 
Withdrawal/Discontinuation, or if available, Protocol Clarification Letter. 
Subjects may discontinue treatment at any time for any reason or be dropped from treatment 
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons: 
○ The subject or subject’s legally acceptable representative requests to discontinue 
treatment. 
o The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the subject at unnecessary risk from continued 
administration of study drug. 
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o The subject has a confirmed positive serum pregnancy test. 
o The subject has a positive urine drug screen at any time during the course of the trial.  
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed. 
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment. 
 Withdrawal from the Trial 
5.8.2
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial. 
If a subject withdraws from the study, they will no longer receive treatment or be followed at 
scheduled protocol visits. 
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures. 
 
Subject Replacement Strategy 
5.9
A subject who discontinues from the trial may be replaced at the discretion of the Sponsor.  
 Beginning and End of the Trial 
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator). 
A trial may be paused during review of newly available preclinical/clinical safety, PK, PD, 
efficacy or biologic data or other items of interest, prior to a final decision on continuation or 
termination of the trial.  It may be necessary to keep the trial open for gathering/reviewing of 
additional supportive data to optimally complete the objective(s) of the trial.  If necessary, 
the appropriate amendment(s) to the protocol and/or appropriate communication(s) will be 
generated.  The overall trial end will then not be identified until the Sponsor has made the 
decision to end the trial following this review period.  The Competent Authority(ies) and 
Institutional Review Board(s)/Independent Ethics Committee(s) [IRB(s)/IEC(s)] will be 
appraised of the maximum duration of the trial beyond the last subject out and the 
justification for keeping the trial open. 
 Clinical Criteria for Early Trial Termination 
5.11
There are no pre-specified criteria for terminating the trial early. 
. 
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6.0 TRIAL FLOW CHART 
Table 3 Trial Flow Chart – Panels A and B  
Panels A and B (Subjects with HI) 
 
Screening 
Up to 28 
days 
Check-in 
Day -2/Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Post-
triala 
 
Hours 
Predose 
0 
0.5 
0.75 
1 
1.5 
2 
3 
4 
4.5 
6 
8 
9 
10 
12 
24 
48 
72 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent for Future Biomedical 
Research  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Identification Card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------X  
Clinic Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Child-Pugh Scale classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead Electrocardiogramb 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Vital Signs (heart rate, blood pressure)  
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Vital 
Signs 
(respiratory 
rate, 
body 
temperature) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
IV MK-3866 Administrationc 
 
 
 
X-------X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Panels A and B (Subjects with HI) 
 
Screening 
Up to 28 
days 
Check-in 
Day -2/Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Post-
triala 
 
Hours 
Predose 
0 
0.5 
0.75 
1 
1.5 
2 
3 
4 
4.5 
6 
8 
9 
10 
12 
24 
48 
72 
Adverse Events Monitoring 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Laboratory Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Safety Tests (Hematology, 
Urinalysis, Chemistry) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Serum β-Human Chorionic Gonadotropin 
(β-hCG) (females only) 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Follicle Stimulating Hormone 
(FSH) - if applicable 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug/Alcohol/Cotinine Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen (per site SOP)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Genetic Analysise 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Plasma MK-3866 Assayf 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Urine for Urinary MK-3866 Assayg 
 
 
X 
X-------------------------------------------------------------------------------------------------X 
 
 
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Panels A and B (Subjects with HI) 
 
Screening 
Up to 28 
days 
Check-in 
Day -2/Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Post-
triala 
 
Hours 
Predose 
0 
0.5 
0.75 
1 
1.5 
2 
3 
4 
4.5 
6 
8 
9 
10 
12 
24 
48 
72 
 
 
 PK = pharmacokinetic 
a. All subjects who receive at least one dose of MK-3866 will return to the Clinical Research Unit (CRU) approximately 14 days after the last dose for follow-up 
procedures, and to determine if any adverse events have occurred since the last study visit. 
b. Screening and predose ECGs will be performed in triplicate. At other times, single ECGs will be performed. 
c. MK-3866 will be administered via a 30-minute IV infusion. 
d. Women who are of non-childbearing potential (confirmed with FSH test) will not have pregnancy testing at check-in. 
e. 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. 
f. PK sampling scheme in plasma: 
 
Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, 72 hours postdose 
g. PK sampling scheme in urine: 
 
Predose, then pooled in the following increments: 0-4, 4-8, 8-12, 12-24  hours postdose 
 
 
  
 
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Table 4 Trial Flow Chart – Panel C 
Panel C (Healthy Control Subjects) 
 
Screening 
Up to 28 days 
Check-in 
Day -2/Day -1 
Day 1 
Day 
2 
Day 
3 
Post-
triala 
 
Hours 
Predose 
0 
0.5 
0.75 
1 
1.5 
2 
3 
4 
4.5 
6 
8 
9 
10 
12 
24 
48 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent for Future Biomedical 
Research  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Identification Card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------------X  
Clinic Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead Electrocardiogramb 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs (heart rate, blood pressure)  
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Vital Signs (respiratory rate, body 
temperature) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
IV MK-3866 Administrationc 
 
 
 
X--------X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Monitoring 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
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Panel C (Healthy Control Subjects) 
 
Screening 
Up to 28 days 
Check-in 
Day -2/Day -1 
Day 1 
Day 
2 
Day 
3 
Post-
triala 
 
Hours 
Predose 
0 
0.5 
0.75 
1 
1.5 
2 
3 
4 
4.5 
6 
8 
9 
10 
12 
24 
48 
Laboratory Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Safety Tests (Hematology, 
Urinalysis, Chemistry) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Serum β-Human Chorionic 
Gonadotropin (β-hCG) (females only) 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Follicle Stimulating Hormone 
(FSH) - if applicable 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug/Alcohol/Cotinine Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen (per site SOP)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Genetic Analysise 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Plasma MK-3866 assayf 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Urine for Urinary MK-3866 Assayg 
 
 
X 
X-----------------------------------------------------------------------------------------------------X 
 
 
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Panel C (Healthy Control Subjects) 
 
Screening 
Up to 28 days 
Check-in 
Day -2/Day -1 
Day 1 
Day 
2 
Day 
3 
Post-
triala 
 
Hours 
Predose 
0 
0.5 
0.75 
1 
1.5 
2 
3 
4 
4.5 
6 
8 
9 
10 
12 
24 
48 
 
 
 PK = pharmacokinetic 
a. All subjects who receive at least one dose of MK-3866 will return to the Clinical Research Unit (CRU) approximately 14 days after the last dose for follow-up 
procedures, and to determine if any adverse events have occurred since the last study visit. 
b. Screening and predose ECGs will be performed in triplicate. At other times, single ECGs will be performed. 
c. MK-3866 will be administered via a 30-minute IV infusion. 
d. Women who are of non-childbearing potential (confirmed with FSH test) will not have pregnancy testing at check-in. 
e. 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. 
f. PK sampling scheme in plasma: 
 
Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48 hours postdose 
g. PK sampling scheme in urine: 
 
Predose, then pooled in the following increments: 0-4, 4-8, 8-12, 12-24  hours postdose 
 
 
 
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7.0 TRIAL PROCEDURES 
 
Trial Procedures 
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations. 
 Administrative Procedures 
7.1.1
 Informed Consent 
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place.  
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative 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 or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
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7.1.1.1.2 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. 
 Inclusion/Exclusion Criteria 
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
 Subject Identification Card 
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card. 
 Medical History 
7.1.1.4
A medical history will be obtained by the investigator or qualified designee. 
 Prior and Concomitant Medications Review 
7.1.1.5
7.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 14 days before the first dose of trial medication. 
7.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. 
 Assignment of Screening Number 
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects. 
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. 
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.   
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 Assignment of Treatment Number 
7.1.1.7
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment number.  The treatment number identifies the subject for all procedures occurring 
after treatment allocation.  Once a treatment number is assigned to a subject, it can never be 
re-assigned to another subject. 
A single subject cannot be assigned more than 1 treatment number. 
 Trial Compliance  
7.1.1.8
Administration of trial medication will be witnessed by the investigator and/or trial staff. 
 Clinical Procedures/Assessments 
7.1.2
 Body Weight and Height 
7.1.2.1
Body weight and height will be obtained with the subjects’ shoes off, jacket or coat removed, 
as follows: 
• Document the subject’s weight in kilograms (kg), to the nearest 0.1 kg.  
• Measure the subject’s height on a calibrated stadiometer.  Document this height in 
meters, to the nearest 0.01 meter (0.01 meter = 1 centimeter, cm).  
 Body Mass Index 
7.1.2.2
Body Mass Index (BMI) equals a subject’s weight in kilograms divided by height in meters 
squared 
(BMI=kg/m2). Subject’s 
BMI 
will 
be 
documented 
to 
the 
nearest 
0.1 kilogram/(meter)2.  Subject’s BMI will not be rounded to the nearest whole number. 
 12-Lead Electrocardiogram 
7.1.2.3
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Subjects may need to be shaved to ensure proper lead 
placement. Female subjects may need to remove their bra. The ECG instrument calibration 
will be current and the machine will be assessed for correct date and time prior to each use. 
Subjects should be resting in the semi-recumbent position for at least 10 minutes prior to 
each ECG measurement. Subject position during ECG collection should be consistent 
throughout the study. 
Fridericia’s formula will be used to correct QT. 
 Vital Signs (Blood Pressure, Pulse Rate, Respiratory Rate, Body Temperature) 
7.1.2.4
Subjects should be seated (or semi-recumbent if indicated for other procedures or adverse 
events) for at least 10 minutes prior to having vital sign measurements obtained. The correct 
size of the blood pressure cuff and the correct positioning on the subjects' arm is essential to 
increase the accuracy of blood pressure measurements. The same method (e.g., manual or 
automated) must be used for all measurements for each individual subject and should be 
same for all subjects. 
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Body temperature will be measured. The same method must be used for all measurements for 
each individual subject and should be the same for all subjects. 
Additional vital signs measurements may be performed as deemed medically necessary by 
research personnel. Additional vital sign measurements will be taken after the subject has 
been in a semi-recumbent position for a minimum of 3 minutes. All unscheduled vital sign 
measurements will be reported and transferred to the eCRF. 
Subjects will remain seated, except as otherwise required for study procedures or personal 
needs, for the first 4 hours after dosing. Should the need to move about occur during the first 
4 hours after each dose, subjects may be escorted to such procedures or activities by research 
personnel as deemed medically necessary. 
 Laboratory Procedures/Assessments 
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn/collected over the course of the trial 
(from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.3. 
 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5. 
Table 5 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Follicle stimulating hormone 
(FSH), if applicable 
Hemoglobin 
Alkaline phosphatase (ALP) 
Bilirubin 
Serum β-human chorionic 
gonadotropin (β-hCG) 
Platelet count 
Alanine aminotransferase (ALT) 
Glucose 
Hepatitis B surface antigen 
Red blood cell count 
Amylase 
Ketones 
Hepatitis C antibody 
WBC: 
total 
and 
differentials including: 
Absolute lymphocytes 
Absolute monocytes 
Absolute eosinophils 
Absolute basophils 
Absolute neutrophils 
Aspartate 
aminotransferase 
(AST) 
Leukocyte esterase Human 
immunodeficiency 
virus (HIV) 
Blood urea nitrogen (BUN) 
Nitrite 
Urine drug, cotinine, and 
alcohol screen 
(amphetamines, 
benzodiazepines, 
barbiturates, 
cannabinoids, 
cocaine, opiates, cotinine, 
alcohol) 
Bicarbonate 
pH 
Bilirubin, direct 
Protein 
 
Bilirubin, total 
Specific gravity 
International 
normalized 
ratio (INR) 
 
Calcium (Ca) 
Urobilinogen 
 
 
Chloride (Cl+) 
Microscopic exam, 
if abnormal results 
are noted  
 
Creatinine 
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Hematology 
Chemistry 
Urinalysis 
Other 
 
Creatinine phosphokinase (CPK) 
 
 
 
Gamma glutamyl transpeptidase 
(gGT) 
 
 
 
Glucose 
 
  
 
Lactate dehydrogenase (LDH) 
 
 
 
Lipase 
 
 
 
Phosphorus 
 
 
 
Potassium (K+) 
 
  
 
Protein, total 
 
 
 
Sodium (Na+) 
 
  
  
Laboratory safety tests will be performed after at least an 8-hour fast.   
 Pharmacokinetic/Pharmacodynamic Evaluations 
7.1.3.2
The decision as to which plasma and/or urine samples collected will be assayed for 
evaluation of PK/PD will be collaboratively determined by the Department of Quantitative 
Pharmacology and Pharmacometrics (QP2) and the appropriate department within Early-
Stage Development, (e.g., samples at lower doses may not be assayed if samples at higher 
doses reveal undetectable drug concentrations).  If indicated, these samples may also be 
assayed and/or pooled for assay in an exploratory manner for metabolites and/or additional 
PD markers. 
7.1.3.2.1 Blood Collection for Plasma MK-3866 
For all subjects, blood samples for the determination of MK-3866 plasma concentration will 
be collected and processed at scheduled time points as delineated in the Study Events Flow 
Chart (Section 6.0).  
Instructions for blood sampling, collection, processing, and sample shipment for MK-3866 
will be provided in the Study Operations Manual. 
7.1.3.2.2 Urine Collection for Urinary MK-3866 
Prior to the predose sample, each subject will be instructed as to urine collection methods.  
Urine samples for determination of MK-3866 concentrations will be collected at over 
selected intervals as outlined in the Study Events Flow Chart (Section 6.0). 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-3866, 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 
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encouraged to void their bladder again to complete the collection. If they do void at any time 
during the collection interval, the 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. 
Instructions for urine sampling, collection, processing, and sample shipment for MK-3866 
will be provided in the Study Operations Manual. 
 Planned Genetic Analysis Sample Collection 
7.1.3.3
Instructions for Planned Genetic Analysis sampling, collection, processing, and sample 
shipment will be provided in the Study Operations Manual. 
 Future Biomedical Research Samples 
7.1.3.4
The following specimens are to be obtained as part of Future Biomedical Research: 
• DNA for future research 
 Other Procedures 
7.1.4
 Withdrawal/Discontinuation 
7.1.4.1
The investigator or trial coordinator must notify the Sponsor when a subject has been 
discontinued/withdrawn from the trial.  If a subject discontinues for any reason at any time 
during the course of the trial, the subject may be asked to return to the clinic (or be 
contacted) for a post-trial visit (approximately 14 days after the last dose of trial drug is given 
to have the applicable procedures conducted.  However, the investigator may decide to 
perform the post-trial procedures at the time of discontinuation or as soon as possible after 
discontinuation.  If the post-trial visit occurs prior to 14 days after the last dose of trial drug 
is given, the investigator should perform a follow-up phone call 14 days after the last dose of 
trial drug to determine if any adverse events have occurred since the post-trial clinic 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 7.2 - Assessing and 
Recording Adverse Events. 
7.1.4.1.1 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 (clinical.specimen.management@merck.com).  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 
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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. 
7.1.4.1.2 Lost to Follow-up 
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed: 
• The site must attempt to contact the subject and reschedule the missed visit..  If 
the subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule. 
• The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g. phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record. 
• Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines. 
 Subject Blinding/Unblinding 
7.1.4.2
This is an open label trial; there is no blinding for this trial. 
 Domiciling 
7.1.4.3
Subjects will report to the clinical research unit (CRU) the evening two days prior to the 
scheduled day of trial drug administration. Subjects who are enrolled in Panels A and B 
(subjects with HI) will remain in the unit until at least 72 hours post-dose. Subjects who are 
enrolled in Panel C (healthy control subjects) will remain in the unit until at least 24 hours 
post-dose.   At the discretion of the investigator, subjects may be requested to remain in the 
CRU longer. 
 Calibration of Critical Equipment 
7.1.4.4
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site. 
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Critical equipment for this trial includes: IV pumps, vital sign machines, ECG machines, 
scales, centrifuges, refrigerators, and freezers. 
 Visit Requirements 
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 Screening 
7.1.5.1
Approximately 28 days prior to treatment allocation/randomization, potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1. 
Subjects with HI who do not qualify based on a reversible condition or mild intercurrent 
illness may be rescreened after the underlying condition is resolved. Rescreening should 
include all screening procedures listed in the protocol flow chart, including consent review. 
Rescreen procedures cannot be conducted the day prior to treatment allocation if there are 
Day -2/Day -1 procedures planned per protocol. 
 Treatment Period 
7.1.5.2
A single IV dose of MK-3866 will be administered on Day 1. 
 Discontinued Subjects Continuing to be Monitored in the Trial 
7.1.5.3
If the subject discontinues, the subject will be asked to return to the clinic for the end-of-trial 
assessment. Any adverse events which are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 7.2. 
 Post-Trial 
7.1.5.4
Subjects will be required to return to clinic approximately 14 days after the last dose of trial 
drug for the post-trial visit.  If the post-trial visit occurs less than 14 days after the last dose 
of trial drug, a subsequent follow-up phone call should be made at 14 days post the last dose 
of trial drug to determine if any adverse events have occurred since the post-trial clinic visit. 
 Critical Procedures Based on Trial Objectives: Timing of Procedure  
7.1.5.5
For this trial, the PK blood sample for MK-3866 is the critical procedure.  
At any post-dose timepoint, the PK blood sample MK-3866 needs to be collected as close to 
the exact timepoint as possible.  All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Trial procedures can be performed prior or after the 
prescribed/scheduled time.   
The order of priority can be changed during the trial with joint agreement of the investigator 
and the Sponsor Clinical Director.   
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.   
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The following variance in procedure collection times will be permitted. 
• PK collection as outlined in Table 6 below 
Table 6 Pharmacokinetic Collection Windows 
Collection Time 
Collection Window 
0-1 hour 
±5 minutes 
˃1 hour 
±15 minutes 
˃24 hours 
±30 minutes 
• Predose standard safety evaluations:   
o Vital signs and ECG: ±3 hours 
o Laboratory safety tests and physical examinations: ±24 hours 
• Postdose standard safety evaluations (vital signs, ECG, laboratory safety tests, 
physical exam):  ±30 minutes 
 Trial Procedures Modifications Permitted within Protocol Parameters 
7.1.5.6
Up to additional 50 mL of blood may be drawn for safety, PK and/or PD analyses.  The total 
blood volume withdrawn from any single subject will not exceed the maximum allowable 
volume during his/her participation in the entire trial (Section 12.3).  
This is a Phase I assessment of MK-3866 in humans, and the PK, PD and safety profiles of 
the compound is still being elucidated.  This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of Phase I clinical trials.   
The timing of procedures for assessment of safety procedures (e.g., vital signs, ECG, safety 
laboratory tests, etc.) currently outlined in the protocol may be modified during the trial 
based on newly available safety, tolerability, PK or PD data (e.g., to obtain data closer to the 
time of peak plasma concentrations).  Additional laboratory safety tests may be added to 
blood samples previously drawn to obtain additional safety information (e.g., adding 
creatinine kinase to serum chemistry panel that was already drawn). These changes will not 
increase the number of trial procedures for a given subject during his/her participation in the 
entire trial.  
It is understood that the current trial may employ some or none of the alterations described 
above.  Any alteration made to this protocol to meet the trial objectives must be detailed by 
the Sponsor in a letter to the Trial File and forwarded to the investigator for retention.  The 
letter may be forwarded to the IRB/ERC at the discretion of the investigator. 
 
Assessing and Recording Adverse Events 
7.2
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 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
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symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use. 
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
For randomized subjects only, all adverse events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by investigator if they are the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. From the time of 
treatment allocation/randomization 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 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome. 
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). 
 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
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 non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.” 
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All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. 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). 
 Reporting of Pregnancy and Lactation to the Sponsor 
7.2.2
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 treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization 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). 
 Immediate Reporting of Adverse Events to the Sponsor 
7.2.3
 Serious Adverse Events 
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that: 
● Results in death; 
● Is life threatening; 
● Results in persistent or significant disability/incapacity; 
● Results in or prolongs an existing inpatient hospitalization; 
● Is a congenital anomaly/birth defect; 
● Is an 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 SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes. 
● Is a cancer; 
● Is associated with an overdose. 
Refer to Table 7 for additional details regarding each of the above criteria. 
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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization 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. 
 Events of Clinical Interest 
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization 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). Events of clinical interest for this trial include: 
1.  an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, 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 must trigger 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
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and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
It may also be appropriate to conduct additional evaluation for an underlying etiology in 
the setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and 
alkaline phosphatase that do not meet the criteria noted above. In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this trial. 
 Evaluating Adverse Events 
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 7. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 7 for instructions in evaluating adverse events. 
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Table 7 Evaluating Adverse Events 
 
Maximum 
Mild 
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated) 
Intensity 
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 (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that: 
 
†Results in death; or 
 
†Is 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 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.  (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or 
 
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or 
 
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Sponsor's product to be discontinued? 
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 AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test 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 AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the 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 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
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Relationship 
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued) 
to Sponsor's 
Product 
(continued)  
Dechallenge 
Was the Sponsor's product discontinued or dose/exposure/frequency reduced? 
      If yes, did the AE resolve or improve? 
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge. 
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the 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 AE recur or worsen? 
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge. 
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the 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 SPONSOR 
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the 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). 
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship. 
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.  
No, there is not a reasonable 
possibility of Sponsor's product 
relationship 
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.) 
 
  
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 Sponsor Responsibility for Reporting Adverse Events  
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.  
8.0 STATISTICAL ANALYSIS PLAN 
 
Statistical Analysis Plan Summary 
8.1
 Source of Variance Estimates: Precision and Sample Size  
8.1.1
The sample size selected for each population to evaluate the effect of HI on the PK of 
MK-3866 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 estimates of ratios of geometric means 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 estimated between-subject variance for log 
AUC0-∞ is 0.0196 log ngƎhr/mL from a previous study (PN001). Since the between subject 
variability in severe hepatic insufficient subjects is usually higher in many studies, the 
between subject variability obtained from healthy were inflated by a factor of 2 for severe 
hepatic insufficient subjects and was used for the following calculations. With 6 hepatic 
insufficient subjects and 6 healthy matched subjects, the half-width of the 90% confidence 
interval for the arithmetic mean AUC0-∞ on the log scale will be 0.179 log ng•hr/mL. The 
lower and upper 90% confidence limits for the true ratio of geometric meansr will be given 
by OBS/1.163 and OBS x 1.197, where OBS is the observed ratio of geometric means.  Thus, 
for example, if the observed ratio of geometric means was 1.5, the 90% confidence interval 
would be (1.25, 1.79).  
 Statistical Core Methods:  
8.1.2
 Primary PK Analysis 
8.1.2.1
Separately for each pharmacokinetic parameter, individual values of AUC0-∞, AUC0-last, 
AUC0-24, Ceoi, and CL will be natural log-transformed and evaluated with a linear fixed 
effects model containing a categorical effect for populations. 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.  
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To compare subjects with HI in each of the hepatic insufficient categories (moderate HI and 
severe HI) to matching subjects with normal hepatic function, a two sided 90% confidence 
interval for the true difference in means (HI – normal hepatic function) will be calculated for 
each PK parameters (AUC0-∞, AUC0-last, AUC0-24, Ceoi, and CL) using the mean square 
error from the model and referencing a t-distribution. For each of the HI populations, these 
confidence limits will be exponentiated to obtain the 90% confidence interval for the true 
ratio of geometric means (HI/normal hepatic function) for each pharmacokinetic parameter. 
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, 
AUC0-24, Ceoi, and CL. 
Individual values will be listed for each PK parameter (AUC0-∞, AUC0-last, AUC0-24, 
Ceoi, Tmax, CL, Vz, and apparent terminal t½) 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). 
 Secondary PK Analysis 
8.1.2.2
8.1.2.2.1 Objective 1 
Separately for each urine pharmacokinetic parameter, individual values of fe and CLr will be 
natural log-transformed and evaluated with a linear fixed effects model, which is described in 
the primary analysis. Ninety-five percent (95%) confidence intervals for the least squares 
means for each population will be constructed. To compare subjects with HI in each of the 
hepatic insufficient categories (moderate HI and severe HI) to matching subjects with normal 
hepatic function, a two sided 90% confidence interval for the true difference in means (HI – 
normal hepatic function) will be calculated for each urine PK parameters (fe and CLr).  
Individual values will be listed for each urine PK parameter (fe and CLr) by population, and 
non model-based descriptive statistics will be provided 
8.1.2.2.2 Objective 2 
The safety and tolerability of MK-3866 will be evaluated by clinical assessment of adverse 
experiences and other safety measurements. Summary statistics for the laboratory safety 
tests, ECGs, and/or vital signs may also be provided, as deemed clinically appropriate. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
Investigational Product  
9.1
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 
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investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by the Sponsor as summarized in Table 8. 
Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3866 180 mg 
Lyophilized Powder for Injection 
 
MK-3866 clinical supplies will be supplied as a sterile lyophilized powder to be reconstituted 
and diluted in saline for IV infusion. The lyophilized powder will be reconstituted at the 
CRU with 12 mL of 0.9% sodium chloride for injection (normal saline) in the original vial to 
make a stock solution that is further diluted with saline to accommodate the study protocol 
dose of 150 mg. 
 
Packaging and Labeling Information 
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
Clinical Supplies Disclosure 
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. MK-3866 IV infusion is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
 
Storage and Handling Requirements 
9.4
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. 
 
Discard/Destruction/Returns and Reconciliation 
9.5
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. 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 Confidentiality 
10.1
 Confidentiality of Data 
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol. 
 Confidentiality of Subject Records 
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor. 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations. 
 Confidentiality of Investigator Information 
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include: 
1. name, address, telephone number and e-mail address; 
2. hospital or clinic address and telephone number; 
3. curriculum vitae or other summary of qualifications and credentials; and 
4. other professional documentation. 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures. 
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request. 
 Confidentiality of IRB/IEC Information 
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies. 
 Compliance with Financial Disclosure Requirements 
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.   
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data. 
 Compliance with Law, Audit and Debarment 
10.3
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 Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 - 
Merck Code of Conduct for Clinical Trials. 
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. 
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.   
ICH Good Clinical Practice 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. 
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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 [Clinical Study 
Report (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. 
 Compliance with Trial Registration and Results Posting Requirements 
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries. 
 Quality Management System 
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, 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. 
 Data Management 
10.6
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. 
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately. 
 Publications 
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later. 
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information. 
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript. 
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript. 
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines. 
11.0 LIST OF REFERENCES 
None 
 
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12.0 APPENDICES 
 Merck Code of Conduct for Clinical Trials 
12.1
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, 
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.  
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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.   
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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 Collection and Management of Specimens for Future Biomedical Research 
12.2
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 7.1.3.4 – 
Future Biomedical Research Samples will be used in various experiments to understand: 
o The biology of how drugs/vaccines work 
o Biomarkers responsible for how a drug/vaccine enters and is removed by the body 
o Other pathways drugs/vaccines may interact with 
o 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 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 
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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. eCRF Documentation for Future Biomedical Research Specimens 
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed. 
d. Future Biomedical Research Specimen(s) 
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the 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. 
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 
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records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
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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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 
clinical.specimen.management@merck.com. 
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; 
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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 Approximate Blood Volumes Drawn by Trial Visit and by Sample Types 
12.3
Panels A and B 
Pre-trial 
Treatment Period 
Post-trial 
Total 
Collections 
mL Per 
Collection 
Total mL/ 
Test 
Laboratory safety tests 
  
1 
3 
1 
5 
12.5 
62.5 
HIV/Hepatitis Screen (at 
the discretion of the 
investigator) 
  
1 
- 
- 
1 
5.0 
5.0 
Blood for Planned Genetic 
Analysis  
- 
1 
- 
1 
8.5 
8.5 
Blood (plasma) for 
MK-3866 
- 
15 
- 
15 
6.0 
90.0 
Total Blood Volume Per Subject for Panels A and B† 166.0 mL 
* Pre-trial laboratory safety tests will include serum β-hGC testing for all females and follicle-stimulating 
hormone (FSH) testing for post-menopausal females 
† If additional pharmacokinetic and/or safety analysis is necessary, additional blood (up to 50 mL) may be 
obtained.   
 
Panel C 
Pre-trial 
Treatment Period 
Post-trial 
Total 
Collections 
mL Per 
Collection 
Total mL/ 
Test 
Laboratory safety tests* 
  
1 
2 
1 
4 
12.5 
50.0 
HIV/Hepatitis Screen (at 
the discretion of the 
investigator) 
  
1 
- 
- 
1 
5.0 
5.0 
Blood for Planned Genetic 
Analysis  
- 
1 
- 
1 
8.5 
8.5 
Blood (plasma) for 
MK-3866 
- 
14 
- 
14 
6.0 
84.0 
Total Blood Volume Per Subject for Panel C† 147.5 mL 
* Pre-trial laboratory safety tests will include serum β-hGC testing for all females and follicle-stimulating 
hormone (FSH) testing for post-menopausal females 
† If additional pharmacokinetic and/or safety analysis is necessary, additional blood (up to 50 mL) may be 
obtained.  
 
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13.0 SIGNATURES 
 Sponsor's Representative 
13.1
TYPED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED 
 
 Investigator 
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties. 
TYPED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED 
 
 
 
 
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14.0 APPENDIX 1 
 Child-Pugh Scale for the Assessment of Hepatic Impairment 
14.1
Parameter 
Score for Observed Findings 
1 
2 
3 
Encephalopathy Grade 
None 
1 or 2 
3 or 4 
Ascites 
Absent 
Slight 
Moderate to Severe 
Serum 
Bilirubin 
(mg/dL) 
˂2 
2–3 
˃3 
Serum Albumin (g/dL) 
˃3.5 
2.8–3.5 
˂2.8 
International 
Normalized 
Ratio 
(INR) 
˂1.7 
1.7–2.3 
˃2.3 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/angered, tremor, impaired handwriting, 5 cps waves 
Grade 2: lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity 
 
 
 
MK-3866-006 FINAL Protocol/Amendment 
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054MKJ