Conditions: Fungal Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics and safety of posaconazole intravenous solution in Chinese participants at high risk for invasive fungal infections. Neutropenic participants undergoing chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes will be enrolled in the study. The primary hypothesis is to evaluate the pharmacokinetic parameters of intravenous (IV) posaconazole (POS) solution in Chinese participants at high risk of invasive fungal infections and determine the percentage of Chinese participants who reach steady-state concentration averages of POS in blood plasma of 500 ng/ml and higher. Two subgroups were evaluated: Subgroup 1 from serial PK blood draw sampling and Subgroup 2 from sparse limited PK blood draw sampling.

Detailed description:

Arms:
arm 1: All participants will receive posaconazole 300 mg intravenous (IV) infusion twice on Day 1 followed by 300 mg IV infusion once daily on Days 2 to 10 (±1). At the discretion of the investigator, participants will received posaconazole 300 mg IV infusion once daily or 200 mg oral suspension three times daily for up to 18 additional days.

Interventions: intervention 1: Posaconazole
Intervention descriptions: intervention 1: Posaconazole 18 mg/mL IV solution; posaconazole 40 mg/mL oral suspension

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03336502
Document Date: 
24-Jul-2017
Pharmacokinetics and Safety of Intravenous Posaconazole 
(MK-5592, POS) in Chinese Subjects at High Risk for Invasive 
Fungal Infections


Product:  MK-5592 
1
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
THIS PROTOCOL 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, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
Pharmacokinetics and Safety of Intravenous Posaconazole (MK-5592, POS) in Chinese 
Subjects at High Risk for Invasive Fungal Infections
IND NUMBER:  Not Applicable
EudraCT NUMBER:  Not Applicable 
 
 
04Q460


Product:  MK-5592 
2
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................... 9
2.0
TRIAL DESIGN.......................................................................................................... 9
Trial Design ............................................................................................................. 9
2.1
Trial Diagram........................................................................................................ 10
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 10
Primary Objective(s) & Hypothesis(es) .............................................................. 10
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 10
3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 11
Background ........................................................................................................... 11
4.1
Pharmaceutical and Therapeutic Background .................................................... 11
4.1.1
Rationale................................................................................................................ 13
4.2
Rationale for the Trial and Selected Subject Population .................................... 13
4.2.1
Rationale for Dose Selection/Regimen............................................................... 13
4.2.2
4.2.2.1
Starting Dose for This Trial ......................................................................... 14
4.2.2.2
Maximum Dose/Exposure for This Trial..................................................... 14
4.2.2.3
Rationale for Dose Interval and Trial Design .............................................. 14
Rationale for Endpoints ...................................................................................... 14
4.2.3
4.2.3.1
Pharmacokinetic Endpoints ......................................................................... 14
4.2.3.2
Safety Endpoints .......................................................................................... 15
4.2.3.3
Efficacy Endpoints....................................................................................... 15
4.2.3.4
Future Biomedical Research........................................................................ 16
Benefit/Risk ........................................................................................................... 16
4.3
5.0
METHODOLOGY ................................................................................................... 17
Entry Criteria........................................................................................................ 17
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 17
5.1.1
Subject Inclusion Criteria.................................................................................... 17
5.1.2
Subject Exclusion Criteria .................................................................................. 18
5.1.3
Trial Treatment(s) ................................................................................................ 21
5.2
Dose Selection/Modification .............................................................................. 22
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 22
 
 
04Q460


Product:  MK-5592 
3
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Timing of Dose Administration.......................................................................... 22
5.2.2
Trial Blinding/Masking....................................................................................... 22
5.2.3
Randomization or Treatment Allocation............................................................ 23
5.3
Stratification.......................................................................................................... 23
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 23
5.5
Rescue Medications & Supportive Care............................................................. 23
5.6
Diet/Activity/Other Considerations..................................................................... 23
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 23
5.8
Subject Replacement Strategy............................................................................. 24
5.9
Beginning and End of the Trial ........................................................................... 24
5.10
Clinical Criteria for Early Trial Termination ................................................... 24
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 25
7.0
TRIAL PROCEDURES ........................................................................................... 28
Trial Procedures ................................................................................................... 28
7.1
Administrative Procedures.................................................................................. 28
7.1.1
7.1.1.1
Informed Consent......................................................................................... 28
7.1.1.1.1
General Informed Consent.................................................................... 28
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 28
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 29
7.1.1.3
Subject Identification Card .......................................................................... 29
7.1.1.4
Medical History ........................................................................................... 29
7.1.1.5
Prior and Concomitant Medications Review ............................................... 29
7.1.1.5.1
Prior Medications.................................................................................. 29
7.1.1.5.2
Concomitant Medications..................................................................... 29
7.1.1.6
Assignment of Screening Number............................................................... 30
7.1.1.7
Assignment of Randomization Number....................................................... 30
7.1.1.8
Trial Compliance (Assignment of Allocation Number/ Medication/Diet) .. 30
Clinical Procedures/Assessments........................................................................ 31
7.1.2
7.1.2.1
Physical Examination................................................................................... 31
7.1.2.2
Height, Weight and BMI.............................................................................. 31
7.1.2.3
12-Lead ECG ............................................................................................... 31
 
 
04Q460


Product:  MK-5592 
4
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
7.1.2.4
Vital Sign Measurements (Heart Rate, Blood Pressure, Respiratory Rate 
and Temperature)......................................................................................... 32
7.1.2.5
Clinical Signs and symptoms of IFI............................................................. 32
7.1.2.6
Radiological Tests........................................................................................ 32
7.1.2.7
Infusion Site Examination............................................................................ 32
7.1.2.8
Survival Assessment .................................................................................... 32
Laboratory Procedures/Assessments .................................................................. 32
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 33
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 33
7.1.3.2.1
Blood Collection for Plasma MK-5592................................................ 33
7.1.3.3
Future Biomedical Research........................................................................ 34
Other Procedures................................................................................................. 34
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 34
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 34
7.1.4.2
Blinding/Unblinding .................................................................................... 34
7.1.4.3
Domiciling ................................................................................................... 35
7.1.4.4
Calibration of Critical Equipment................................................................ 35
Visit Requirements.............................................................................................. 35
7.1.5
7.1.5.1
Screening...................................................................................................... 35
7.1.5.2
Treatment Period Visit................................................................................. 35
7.1.5.3
Post-Trial...................................................................................................... 36
7.1.5.4
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 36
7.1.5.5
Trial 
Design/Dosing/Procedures 
Modifications Permitted 
within 
Protocol Parameters ..................................................................................... 37
Assessing and Recording Adverse Events .......................................................... 37
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 38
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 38
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 39
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 39
7.2.3.2
Events of Clinical Interest............................................................................ 39
Evaluating Adverse Events ................................................................................. 40
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 43
7.2.5
 
 
04Q460


Product:  MK-5592 
5
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 43
Statistical Analysis Plan Summary ..................................................................... 43
8.1
Statistical Analysis Plan ....................................................................................... 43
8.2
Hypotheses/Estimation ....................................................................................... 43
8.2.1
Analysis Endpoints ............................................................................................. 44
8.2.2
Approaches to Analyses...................................................................................... 44
8.2.3
8.2.3.1
Pharmacokinetics ......................................................................................... 44
8.2.3.2
Safety ........................................................................................................... 45
8.2.3.3
Sample Size.................................................................................................. 45
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 46
Investigational Product ........................................................................................ 46
9.1
Packaging and Labeling Information ................................................................. 46
9.2
Clinical Supplies Disclosure................................................................................. 46
9.3
Storage and Handling Requirements.................................................................. 46
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 46
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 47
Confidentiality....................................................................................................... 47
10.1
Confidentiality of Data ....................................................................................... 47
10.1.1
Confidentiality of Subject Records ..................................................................... 47
10.1.2
Confidentiality of Investigator Information........................................................ 47
10.1.3
Confidentiality of IRB/IEC Information............................................................. 48
10.1.4
Compliance with Financial Disclosure Requirements....................................... 48
10.2
Compliance with Law, Audit and Debarment ................................................... 48
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 50
10.4
Quality Management System............................................................................... 50
10.5
Data Management................................................................................................. 50
10.6
Publications ........................................................................................................... 51
10.7
11.0
LIST OF REFERENCES......................................................................................... 52
12.0
APPENDICES........................................................................................................... 53
Merck Code of Conduct for Clinical Trials........................................................ 53
12.1
 
 
04Q460


Product:  MK-5592 
6
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 55
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 61
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................... 70
Algorithm for Assessing Out-of-Range Laboratory Values ............................. 71
12.5
POS IV Solution Preparation and Administration............................................ 72
12.6
MK-5592 Plasma Assays—Sample Collection, Handling, Labeling, 
12.7
Storage, and Shipment ......................................................................................... 74
Defining 
Opportunistic 
Invasive 
Fungal 
Infections 
(European 
12.8
Organization for Research and Treatment of Cancer/Invasive Fungal 
Infections Cooperative Group, National Institute of Allergy and Infectious 
Diseases Mycoses Study Group) .......................................................................... 76
ECOG Performance Status.................................................................................. 85
12.9
Product Circular of Posaconazole Oral Suspension.......................................... 86
12.10
List of Abbreviations .......................................................................................... 115
12.11
13.0
SIGNATURES......................................................................................................... 117
Sponsor's Representative ................................................................................... 117
13.1
Investigator.......................................................................................................... 117
13.2
 
 
04Q460


Product:  MK-5592 
7
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
LIST OF TABLES
Table 1 Prohibited Medications Prior to Start of Study Treatment and During Study 
Treatment .................................................................................................................... 20
Table 2 Trial Treatment .......................................................................................................... 21
Table 3 Laboratory Tests ........................................................................................................ 33
Table 4 Evaluating Adverse Events........................................................................................ 41
Table 5 PK Parameters Based on Previous Studies................................................................ 45
Table 6 Product Descriptions.................................................................................................. 46
 
 
04Q460


Product:  MK-5592 
8
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
LIST OF FIGURES
Figure 1 Study Design ............................................................................................................ 10
 
 
04Q460


Product:  MK-5592 
9
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
Pharmacokinetics and Safety of Intravenous Posaconazole (MK-5592, 
POS) in Chinese Subjects at High Risk for Invasive Fungal Infections
Trial Phase
Phase I b
Clinical Indication
Prophylaxis of invasive fungal infections
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Only one treatment regimen
Number of trial subjects
Approximately 70 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 10
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 84 days
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of 14 days, each 
subject will be receiving POS intravenous (IV) solution 300 mg Q12h
on Day 1, followed by 300 mg QD on Day 2 through 10 (±1) via 
central line administration. Then, subjects will receive IV solution 300 
mg QD or oral suspension 200 mg TID for up to 18 (±1) days at the 
discretion of investigator. The total treatment duration is at least 10
(±1) days to up to 28 days. After the end of treatment (EOT) each 
subject will be followed for 30 days for safety. Also, subjects will 
have a survival assessment at any day from Days 60 to 70.
A list of abbreviations used in this document can be found in Section 12.11.
2.0 TRIAL DESIGN
Trial Design
2.1
This is an open-label, single arm, multi-center, and two sub-groups trial of MK-5592 in 
Chinese Subjects at High Risk for Invasive Fungal Infections (IFIs) to be conducted in 
conformance with Good Clinical Practices.
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.
 
 
04Q460


Product:  MK-5592 
10
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Trial Diagram
2.2
This is an open-label, single arm, multi-center study with two sub-groups. At least 3 
investigative sites in China will be selected for this study.
Subjects will be allocated to one treatment group with same treatment regimen; while there 
will be 2 subgroups for different pharmacokinetic sampling schemes as indicated below 
(Figure 1, Trial Design). Approximately 30 subjects will be allocated to subgroup 1, and 
about 40 subjects will be allocated to subgroup 2. The two subgroups will receive same 
treatment but different blood sample collection schemes in order to characterize the 
pharmacokinetics in the whole study population. 
After a screening phase of 14 days, each subject will receive POS intravenous (IV) solution 
300 mg Q12h on Day 1, followed by 300 mg QD on Day 2 through 10 (±1) via central line 
administration. Then, subjects will receive IV solution 300 mg QD or oral suspension (OS) 
200 mg TID for up to 18 (±1) days at the discretion of investigator. The investigator could 
switch the subject back to POS IV solution treatment during oral treatment period if the 
subject is unable to tolerate oral suspension. The total treatment duration is at least 10 (±1)
days to up to 28 days. After the end of treatment (EOT), each subject will be followed for 30 
days for safety.  A survival assessment will be performed on any day from Days 60 to 70. 
The trial design is depicted in Figure 1.
Figure 1 Study Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
Objective: To characterize the pharmacokinetics of POS IV solution in Chinese subjects at
high risk for invasive fungal infections.
Hypothesis: The pharmacokinetics parameters (e.g., steady-state Cavg, AUC0-24hr) of POS IV 
solution in Chinese subjects at high risk of invasive fungal infections will be estimated.  
Percentage of Chinese subjects with steady-state Cavg ≥500 ng/ml will be estimated.
Secondary Objective(s) & Hypothesis(es)
3.2
Objective: To evaluate the safety and tolerability of POS IV solution in Chinese subjects at 
high risk for invasive fungal infection.
 
 
04Q460


Product:  MK-5592 
11
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-5592.
Pharmaceutical and Therapeutic Background
4.1.1
Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in patients 
receiving treatment for hematologic disease. In particular, patients with prolonged 
neutropenia and/or severe immunosuppression are at increased risk. 
MK-5592, or Posaconazole (POS), a broad-spectrum triazole antifungal compound 
discovered by Merck Research Laboratories, exhibits potent antifungal activity against a 
variety of yeasts and molds, including strains that are resistant to amphotericin B (AMB), 
fluconazole (FLZ), voriconazole (VOR), or itraconazole (ITZ). The mechanism of action, 
selective inhibition of the α-C14 demethylase (a member of CYP P450 cytochrome system; 
CYP51A) involved in ergosterol biosynthesis of yeast and filamentous fungi, is similar to 
that of the other azoles. Therefore, POS has an important role in the prophylaxis and 
treatment of IFIs against Aspergillus, Candida, Zygomycetes and Fusarium infections [1].
POS IV solution was approved (Noxafil IV) for prophylaxis of patients with high risk of IFIs 
by FDA in Mar-2014, and also approved by EMA in Sep-2014.
In EU and US, the POS IV solution was approved by bridging with oral suspension.  A Phase 
1B/3 study (Study P05520) [2] was conducted as a PK and safety bridging study and sought 
to bridge to exposures within the pre-defined target exposure range previously found to be 
safe and efficacious  based on trials of POS oral suspension.  Based on the exposure-response 
relationship found in earlier controlled studies of POS oral suspension in the prophylaxis of 
IFI setting (C/I98 -316 and P01899) as well as the studies that were conducted in the 
refractory IFI setting (P00041), with higher exposures associated with a higher likelihood of 
clinical response, clinical response was greater with increasing exposure to POS, with 
responses of >70% in the highest quartile (4th quartile) of exposure. By contrast, no 
association was demonstrated with high concentrations of POS and adverse experiences in 
the previous POS oral suspension controlled studies. The ranges of desirable exposure agreed 
with FDA/EMA as shown below:

Mean steady-state Cavg of approximately 1,200 ng/mL, with at least 90% of the subjects
between 500 ng/mL and 2,500 ng/mL.

No subject with Cavg at steady-state above 3,650 ng/mL.

No subject with Cavg at steady-state below 200 ng/mL.
To support the bridging concept, a population PK model was developed including the data 
from the 3 healthy volunteer studies (P04985, P06356 and P07783) and 1 study in high-risk 
subjects (P05520) for simulation purposes and calculation of the relevant exposure 
parameters (AUCτ, Cavg, and Cmin).  Simulations with the population PK model indicated that 
after once-daily maintenance administration of 300 mg POS IV solution (following Q12h
dosing on Day 1), 99.7% and 93.6% of the high-risk subjects have a Cavg and Cmin above 500 
 
 
04Q460


Product:  MK-5592 
12
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
ng/mL, respectively, thereby achieving exposures that are known to be effective and well 
tolerated as prophylaxis against IFIs. 
Based on previous knowledge of pharmacokinetic profile and its metabolism pathway, there 
is no apparent ethnic difference in pharmacokinetics of POS. Similar bridging strategies will 
be used in this project. 
POS was developed initially as an oral suspension. The oral POS suspension (Noxafil®) is a 
white, opaque, immediate release, formulation with a concentration of 40 mg/mL, which was 
launched in China in June 2013. It is known that the absorption of POS after oral 
administration is relatively low and less predictable, especially in patients who are fasting or 
who have limited oral intake due to gastrointestinal diseases such as diarrhea or 
chemotherapy-induced mucositis.  The exposure of POS oral suspension is influenced by 
food, and high fat food could increase the exposure of oral suspension. Exposure to 
posaconazole oral suspension after a single dose was increased by about 2.6-fold when given 
with a nutrient supplement and by about 4-fold when given with a high-fat meal.  
Since the efficacy of POS could be limited by the extent of exposures and sick patients are 
not reliably taking sufficient food to boost the exposure of POS, new IV formulations of POS 
have been developed to achieve a higher, more predictable exposure with reduced variability 
compared to POS oral suspension. POS IV solution is an aqueous injectable solution 
containing 18 mg/mL of POS to be diluted in 5 % dextrose in water or sodium chloride 0.9%
prior to IV administration. The primary excipient in POS IV Solution is sulfobutylether-β-
cyclodextrin (SBEβCD). The new IV formulations are administered as once daily (QD). 
Phase Ib studies have been conducted in Caucasian patients treated with POS IV solution 
given as antifungal prophylaxis. In Caucasian patients, the mean steady-state Cavg exposure 
for POS IV solution 300 mg QD was 1500 ng/ml. With this new formulation, the desired 
exposure target (steady-state Cavg around 1200 ng/mL) was more consistently achieved. This 
target concentration is associated with a higher response rate in subjects with invasive
aspergillosis [2].
Besides posaconzole, IV formulation of other antifungal agent (such as itraconazole) has also 
been developed to show the benefits of IV formulation in the prophylaxis of IFIs. The PK 
studies of itraconazole show that the bioavailability of IV formulation is better than capsule 
and oral solution, and could achieve the desired steady plasm drug concentration more 
quickly [3]. Clinical studies of itraconazole show that the IV formulation could use for the 
treatment and prophylaxis of IFI [4, 5] and could be used as sequential therapy. Traditionally, 
the treatment or prophylaxis of bacterial infections and IFI is initially with intravenous 
therapy, followed by physician-directed switch to oral therapy. Also, the cost-effectiveness of 
sequential therapy is better than oral therapy alone. Therefore, the sequential therapy of 
antifungal agent has been used widely in clinics. In China, some studies show that the 
prophylactic effect of sequential therapy of itraconazole for Prophylaxis of IFI is better than 
systemic antifungal therapy alone, and the adverse events did not increase [6].
 
 
04Q460


Product:  MK-5592 
13
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
To support China registration of IV solution, PK in Chinese needs to be characterized. 
Similar with global registration strategies, China registration strategy will also use a 
population PK study to establish the exposure in Chinese and bridge with previously 
established exposures of POS oral suspension as basis for approval. The subjects in this 
population PK study will be the subjects with high risk of IFIs due to being severely 
immunocompromised, such as those with hematologic malignancies with prolonged 
neutropenia from chemotherapy. This population are the future targeted population, and also 
are similar with the subjects in global IV pivotal study (i.e. P05520).  In China, a healthy 
volunteer PK study for oral suspension was conducted already, and the results are 
comparable with that in global studies. To support China registration of IV solution, a 
healthy volunteer PK (PN111) was finished, and a population PK study (PN120, i.e. this 
protocol) in prophylaxis population will be conducted.
In China, POS oral suspension has been approved for prophylaxis of invasive fungal 
infection. The patients at risk for invasive fungal infection include neutropenia. Neutropenic 
Chinese subjects between 18 to 70 (inclusive) years of age undergoing chemotherapy for 
acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) with high risk of 
IFIs will be enrolled in this study. This study population is consistent with the approved 
indication for the oral suspension.
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.
In this study, patients at risk for invasive fungal infection will be enrolled.  
Rationale for Dose Selection/Regimen
4.2.2
The objective of this study is to characterize the PK and safety profiles of POS IV Solution in 
Chinese subjects at high risk for invasive fungal infection. Global Phase Ib/III studies have 
been conducted in patients (AML/MDS and HSCT) treated with POS IV solution given as 
antifungal prophylaxis. In the global phase 1b/III study, the two doses of POS have been 
investigated. The 300 mg dose was selected as the final clinical dose. Among 49 serial PK-
evaluable subjects treated with 300 mg dose of POS IV solution, 46 of 49 (94%) subjects 
attained steady-state Cavg between 500 ng/mL and 2500 ng/mL and 3 of 49 (6%) subjects 
attained steady-state Cavg between 2500 ng/mL and 3650 ng/mL. None of these 49 subject’s 
steady-state Cavg was below 500 ng/mL or exceeded 3650 ng/mL. These exposure data are 
within desirable ranges to be efficacious and safe. The safety of the drug when given to all 
subjects was closely evaluated. POS IV solution at a dose of 300 mg QD (following 300 mg 
Q12h loading dose at Day 1) was well tolerated in this patient population and the safety 
profile seen in the study was similar to that previously reported for POS oral suspension [7].
The approved dose by FDA and EMA is 300 mg Q12h for the first day, and then 300 mg QD 
for the rest of the treatment therapy. This dosing regimen was evaluated in a Phase 1b/3 
study (P05520) designed to demonstrate that this dosing regimen could provide POS 
exposure within the pre-defined target exposure range as indicated above. Based on previous 
knowledge of pharmacokinetic profile and its metabolism pathway, there is no apparent 
 
 
04Q460


Product:  MK-5592 
14
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
ethnic difference in pharmacokinetics of POS IV expected. So the same dose and dose 
regimen as that approved in US and Europe has been selected for this study.  Also based on 
the physician’s judgment, the patients could also be switched to oral suspension or oral 
tablet. In China, only oral suspension formulation was approved, so in this study, the patients 
could be switched to oral suspension only.
4.2.2.1
Starting Dose for This Trial
Posaconazole has a half-life of approximately 30 hours. It may take 6-8 days to reach steady-
state. It is desirable to achieve therapeutic level promptly, so a loading dose of two times 300 
mg treatment on first day has been used for this study. 
4.2.2.2
Maximum Dose/Exposure for This Trial
The duration for this study is related to the duration at risk for invasive fungal infection. 
Twenty-eight days’ treatment duration was considered to be adequate to address the study 
objective and provide potential medical benefits for study subjects.
4.2.2.3
Rationale for Dose Interval and Trial Design
The pharmacokinetic profile of posaconazole supports its once daily dose interval and once 
daily dosing is also very desirable for better compliance.
There is no restriction on food intake for POS IV solution treatment. In this study, the follow 
up treatment could be oral suspension of POS, which was approved for prophylaxis of IFIs in 
China. For POS oral suspension administration, drug should be given under the guidance of 
physicians and local label and should be administered with food or immediately after eating 
(i.e., within 20 minutes). Based on prior study experiences, to achieve high exposure of POS 
oral suspension, high fat food would be recommended with dosing if the subjects could 
tolerate. The food intake information during oral suspension dosing period will be recorded 
in the study medication diary.
Considering the objective nature of study, an open label study is considered to be adequate to 
serve its purpose.
Rationale for Endpoints
4.2.3
4.2.3.1
Pharmacokinetic Endpoints
In this study, primary key parameter: Steady-state of Cavg, where Cavg is defined as AUC0-24hr
divided by the dosing interval.
Other parameters: Cmin, Cmax, Tmax, AUC0-24hr determined from plasma samples taken at 
steady-state as described under Study Procedures. In addition, the POS plasma concentration-
time data were to be used to estimate the following PK parameters, as the data allowed:
–
Cmin – POS trough level immediately before a subject receives the dose of POS IV 
solution on the day specified in the protocol.
–
Cmax – Observed maximum plasma concentration.
–
Tmax – Time of observed maximum plasma concentration.
 
 
04Q460


Product:  MK-5592 
15
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
–
AUC – Area under the plasma concentration versus time curve.
–
CL – Total body clearance.
Besides Cmin which could be observed from subgroup 2, all other observed parameters are 
from subgroup 1, and the rest parameters are calculated.
The time points for PK samples as below for each sub-group.
Subgroup 1/serial PK:
–
Blood samples for the determination of plasma trough POS levels will be drawn on 
Days 3, 6, 10 (±1), 15 (±1), 22 (±1), and 28 (or the end of treatment) for PK POS 
evaluation.
–
Additional PK samples will be drawn on Day 10 (±1) to further characterize 
additional PK parameters including AUC0-24hr.
–
PK Samples for sub-group 1 Subjects: Day 10 (±1) to be collected at pre-dose, 
1 hour post start of infusion, immediately before the end of infusion, 
approximately 15 minutes after the end of infusion, and approximate 4, 8, 12 
and 24 hours post start of infusion (Detailed information please refer Trial 
Flow Chart, Section 6).
Subgroup 2/sparse PK:
–
Blood samples for the determination of plasma trough POS levels will be drawn on 
Days 3, 6, 10 (±1), 15 (±1), 22 (±1), and 28 (or the end of treatment) for PK POS 
evaluation.
4.2.3.2
Safety Endpoints
Clinical evaluations including medical history, physical examinations, weight, height, 12-
lead electrocardiograms, vital signs, radiological tests and routine hematology, chemistry, 
and urinalysis will be performed.
Subjects will be assessed for adverse events (AEs). The rate of AE leading to discontinuation 
and medically significant changes in clinical laboratory tests will be listed and summarized.
Safety variables to be assessed include: AE, treatment-related AE, AE leading to 
discontinuation of study drug, serious adverse events (SAEs), treatment-related serious 
adverse events, and death. Safety will be assessed during the whole study, and serious 
adverse events will be reported for up to 30 days following completion of study therapy.
4.2.3.3
Efficacy Endpoints
Although the main objective for this study is to evaluate pharmacokinetics from subjects at 
high risk for IFI, we will also observe the clinical signs and symptoms of IFI during the 
whole study period; the physician can also add further test if an IFI is suspected based on the 
signs and symptoms.
Subjects will be evaluated for the presence of a fungal infection as per standard of care 
during the treatment of study. Possible, probable, or proven IFI events (per EORTC/MSG 
version 2008 criteria) [8] will be reported on the eCRF. If a possible, proven, or probable IFI 
 
 
04Q460


Product:  MK-5592 
16
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
is confirmed, or upon clinical judgment, the subject is to be discontinued from the study. 
Details regarding the evaluation of all clinical signs, symptoms, radiology results (e.g. CT or 
MRI) and other laboratory testing results (e.g. mycological results, including cytology, direct 
microscopy, or culture; and indirect testing, including β-D-glucan detected in serum or 
Galactomannan antigen detected in body fluids such as plasma, serum, bronchoalveolar 
lavage fluid, or cerebral spinal fluid) for the presence of a fungal infection (possible, 
probable, or proven IFI) should be documented. These lab tests should be pursued based on 
clinical judgment.
In addition, a survival assessment, if the subject is alive or dead, will be performed any da y 
from Days 60 to 70. If the subject dies, the date of death will be recorded. 
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA specimens collected 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 specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. 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.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
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.
 
 
04Q460


Product:  MK-5592 
17
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with high risk of invasive fungal infection between the ages of 18 and 
70 years (inclusive) will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Subject is a Chinese male or female residing in China and between 18 to 70 (inclusive) 
years of age at the pre-study (screening) visit.
Female subjects of reproductive potential must demonstrate a serum β-hCG level 
consistent with the nongravid state at the pre-study (screening) visit and agree to use 
(and/or have their partner use) two (2) acceptable methods of birth control beginning at 
the pre-study visit throughout the study and until 30 days after the last dose of study drug. 
Acceptable methods of birth control two (2) of the following: intrauterine device (IUD-
with or without local hormone release), diaphragm, spermicides, cervical cap, 
contraceptive sponge, and /or condoms. Abstinence is an alternative life style and 
subjects practicing abstinence may be included in the study.
Females of non-childbearing potential between 18 to 70 (inclusive) years of age at the 
pre-study (screening) visit may also be enrolled. A female of non- childbearing potential 
is defined as:
•
A female who is postmenopausal without menses for at least 1 year and an FSH value
in the postmenopausal range upon pre-study (screening) evaluation.
and/or
•
A female who is status post hysterectomy, bilateral oophorectomy or bilateral tubal
ligation.
•
Documented hysterectomy or bilateral oophorectomy must be confirmed with 
medical records of the actual procedure or confirmed by an ultrasound. Bilateral tubal 
ligation must be confirmed with medical records of the actual procedure otherwise the 
subject will be excluded. Information must be captured appropriately within the site's 
source documents.
2. Subject has a Body Mass Index (BMI) range of ≥15 and ≤30 kg/m2 (after rounding) at the 
pre-study (screening) visit. BMI is calculated by taking the subject’s weight in kg and 
dividing by the subject’s height in meters, squared. The subjects should weigh ≥40 and ≤ 
80 kg.
3. Each subject must have a central line catheter (Peripherally Central Venous Catheter is 
also acceptable) already in place as part of the standard of care for the subject’s
underlying disease.
 
 
04Q460


Product:  MK-5592 
18
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
4. Subject is anticipated (likely to develop within 3 days to 5 days) or documented 
prolonged neutropenia (absolute neutrophil count [ANC] <500/mm3 [0.5 x 109/L]) at 
baseline and likely to last for at least 7 days due to:
a.
Standard intensive induction chemotherapy, anthracycline-based or other accepted 
regimen (excluding any investigational agent), for a new diagnosis of acute 
myelogenous leukemia (AML);
b. Reinduction chemotherapy for AML in first relapse; or
c.
Myelosuppressive induction therapy for myelodysplastic syndromes (MDS) in 
transformation to AML or other diagnoses of secondary AML (therapy related, 
antecedent hematological disorders) other than chronic myelogenous leukemia in 
blast crisis
5. Each subject must be free of any clinically significant disease (other than the primary 
hematologic disease) that would interfere with the administration of study medication or 
study evaluations.
6. Each subject must be able to tolerate the administration of central IV solution medication.
7. Subject is willing to comply with the study restrictions.
8. Each subject must be willing and able to provide written informed consent for the trial. 
The legal representative for a subject who otherwise is unable to provide independent 
consent at the discretion of the investigator may provide written informed consent for the
subject. 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.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Subject is under the age of legal consent.
2. Female subject is pregnant, or has intended to become pregnant during the study, or is 
nursing.
3. Subject is mentally or legally incapacitated, has significant emotional problems at the 
time of pre-study (screening) visit or expected during the conduct of the study or has a 
history of a clinically significant psychiatric disorder over the last 5 years. Subjects who 
have had situational depression may be enrolled in the study at the discretion of the 
investigator.
4. Subject has received systemic antifungal therapy (oral, intravenous, or inhaled) within 30 
days of study enrollment for reasons other than antifungal prophylaxis.
5. A subject has known (including a possible, probable, or proven fungal infection per 
EORTC/MSG version 2008 criteria) [8] or suspected invasive or systemic fungal 
infection at Baseline.
6. Subject has taken posaconazole within 10 days prior to study enrollment.
 
 
04Q460


Product:  MK-5592 
19
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
7. Subject has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or 
participated in another investigational study within 4 weeks prior to the pre-study 
(screening). The 4 week window will be derived from the date of the last study procedure 
(i.e. post-study, AE follow-up, etc.) in the previous study to the pre-study/screening visit 
of the current study.
8. Subject has had a history of Type I hypersensitivity or idiosyncratic reactions to azole 
agents.
9. Subject has a history of significant multiple and/or severe allergies (including latex 
allergy), or has had an anaphylactic reaction or significant intolerability to prescription or 
non-prescription drugs or food.
10. Subject has had moderate or severe liver dysfunction at baseline, in this protocol defined 
as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater 
than three times the upper limit of normal (ULN), AND a total bilirubin level greater than 
two times the ULN.
11. Subject with chronic active hepatitis, cirrhosis, Hepatocellular Carcinoma (HCC), or 
other hepatic disease caused by virus.
12. Subject has had an ECG with a prolonged QTc interval by manual reading: QTc greater 
than 500 msec.
13. Excluded treatments prior to specific study phases. Subject has taken one of the following 
drugs listed in the Table 1 below more recently than the indicated washout period prior to 
study treatment.
14. Excluded treatments during the study treatment period. Subject has to take one of the 
following drugs that are listed in Table 1 during the study.
 
 
04Q460


Product:  MK-5592 
20
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Table 1 Prohibited Medications Prior to Start of Study Treatment and During Study 
Treatment
Prohibited Medications Prior to Start of Study Treatment and During Study 
Treatment
Washout Period a
Systemic antifungal therapy (oral, intravenous or inhaled) other than study drugs 
for reasons other than antifungal prophylaxis.
30 days
Investigational drugs (new chemical or biological entities): Investigational use of 
approved products or chemotherapy regimens may be permitted with the approval 
of the sponsor’s project physician prior to use.
30 days
Prophylaxis of IFI with posaconazole.
10 days
Medications that are known to interact with azoles and may lead to life-threatening 
side effects: astemizole, cisapride, ebastine, halofantrine, pimozide, quinidine, and 
terfenadine.
10 days (astemizole)
24 hours (others) 
Ergot alkaloids (ergotamine, dihydroergotamine or other licensed or investigational 
members of this class).
2 days
Medications known to lower the serum concentration/efficacy of azole antifungals: 
barbiturates, carbamazepine, cimetidine, isoniazid, phenytoin, rifabutin, rifampin, 
and St. John’s Wort (hypericum perforatum).
24 hours
Prophylactic use of nonabsorbable antifungal drugs: Nasal sprays of amphotericin 
B and aerosolized amphotericin B are prohibited.
24 hours
HMG-CoA reductase inhibitors metabolized via CYP3A4 (eg, simvastatin, 
lovastatin, and atorvastatin).
24 hours
Cyclophosphamide b
24 hours
a: These waiting times should be observed prior to start of study treatment and during study treatment in
subjects receiving a prohibited drug. No concurrent use is permitted. Deviations from these washout periods 
must be approved by the sponsor prior to use of study drug or prohibited agent.
b: Low dose cyclophosphamide use is allowed during the treatment period with a temporary interruption of
study therapy on the day of cyclophosphamide dosing.
HMG-CoA=beta-hydroxy-beta-methylglutaryl-CoA; IFI = invasive fungal infection
15. There is any concern by the investigator regarding the safe participation of the subject in 
the study, or for any other reason, the investigator considers the subject inappropriate for 
participation in the study. Subject has had any condition that, in the opinion of the 
investigator, may interfere with optimal participation in the study, i.e., any condition
requiring the use of prohibited drugs or unstable medical conditions other than the 
hematological disorder such as cardiac or neurologic disorder or impairment expected to 
be unstable or progressive during the course of this study (e.g., seizures or demyelinating 
syndromes, acute myocardial infarction within 3 months of study entry, myocardial 
ischemia, or unstable congestive heart failure, unstable arrhythmias, atrial fibrillation 
with ventricular rate <60/min, or history of torsades de pointes, symptomatic ventricular 
or sustained arrhythmias, unstable electrolyte abnormalities [e.g., ≥ Grade 2 
hypokalaemia or hypomagnesaemia]).
16. Subject has had prior enrollment in this study, or other POS studies within 90 days of 
study entry.
17. Subject has had an Eastern Cooperative Oncology Group (ECOG) [9] performance status 
>2 prior to induction chemotherapy for the subject’s underlying disease.
 
 
04Q460


Product:  MK-5592 
21
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
18. Subject has had a creatinine clearance level (measured or calculated) below 50 mL/min
based on the Cockcroft-Gault equation; the Cockcroft-Gault equation is as follows:
ClCr = (140-age[yr])(body wt [kg])*(0.85 if female)
(72)(serum creatinine [mg/dL])
When creatinine is measured in micromole/litre, use the following formula:
ClCr = (140-age[yr])(body wt[kg])*(0.85 if female)
              (72)(serum creatinine [micromol/L] x 0.0113)
19. Subject has known or suspected Gilbert’s disease.
20. Subject is or has an immediate family member (e.g., spouse, parent/legal guardian, 
sibling or child) who is investigational site or sponsor staff directly involved with this 
trial.
Trial Treatment(s)
5.2
MK-5592 IV solution to be used in this trial is outlined below in Table 2.
Table 2 Trial Treatment
Study Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
Regimen/Treatment 
Period
Use 
MK-5592
IV solution
300 mg
18 mg/mL
Q12h for the 
first day, and 
QD 
for 
the 
rest of the IV 
treatment
Intravenous
IV Treatment Phase: 
300 mg Q12h at Day 1 
and QD at day 2 - 10 
(±1)
IV or Oral Treatment 
Phase: Day 11 (±1) to 
Day 28 or EOT: 300 mg 
QD for up to 18 (±1) 
days (Based on the 
physician’s judgment)
NO control 
arm
MK-5592
oral 
suspension
200 mg
40 mg/mL
200 mg TID
Oral
Day 11 (±1)  to Day 28 
or EOT: 200 mg TID 
for up to 18 (±1)  days 
(Based 
on 
the 
physician’s judgment)
NO control 
arm
For POS IV solution administration, dosing will occur 300 mg Q12h on Day 1 via central 
line administration. Subsequent dosing will be performed 300
mg once daily at 
approximately the same time each day. 
For POS oral suspension administration, drug should be given under the guidance of 
physicians and local label and should be administered with food or immediately after eating 
(i.e., within 20 minutes). High fat meals will be recommended if applicable, since previous 
studies show that the exposure to POS oral suspension after a single dose was increased by 
about 4-fold when given with a high-fat meal compared with dosing in fasted state.
The study medication diary will be distributed to subjects when they receive oral suspension 
treatment and return to investigator at the visit of last dose.  Medication and food information 
 
 
04Q460


Product:  MK-5592 
22
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
during the POS oral suspension dosing period will be collected daily as indicated in the diary 
(Diary will be provided by 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/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The proposed dosing regimen of POS IV solution for the prophylaxis of invasive fungal 
infections is a loading dose of 300 mg Q12h on the first day, then 300 mg QD thereafter. 
Subject could be switched to oral suspension as 200 mg TID based on the judgment of 
physicians after the  intensive PK samplings are completed on Day 10 (±1 day).
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-5592 IV solution will be administrated through central line for approximately 90 
minutes, the residual volume, if any, should be documented. Subjects will have their IV 
infusions began at approximately the same time each day. The first three IV infusions must 
be given not less than 10 hours or no more than 14 hours apart. The subsequent IV infusions 
must be given not less than 22 hours or no more than 26 hours apart, in order to control one 
source of variability in drug levels. MK-5592 IV solution will be dosing without regard to 
food intake.
If the dosing of MK-5592 IV solution for the other days besides the day 1 is delayed, the 
dose of MK-5592 IV solution for the remaining days of the study should be taken following 
completion of the trough PK blood sampling (see flow chart for applicable study days) with 
at least 8 hours separating the prior day’s dosing. Every attempt should be made to ensure 
that the subject given study medication once daily following the Q12h dosing on Day 1.
If the treatment of the subject switches to POS oral suspension at the discretion of 
investigator from Day 11 (±1) to Day 28 or EOT, which occurs first. For subjects in 
subgroup 1, the intensive PK for POS IV solution must be obtained before switching to oral 
suspension. The oral suspension should be given under the guidance of physicians per local 
label. The POS oral suspension should be administered with food or immediately after eating 
(i.e., within 20 minutes). The investigator may switch the subject back to POS IV solution if 
the subject is unable to dose with food or tolerate oral medication. Subjects who vomit within 
30 minutes of POS oral administration should be given a single replacement dose as soon as 
possible or per guidance of the physician, following appropriate antiemetic treatment.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
 
 
04Q460


Product:  MK-5592 
23
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Randomization or Treatment Allocation
5.3
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Detailed information about prohibited medication please refers Section 7.1.1.5.
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
For POS IV solution administration, there is no restriction on food intake. POS oral 
suspension should be administered with food or immediately after eating (i.e., within 20 
minutes), and the food intake information during oral suspension dosing period will be 
recorded on the study medication diary. Alcohol and caffeine are prohibited on Day 10 (±1)
for subject in subgroup 1.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”. Once a subject is discontinued, he/she shall not 
be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Documentation of a fungal infection (proven, probable or possible IFI) according to 
the European Organization for Research and Treatment of Cancer/Invasive Fungal 
Infections and the National Institute of Allergy and Infectious Diseases Mycoses 
Study Group (EORTC-MSG version 2008) criteria [8];

Subjects with a prolonged QTc interval on a manual measurement (QTc greater than 
500 msec);

A subject who, prior to start of study treatment and during study treatment, requires 
any of the prohibited medications listed in Table 1 of Section 5.1.3.
 
 
04Q460


Product:  MK-5592 
24
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential

Inability to continue to take study medication according to schedule (See Section 
5.2.2 );

Failure to comply with the dosing, evaluations, or other requirements of the study;

A subject with liver function tests (ALT, AST, or total bilirubin) greater than 10 x 
ULN or other clinical or histopathologic evidence of drug-induced hepatoxicity;

A subject who has recovered from neutropenia (ANC ≥500/mm3) and has not 
considered risk factors of IFI remain at the discretion of investigator;

The subject interrupts trial medication administration for more than 3 consecutive 
days;

The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol;

The subject has a confirmed positive serum pregnancy test.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
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, 
pharmacokinetic, pharmacodynamic, 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.
 
 
04Q460






Product:  MK-5592 
27
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
All Panels/Periods
Scheduled Time
Study period
Screening
IV Treatment Phase a
IV or Oral Treatment Phase 
b
Safety 
Follow-up c
By Phone
Survival 
Assessment d
By Phone
Day relative to the first dose of the study
D -14
to D -2
D -1
D1
D2
D3
D4
D5
D6
D10
(±1D)
D15
(±1D)
D22
(±1D)
D28 or 
EOT
D58 or 
EOT +30 D
Any day from 
D60 to D70
m. The study medication diary will be distributed to subjects when they receive oral suspension treatment and return to investigator at the visit of last dose.  
Medication and food information during the POS oral suspension dosing period will be collected daily as indicated in the study medication diary.
n. Infusion site examination will be performed prior to dosing (0 hour) and at the end of infusion on infusion days and, if applicable, on days where IV 
Treatment is substituted for Oral Treatment due to oral tolerability issues during the Oral Treatment Phase for local adverse reactions. During the Oral 
Treatment Phase, any abnormal POS IV infusion site will continue to be inspected at all visits until resolution of the reaction and/or until Day 28 or EOT,
which occur first. The infusion site will be monitored for the presence of local site reactions such as, but not limited to, tenderness, erythema, swelling, 
induration, or frank vein thrombosis. A record of the presence and severity of any reactions, if they occur, is to be obtained. 
o. Catheter use details will be recorded daily during the IV administration and until 5 days after the end of IV therapy. Catheter type, catheter location 
(peripheral or central), catheter insertion and removal days, as well as the reason for the removal, will be recorded. For subject swithed to oral treatment 
during Day 11 (±1) to Day 28 or EOT, catheter use could be not needed. 
p. Clinical laboratory tests should be drawn prior to initiation of study treatment. If the results during screenning period are within 72 hours prior medication, 
the results could also be accepted as Day 1 results.The results of laboratory tests should be documented. The female subject must have a negative serum beta-
hCG result prior to study medication.
q. If  results of these tests obtained within 3 months before screening are available, they can be used as screening.
r. Informed consent for future biomedical research testing must be provided before the DNA sample is obtained. The DNA sample should be obtained before 
the first drug dose on Day 1, or as soon as the informed consent and local regulatory approval for DNA collection and testing are obtained.
s. Plasma trough sampling pre-dose on Day 3, 6, 10 (±1), 15 (±1), 22 (±1) and at the end of therapy (or Day 28) for both subgroup 1 and subgroup 2. The 
trough sample will be taken approx. 24 hours following the previous day’s dose of study drug, while before next daily dose.  The actual time of all PK 
samples should be recorded.
t.
For sub-group 1 subject, Day 10 (±1) blood samples will be collected at pre-dose, 1 hour post start of infusion, immediately before the end of infusion, 
approximately 15 minutes after the end of infusion, and approximate 4, 8, 12 and 24 hours post start of infusion. Blood for Pharmacokinetic assay of MK-
5592 in plasma will be collected within 30 minutes for time pints pre-dose, within approximate 1 minute from time points 0-2 hours, within approximate 5 
minutes from time points 2-8 hours, within approximate 10 minutes for time points 12 -24 hours, and approximate 30 minutes time points >24 hours. 
 
 
04Q460


Product:  MK-5592 
28
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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
7.1.1.1
Informed Consent
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.
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.
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 
 
 
04Q460


Product:  MK-5592 
29
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
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.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use.
A record of all prior medication (prescription or over the counter) taken by the subject within 
7 days before starting the study is to be obtained. A record of chemotherapeutic agents used 
for any chemotherapy regimen within 30 days of start of study treatment is to be obtained. 
The identity of the therapy, the dose, route, and regimen, the dates started and stopped (or 
notation of “continuing” if that is the case), and the reason for use are to be included in the 
record. Subjects receiving other antifungal agents as prophylactic therapy prior to start of 
study treatment should be discontinued from these treatments the day before starting study 
medication.
The medications, supplements, and other substances prohibited prior to start of study 
treatment and during study treatment are listed in Table 1.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Nasal sprays of amphotericin B (AMB) and aerosolized AMB are prohibited during the 
Treatment Phase. Topical nonabsorbable antifungal agents may be used for the treatment of 
mucosal or cutaneous fungal infections. Any other antifungal therapy must be administered 
according to the following criteria. No other systemic antifungal therapy is allowed other 
than study treatment.
Investigational drugs (ie, other drugs not yet approved for marketing by the Food and Drug 
Administration [FDA] or local health authorities) are also prohibited during the treatment 
phase.
 
 
04Q460


Product:  MK-5592 
30
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
POS is a potent inhibitor of CYP3A4. Coadminstration of POS with CYP3A4 substrates may 
result in large increases in exposure of CYP3A4 substrates. Caution is advised during co-
administration of POS with CYP3A4 substrates and the dose of the CYP3A4 substrate may
need to be reduced. Plasma concentrations of the CYP3A4 substrate and/or AEs should be 
closely monitored and the dose adjusted as needed.
Clinical and ECG monitoring (including QTc monitoring) is to be performed when the study 
drug is co-administered with one of the following drugs that have reported a potential risk of 
torsades de pointes: amiodarone, chlorpromazine, clarithromycin, domperidone, droperidol, 
levomethadyl, mesoridazine, methadone, erythromycin, sparfloxacin, and thioridazine.
The drugs listed below are permitted, although their efficacy and safety should be clinically 
monitored and/or serum levels followed with appropriate dosage adjustments as necessary at 
the initiation of study drug, periodically during treatment, and after discontinuation of study 
drug:
• Oral hypoglycemic agents
• Digoxin
• Coumadin-type anticoagulants
• Calcium channel blockers
• Theophylline
• Antiretroviral therapy (eg, efavirenz, atazanavir, or tenofovir).
Posaconazole interferes with the hepatic clearance of triazolam and midazolam, and thus, 
may enhance the sedative effects of these agents. Therefore, these agents are not allowed 
unless monitoring is provided for excessive sedation.
7.1.1.6
Assignment of Screening Number
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 allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Randomization Number
Refer to “Assignment of Allocation Number” in Section 7.1.1.8.
7.1.1.8
Trial Compliance (Assignment of Allocation Number/ Medication/Diet)
Each subject who meets all inclusion criteria and no exclusion criteria study will be eligible 
for enrollment in this study and then assigning a unique allocation number. Allocation 
numbers will be provided by the SPONSOR. The allocation number will never be changed 
and will be used to identify the patient for all procedures occurring after confirming the 
subject will be enrolled in this study.
 
 
04Q460


Product:  MK-5592 
31
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Administration of trial medication will be witnessed by the investigator and/or trial staff if 
subjects stay in the investigative site. 
When subject transfer to POS oral suspension treatment, they will be assigned a study 
medication diary to record the medication and food intake information during POS oral 
suspension dosing period.
Clinical Procedures/Assessments
7.1.2
Study procedures should be completed as close to the prescribed/scheduled time as possible. 
Procedures will be performed in the following order of proximity (below) with regard to the 
prescribed time. These procedures can be done prior or after the time point. For this study the 
blood sample for MK-5592 is the critical parameter and needs to be collected as close to the 
exact time point as possible.
1. Blood sample collection for MK-5592: needs to be collected as close to the exact time 
point as possible.
2. 12-lead ECG: need to be taken after the end of infusion during the IV therapy.
The order of priority of the rest clinical procedures can be changed 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.
7.1.2.1
Physical Examination
The physical examination (at Screening) will include height and weight, as well as an 
evaluation of the subject’s medical condition. The physical examination could be repeated 
during the study duration at investigator’s discretion.
7.1.2.2
Height, Weight and BMI
Body weight and height will be obtained with the subjects’ shoes off, jacket or coat removed. 
BMI equals a person's weight in kilograms divided by height in meters squared. 
(BMI=kg/m2).
Note: BMI will be rounded to the nearest whole number according to the standard convention 
of 0.1-0.4 round down and 0.5-0.9 round up.
7.1.2.3
12-Lead ECG
ECG should be performed after the end of infusion during the IV therapy. Special care must 
be taken for proper lead placement. Subjects may need to be shaved to ensure proper lead 
placement.
Subjects should be resting for at least 10 minutes prior to having ECG readings obtained.
Any clinically significant abnormality must be followed until stabilization or return to 
Baseline.
 
 
04Q460


Product:  MK-5592 
32
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
7.1.2.4
Vital Sign Measurements (Heart Rate, Blood Pressure, Respiratory Rate and 
Temperature)
Subjects should be resting for at least 10 minutes prior to having vital sign measurements 
obtained. Vital signs will include heart rate (HR), blood pressure (BP) and respiratory rate 
(RR). 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.
Body temperature will be measured with an oral, tympanic or axillary thermometer. The 
same method (e.g., oral, tympanic or axillary) must be used for all measurements for each 
individual subject and should be the same for all subjects.
7.1.2.5
Clinical Signs and symptoms of IFI
Clinical signs and symptoms of IFI will be observed during the study treatment period. If the 
physician suspects the IFIs, further testing will be assessed based on the physician’s 
judgment. Possible, probable, or proven IFI events (per EORTC/MSG version 2008 criteria) 
will be reported on the eCRF.
7.1.2.6
Radiological Tests
Radiological tests will be conducted at screening, Day 10 (±1) and Day 28/EOT. Per 
clinically indicated, radiological testing results could be accepted if tested within 7 days; the 
radiology test at day -14 to day -2 occurs within 7 days before day -1, the results could also 
be accepted as day -1. Radiological test information could refer EORTC/MSG version 2008 
criteria.
7.1.2.7
Infusion Site Examination
Infusion site examination will be performed prior to dosing (0 hour) and at the end of 
infusion on infusion days and, if applicable, on days where IV Treatment is substituted for 
Oral Treatment due to oral tolerability issues during the Oral Treatment Phase for local 
adverse reactions. During the Oral Treatment Phase, any abnormal POS IV infusion site will 
continue to be inspected at all visits until resolution of the reaction and/or until Day 28 or 
EOT, which occur first. The infusion site will be monitored for the presence of local site 
reactions such as, but not limited to, tenderness, erythema, swelling, induration, or frank vein 
thrombosis. A record of the presence and severity of any reactions, if they occur, is to be 
obtained.
7.1.2.8
Survival Assessment
Survival assessment, if the subject is alive or dead, will be performed any day from Days 60 
to 70. If the subject dies, the date of death will be recorded.
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/tissue to be drawn/collected over the course of 
 
 
04Q460


Product:  MK-5592 
33
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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 12.4.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 3.
Table 3 Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)
Hemoglobin
Alkaline phosphatase
Glucose
Hepatitis B and C (per site 
SOP)
Platelet count
Alanine aminotransferase (ALT)
Protein
HIV (per site SOP)
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Absolute 
Neutrophil Count
Lactate Dehydrogenase (LDH)
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen (BUN or 
Urea, BUN is prefered)
Chemistry laboratory safety tests will be performed after at least an 8-hour fast. Pre-dose 
laboratory procedures can be conducted up to 24 hours prior to dosing.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
The decision as to which plasma samples collected will be assayed for evaluation of 
pharmacokinetics/pharmacodynamics will be collaboratively determined by the Department 
of Pharmacokinetics, Pharmacodynamics and Drug Metabolism and the appropriate 
department within Early-Stage Development/Clinical Research of MSD China. If indicated, 
these samples may also be assayed and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers.
7.1.3.2.1 Blood Collection for Plasma MK-5592
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the appendix section 12.7.
 
 
04Q460


Product:  MK-5592 
34
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
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 30 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 30 days after the last dose of trial drug 
is given , the investigator should perform a follow-up phone call 30 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 and have their 
specimens and all derivatives destroyed.   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), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
 
 
04Q460


Product:  MK-5592 
35
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
7.1.4.3
Domiciling
Subjects (both subgroup 1 and subgroup 2) will report to the clinical research unit (CRU) on 
Day -1 prior to the scheduled day of trial drug administration on Day 1 and remain in the unit 
during IV therapy period. Subjects could be outpatients if switch to oral therapy at the 
discretion of the investigator, and should come back to unit if switch back to IV therapy 
again judged by the investigator.
7.1.4.4
Calibration of Critical Equipment
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.
Critical Equipment for this trial includes:
None critical equipment was defined in this trial.
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.
7.1.5.1
Screening
Approximately 2 weeks prior to randomization/dosing, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor.
7.1.5.2
Treatment Period Visit
All subjects will be given a card identifying them as a participant in a research. The card will 
contain information detailing an appropriate contact and corresponding telephone number to 
be utilized in the event of an emergency.
At the discretion of the investigator, subjects will report to the clinical research unit (CRU) 
the day prior to the scheduled day of administration of the study drug. After pre-dose 
procedures have been completed and prior to the study drug administration, subjects will be 
assigned a subject number.
Eligibility will be confirmed at Day -1 or pre-dose through review of pregnancy test (females 
only), 12-lead ECG, vital signs, and concomitant medication / adverse events monitoring (see 
Section 6.0).
Approximately 30 subjects will be assigned to sub-group 1, and about 40 subjects will be 
assigned to sub-group 2.
In each sub-group, subjects will receive same regimen, only one treatment group in this 
study. Each subject will be receiving POS IV solution 300 mg Q12h on Day 1, followed by 
300 mg QD on Day 2 through 10 (±1) via central line administration. Then, subjects will 
 
 
04Q460


Product:  MK-5592 
36
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
receive IV solution 300 mg QD or oral suspension 200 mg TID for up to 18 (±1) days at the 
discretion of investigator. The investigator could switch the subject back to POS IV solution 
during oral treatment period if the subject is unable to tolerate oral suspension. The total 
treatment duration is at least 10 (±1) days to up to 28 days. There will be an end of treatment 
(EOT) visit, either at Day 28 or at the end of treatment, depends on which occur earlier.
There is no restriction on food intake for POS IV solution treatment. For POS oral 
suspension administration, drug should be given under the guidance of physicians per local 
label and should be administered with food or immediately after eating (i.e., within 20 
minutes). The food intake information during oral suspension dosing period will be recorded 
on the diary.
PK sampling for sub-group 1 will be continued up to Day 28/ EOT. The time points for serial 
PK in sub-group 1 on Day 10 (±1) are pre-dose, 1 hour post start of infusion, immediately 
before the end of infusion, approximately 15 minutes after the end of infusion, and 
approximate 4, 8, 12 and 24 hours post start of infusion. The serial PK for POS IV solution 
on Day 10 (±1) must be obtained before switching to oral suspension. Blood samples for the 
determination of plasma trough POS levels will be drawn on Days 3, 6, 10 (±1), 15 (±1), 22 
(±1), and 28/ EOT for PK POS evaluation.
PK sampling for sub-group 2 will only focus on trough POS levels, and be drawn on Days 3, 
6, 10 (±1), 15 (±1), 22 (±1), and 28/EOT for PK POS evaluation.
During the treatment period, subjects will be instructed to report any adverse events to the 
investigator. Subjects may be required to remain on the CRU for longer post dose at the 
discretion of the Investigator.
Blood samples for plasma of MK-5592 will be drawn as close as possible to the time points 
provided in Section 6.0. The exact time point of blood sampling will be recorded.
Pre-dose procedures, procedures for study drug administration and post dose procedures are 
listed in the Study Flow Chart in Section 6.0.
7.1.5.3
Post-Trial
Subjects will be required to have a follow-up phone call visit approximately 30 days after the 
last dose of trial drug. If the post-trial visit occurs less than 30 days after the last dose of trial 
drug, another follow-up phone call should be made at 30 days post the last dose of trial drug 
to determine if any adverse events have occurred since the post-trial clinic visit. Also, a 
survival assessment, if the subject is alive or dead, will be performed at any day form Days 
60 to 70. If the subject dies, the date of death will be recorded. This assessment can be a 
phone contact visit.
7.1.5.4
Critical Procedures Based on Trial Objectives: Timing of Procedure 
For this trial, the blood sample for MK-5592 is the critical procedure. 
At any post-dose time point, the blood sample for MK-5592 needs to be collected as close to 
the exact time point as possible.  It is essential that the blood sample collected at the end of 
infusion be collected immediately before the infusion is ended.  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.
 
 
04Q460


Product:  MK-5592 
37
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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.
7.1.5.5
Trial Design/Dosing/Procedures Modifications Permitted within Protocol 
Parameters
The dose and administration of the trial drug to any subject may not be modified. If 
necessary a subject must be discontinued for the reasons described in Section 5.8 - Subject 
Withdrawal/Discontinuation Criteria. 
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 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
For 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 30 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 EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
04Q460


Product:  MK-5592 
38
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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.”
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 30 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).
 
 
04Q460


Product:  MK-5592 
39
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:

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 4 for additional details regarding each of the above criteria.
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 30 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.
7.2.3.2
Events of Clinical Interest
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 
 
 
04Q460


Product:  MK-5592 
40
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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 30 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 
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 according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
04Q460


Product:  MK-5592 
41
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Table 4 Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event 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 new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is 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 (AE):
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
 
 
04Q460


Product:  MK-5592 
42
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Relationship
The following components are to be used to assess the relationship between the test drug 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; or (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 study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the 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 REEXPOSURE 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 AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
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.)
 
 
04Q460


Product:  MK-5592 
43
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of Early Development Statistics – Asia Pacific (EDS-AP), in collaboration 
with the Pharmacokinietics, Pharmacodynamics & Drug Metabolism, Clinical Pharmacology 
/China Clinical Research Departments of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report (CSR).
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Individual values will be listed for the PK parameters as shown below, and the following 
(non-model-based) descriptive statistics will also be provided: N (number of subjects with 
non-missing data), arithmetic mean, standard deviation, arithmetic percent CV (calculated as 
100 × standard deviation/arithmetic mean), median, minimum, maximum, geometric mean, 
and geometric percent CV (calculated as 100 × sqrt (exp(s2) - 1), where s2 is the observed 
variance on the natural log-scale). On Day 10, the PK parameters are steady-state Cavg, 
AUC0-24hr, Cmax, Cmin and Tmax in subgroup 1.The frequency distribution with pre-specified 
exposure in two categories, <500 ng/mL and ≥500 ng/mL, for steady-state Cavg values on 
Day 10 in subgroup 1 will be tabulated. Descriptive statistics (mean and arithmetic percent 
CV) will also be tabulated for trough plasma concentrations in both subgroups by study day 
for MK-5592. In addition, mean trough plasma concentrations in both subgroups will be 
plotted by study day.
A population PK model was developed in non-Chinese healthy volunteer and patients to 
characterize PK and its variability after POS IV administration. Data from this study will be 
added to the dataset and the effect of Chinese ethnicity on the pharmacokinetics of 
posaconazole will be assessed. Also the percentage of the population with steady-state Cavg
≥500 ng/mL will be estimated using the population PK model. Other necessary 
pharmacokinetic parameters will also be estimated from the population PK models.
Statistical Analysis Plan
8.2
Hypotheses/Estimation
8.2.1
The pharmacokinetics parameters (e.g., steady-state Cavg, AUC0-24hr) of POS IV solution in
Chinese subjects at high risk of invasive fungal infections will be estimated. Percentage of
Chinese subjects with steady-state Cavg ≥500 ng/ml will be estimated.
 
 
04Q460


Product:  MK-5592 
44
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Analysis Endpoints
8.2.2
Primary key parameter for POS is steady-state Cavg. Other parameters (Cmin, Cmax, Tmax, 
AUC0-24 hr and CL) for POS IV administration will be determined from plasma samples taken 
at steady-state as described under Study Procedures. 
For subgroup 1, blood samples for the determination of plasma trough POS levels will be 
drawn on Days 3, 6, 10 (±1), 15 (±1), 22 (±1) and 28 (or EOT) for PK POS evaluation. 
Additional PK samples will be drawn on Day 10 (±1) at pre-dose, 1 hour post start of 
infusion, immediately before the end of infusion, approximately 15 minutes after the end of 
infusion, and approximate 4, 8, 12 and 24 hours post start of infusion to further characterize 
additional PK parameters including AUC0-24 hr. 
For subgroup 2, blood samples for the determination of plasma trough POS levels will be 
drawn on Days 3, 6, 10 (±1), 15 (±1), 22 (±1) and 28 (or EOT) for PK POS evaluation. 
Safety endpoints will include all types of adverse experiences, in addition to laboratory safety 
tests, ECGs, and vital signs. Efficacy endpoints including the percentage of IFI and survival 
assessment can be seen in Section 4.2.3.3.
Approaches to Analyses
8.2.3
The following populations are defined for the analysis and reporting of data. All subjects will 
be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated (ASaT): All subjects who received at least one dose of the 
investigational drug. This population will be used for assessments of safety and tolerability. 
Per-Protocol (PP) population: The set of data generated by the subset of subjects who comply 
with the protocol sufficiently to ensure that these data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Compliance covers such 
considerations as exposure to treatment, availability of measurements and absence of major 
protocol deviations. Major protocol deviations will be identified to the extent possible prior 
to unblinding by individuals responsible for data collection/compliance, and its analysis and 
interpretation. Any subjects or data values excluded from analysis will be identified, along 
with their reason for exclusion, in the CSR. At the end of the study, all subjects who are 
compliant with the study procedure as aforementioned and have available data from at least 
one treatment will be included in the primary analysis dataset. This population will be used 
for the PK analysis.
8.2.3.1
Pharmacokinetics
Individual values will be listed for the PK parameters as shown below, and the following 
(non-model-based) descriptive statistics will also be provided: N (number of subjects with 
non-missing data), arithmetic mean, standard deviation, arithmetic percent CV (calculated as 
100 × standard deviation/arithmetic mean), median, minimum, maximum, geometric mean, 
and geometric percent CV (calculated as 100 × sqrt(exp(s2) - 1), where s2 is the observed 
variance on the natural log-scale). On Day 10, the PK parameters are steady-state Cavg, 
AUC0-24hr, Cmax, Cmin and Tmax in subgroup 1. The frequency distribution with pre-specified 
exposure in two categories, <500 ng/mL and ≥500 ng/mL, for steady-state Cavg values on 
Day 10 in subgroup 1 will be tabulated. Descriptive statistics (mean and arithmetic percent 
 
 
04Q460


Product:  MK-5592 
45
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
CV) will also be tabulated for trough plasma concentrations in both subgroups by study day 
for MK-5592. In addition, mean trough plasma concentrations in both subgroups will be 
plotted by study day.
A population PK model was developed in non-Chinese healthy volunteers and patients to 
characterize PK and its variability after POS IV administration. Data from this study will be 
added to the dataset and the effect of Chinese ethnicity on the pharmacokinetics of 
posaconazole will be assessed. Also the percentage of the population with Cavg ≥500 ng/mL
will be estimated using the population PK model. Other necessary pharmacokinetic 
parameters will also be estimated from the population PK models.
8.2.3.2
Safety
Safety will be evaluated in Chinese subjects by clinical assessment of adverse experiences 
and other safety parameters. Adverse experience will be listed and tabulated. Summary 
statistics for the raw laboratory safety tests, ECGs, and/or vital signs may also be computed, 
as deemed clinically appropriate. Descriptive statistics will be provided for the survival 
assessment (any day between Days 60 and 70).
8.2.3.3
Sample Size 
The sample size for this study is based on overall objectives such as PK, safety and 
tolerability. Assuming a mean steady-state Cavg = 1500 ng/mL and a coefficient of variation 
(CV) = 35%, there is a greater than 90% probability that at least 18 out of 20 evaluable 
subjects enrolled in subgroup 1 will have a steady-state Cavg ≥500 ng/mL. These calculations 
are based on the data of steady-state pharmacokinetics from 49 subjects enrolled in an earlier 
study of POS IV solution (P05520, Table 5). In order to have approximately 20 evaluable 
subjects in subgroup 1 and considering a potential dropout rate 30%, approximately 30 
subjects will be enrolled in subgroup 1. The sample size for subgroup 2 is based on prior 
study experience and historical requirements for filing regarding the number of subjects that 
would need to constitute an adequate safety database for this formulation. Therefore, we will 
enroll approximately 30 subjects in subgroup 1 and 40 subjects in subgroup 2. 
Table 5 PK Parameters Based on Previous Studies
Endpoint
Mean
CV
Source
Cavg
1500 ng/ml
0.35
MK-5592 
PN05520
(n=49)
Cmax
3280 ng/ml
0.74
Tmax
1.5 (0.98-4.0)a
hr
-
a Median (minimum-maximum).
 
 
04Q460


Product:  MK-5592 
46
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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 
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 6.
Table 6 Product Descriptions
Treatment 
Group
Product Name 
and Dosage Form
Dose
Potency
Total Dosage 
Forms
Additional 
Information
All (subgroup 
1 and 
subgroup 2)
MK-5592 IV 
solution
Or
MK-5592 oral 
suspension
300 mg/vial
for IV 
solution
200 mg for 
oral 
suspension
18 mg/mL for 
IV solution
40 mg/mL for 
oral 
suspension
1 vial for IV 
solution
200 mg for 
oral 
suspension
NA
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. Treatment (name, strength or potency) 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 
 
 
04Q460


Product:  MK-5592 
47
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
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 
 
 
04Q460


Product:  MK-5592 
48
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
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 member 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 or through a secure password-protected electronic portal 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.
 
 
04Q460


Product:  MK-5592 
49
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with 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 
 
 
04Q460


Product:  MK-5592 
50
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [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 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 Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  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 FDAMA/FDAAA 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 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
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 
 
 
04Q460


Product:  MK-5592 
51
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures 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 
 
 
04Q460


Product:  MK-5592 
52
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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 
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
1. Dolton MH, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposure-response 
relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents 
Chemother. 2012; 56: 2806-13.
2. Clinical Study Report of SCH 56592 P05520. Pharmacokinetics and Safety of Intravenous 
Posaconazole Solution Followed by Oral Posaconazole Suspension (SCH 56592) in 
Subjects at High Risk for Invasive Fungal Infections (Phase 1b; Protocol No. P05520).
3. Fu DX. The pharmacology of itraconazole injection and its clinical use in systemic fungal 
infection. Chinese Journal of New Drugs, 2004, 13: 166-168.
4. Caillot D, Bassaris H, Mcgeer A, et al. Intravenous itraconazole followed by oral 
itraconazole in the treatment of invasive pulmonary aspergillosis in patients with 
hematologic malignancies, chronic granulomatous disease, or AIDS. Clin Infect Dis, 
2001, 33: 883-90.
5. Grigull L1, Kuehlke O, Beilken A, et al. Intravenous and oral sequential itraconazole 
antifungal prophylaxis in paediatric stem cell transplantation recipients: a pilot study for 
evaluation of safety and efficacy. Pediatr Transplant. 2007; 11: 261-6.
6. Liu X, Huang Y, Yang DL, et al. Prophylaxis of invasive fungal infection with different 
administration regimens of itraconazole in patients with acute myeloid leukemia: a report 
from a randomized, controlled trial. Chin J Hematol, 2013, 34: 502-506.
7. SCH56592/MK-5592 Investigator’s Brochure (Version 11-Dec-2014)*.
8. Ben DP, Thomas JW, Peter DD. Revised definitions of invasive fungal disease from the 
European organization for research and treatment of cancer/invasive fungal infections 
cooperative group and the national institute of allergy and infectious diseases mycoses 
study group (EORTC/MSG) consensus group. CID 2008; 46: 1813-21.
9. ECOG Performance Status. http://www.ecog.org/general/perf_stat.html.
*: For those didn’t list reference number.
 
 
04Q460


Product:  MK-5592 
53
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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. 
 
 
04Q460


Product:  MK-5592 
54
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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."
 
 
04Q460


Product:  MK-5592 
55
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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 collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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 Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
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 Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
04Q460


Product:  MK-5592 
56
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
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, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
 
 
04Q460


Product:  MK-5592 
57
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  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 the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
 
 
04Q460


Product:  MK-5592 
58
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   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 Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 specimen destruction can not 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 acquisition.  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 Merck 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 Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor 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 in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
 
 
04Q460


Product:  MK-5592 
59
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
Merck 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
 
 
04Q460


Product:  MK-5592 
60
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. 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/LOB/media/MEDIA3383.pdf
 
 
04Q460


Product:  MK-5592 
61
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
04Q460


Product:  MK-5592 
62
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
63
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
64
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
65
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
66
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
67
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
68
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
69
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460




Product:  MK-5592 
71
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Algorithm for Assessing Out-of-Range Laboratory Values
12.5
For all laboratory values obtained at pre-study (screening) visit evaluation:
A. If all protocol-specified laboratory values are normal, the subject may enter the study.
B.
If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the subject will be 
excluded from the study.
C.
If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion 
criteria is outside the normal range, the following choices are available:
1.
The subject may be excluded from the study;
2.
The subject may be included in the study if the abnormal value(s) is not 
clinically significant (NCS) (the investigator must annotate the laboratory 
value “NCS” on the laboratory safety test source document).
3.
The subject may be included in the study if the abnormality is consistent with 
a pre-existing medical condition which is not excluded per protocol (e.g., 
elevated eosinophil count in a subject with asthma or seasonal allergies) (this 
should be annotated on the laboratory report) or
4.
The abnormal test may be repeated (refer items a. and b. below for 
continuation of algorithm for repeated values).
a.
If the repeat test value is within the normal range, the subject may 
enter the study.
b.
If the repeat test value is still abnormal, the study investigator will 
evaluate the potential subject with a complete history and physical 
examination, looking especially for diseases that could result in the 
abnormal laboratory value in question.  If such diseases can be ruled 
out, and if the abnormal laboratory value is not clinically relevant, then 
the subject may enter the study.
D.
If there is any clinical uncertainty regarding the significance of an abnormal value, 
the Subject will be excluded from the study.
 
 
04Q460


Product:  MK-5592 
72
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
POS IV Solution Preparation and Administration
12.6
The procedure described below is only a draft procedure. It may be altered after the site 
performing the procedure has evaluated it. Any alterations will be documented. 
This is an unblinded study in which the investigator, sponsor and subjects know the treatment. 
Therefore, POS IV vials will be packaged open-label and sent directly to the research staff. 
Storage
POS IV solution should be kept at 2°C to 8°C until ready for use. DO NOT FREEZE.
Treatment Preparation and Administration

POS IV Solution will be diluted with 5% dextrose in water or sodium chloride 0.9%. 
POS IV solution should only be administered with these diluents. Use of other 
infusion solutions may result in particulate formation.

Subjects will have their IV infusions began at approximately the same time each day.
The first three IV infusions must be given not less than 10 hours or no more than 14 
hours apart. The subsequent IV infusions must be given not less than 22 hours or no 
more than 26 hours apart.

Administer via a central venous line, including peripherally central venous catheter 
(PICC) or a dedicated lumen of a central venous catheter (CVC) by slow infusion 
over approximately 90 minutes. POS IV solution is not for bolus administration.

If any problems occur with the pump, tubing or cannulae during treatment 
administration, the research staff must be the only member of staff who resolves the 
issue. The study center must be prepared with replacement supplies so as not to 
interrupt the study drug infusion. The research staff must be available throughout IV 
treatment administration.

All POS IV vials, used and unused, must be retained for drug accountability.
Preparation
1. Equilibrate the refrigerated vial of POS IV solution to room temperature.
2. Gently invert the vial 10 times and aseptically transfer 16.7 mL (18 mg/mL, 1 vial) of 
POS IV solution to an intravenous bag containing approximately 133.3 mL of 5% 
dextrose in water or sodium chloride 0.9%. NOTE: The final volume of the bag 
should be 150 mL. 
3. Gently invert the intravenous bag containing the POS IV solution 10 times.
4. POS IV solution is a single dose sterile solution without preservatives. Once admixed, 
the product should be used immediately. If not used immediately, the solution can be 
stored up to 24 hours refrigerated 2-8°C (36-46°F). This medicinal product is for 
single use only and any unused solution should be discarded.
5. Parenteral drug products should be inspected visually for particulate matter prior to 
administration, whenever solution and container permit. Once admixed, the solution 
of Noxafil ranges from colorless to yellow. Variations of color within this range do 
not affect the quality of the product.
 
 
04Q460


Product:  MK-5592 
73
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Administration
1. Prime IV tubing completely with 5% dextrose in water or sodium chloride 0.9%.
2. Remove the covering on the port of the POS admixture IV bag and insert the solution 
set into the appropriate port.
3. If the standard solution set does not contain a 0.22 micron or less filter, then one must 
be attached at the end of the solution set.
4. Hang the POS admixture IV bag on one IV pole vertically.
5. Thread the primed IV tubing through the pump.
6. Connect the IV tubing to the central venous catheter that is inserted into the subject’s 
vein.
7. Program the pump to deliver the contents of the bag in approximately 90 minutes
(follow instructions supplied in the manual for the pump). 
8. Start the pump and infuse the entire contents of the POS admixture.
9. Flush the line according to guidelines for local standard of care for central catheters 
after intermittent infusions using 25 mL of 5% dextrose in water or sodium chloride 
0.9%. No drug should be added to this 25 mL. Complete the flushing over a period no 
less than 2 minutes and no more than 15 minutes.
10. Dispose of the IV bags and solution set according to the hospital’s 
Hazardous/Medical Waste policy.
 
 
04Q460


Product:  MK-5592 
74
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
MK-5592 Plasma Assays—Sample Collection, Handling, Labeling, Storage, and 
12.7
Shipment
The following sample
handling instruction is an example. Please consult Drug 
Metabolism/Pharmacokinetics (DMPK) and sample analysis laboratory for MK-5592
information on MK-5592 blood sample collection, handling, storage and shipment.
PK Sample Collection and Processing Procedure for MK-5592
Method LCMSC 549 
Human Plasma (K2EDTA)
For specific time points of sample collection, please refer to the Study Flow Chart (Section 
6.0).
One (1) 4 mL Vacutainer tube (lavender top, 13 x 75 mm, spray coated K2EDTA, BD 
Vacutainer # 367844 or equivalent) will be collected for PK analysis at each of the time 
points specified in the clinical protocol. Fill tube as completely as possible to ensure 
sufficient sample volume for the required tests.
Immediately after the sample is drawn, gently invert the tube 8 to 10 times to thoroughly mix 
the anticoagulant and place the tube in a cryoblock (in an upright position) or in an ice water 
mixture to the approximate height of the blood in the tube. (Samples can be stored cold for 
up to 30 minutes prior to centrifugation.) Centrifuge the sample under refrigeration 2 ºC to 8 
ºC at 2500 to 3000 rpm (approximately 650 to 1450 x g) for 10 to 15 minutes to achieve a 
clear plasma layer over the red cells (the speed and time may be varied according to the make 
and model of centrifuge used). Immediately transfer the plasma to a properly labeled 
polypropylene sample storage tube, cap and freeze samples at -20 ºC until shipment. Samples 
should be place in freezer within 60 minutes after sample collection.
Sample Labeling
1. Whole Blood Samples. Vacutainers containing whole blood should be labeled (non-bar-
coded) as appropriate.  
2. Plasma Samples. Tubes containing plasma samples should be labeled with the pre-printed 
bar-coded labels with the allocation number, day, date and time (hours post-dose) 
provided by the Sponsor. Labels should be placed on the tubes toward the top 30% of the 
tube in order for the level of plasma in the tube to be viewed. Only one (1) layer of label 
should be placed on the tube (not 2). This is critical for the proper functioning of the 
automated liquid handling station.
Sample Shipment
•
Only the plasma samples need to be shipped to the central lab and all the remaining full 
blood samples could be destroyed at study site.
•
All sample shipments should be preceded by a phone call or fax prior to their receipt. All 
HIV positive or other known infectious sample shipments must be preceded by a phone 
call or facsimile prior to their receipt. 
•
Detailed sample inventory information must accompany the samples. Lack of paperwork 
or illegible information will delay sample login and project initiation. Samples that are 
 
 
04Q460


Pr o d uct:   M K -5 5 9 2 
7 5
Pr ot oc ol/ A me n d me nt N o.: 1 2 0- 0 0 
M K - 5 5 9 2- 1 2 0- 0 0 Fi nal Pr ot oc ol
2 4- J ul- 2 0 1 7
C o nfi de ntial
u nclearl y or i nc om pletel y  l abele d m a y  be s u bject t o a d diti o nal ha n dli n g fees. S u b missi o n 
of sa m ple i n ve nt or y  i nf or mati o n i n electr o nic f or m is e nc o ura ge d.
•
Fr oze n sa m ples s h o ul d be s hi p pe d via o ver ni g ht c o urier wit h a n a de q uate a m o u nt of dr y  
ice M o n da y t hr o u g h Fri da y t o the f oll o wi n g:
N ote: Sa m ple st ora ge f or t his st u d y  is - 2 0º C.
 
 
C CI
0 4 Q 4 6 0


Product:  MK-5592 
76
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Defining Opportunistic Invasive Fungal Infections (European Organization for 
12.8
Research and Treatment of Cancer/Invasive Fungal Infections Cooperative 
Group, National Institute of Allergy and Infectious Diseases Mycoses Study 
Group)
 
 
04Q460


Product:  MK-5592 
77
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
78
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
79
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
80
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
81
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
82
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
83
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
84
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
 
 
04Q460


Product:  MK-5592 
85
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
ECOG Performance Status 
12.9
ECOG PERFORMANCE STATUS*
Grade ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
* 
As 
published 
in 
Am. 
J. 
Clin. 
Oncol.:
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
 
 
04Q460


Product:  MK-5592 
86
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Product Circular of Posaconazole Oral Suspension
12.10
Approved date: Jun.3, 2013
Modified date: July 18, 2013; Oct 18, 2014; Feb 3, 2015; Jun 9, 2017
Product Circular of Posaconazole Oral Suspension
Please read this leaflet carefully before you start to take this medicine.
[Name]
Generic Name: Posaconazole Oral Suspension
Brand Name: Noxafil®
English Name: Posaconazole Oral Suspension
Chinese Pin Yin: Boshakangzuo Koufuhunxuanye   
[Composition]
Active Ingredient: Posaconazole
Chemical 
Name: 
4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-
ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-
2,4-dihydro-3H-1,2,4- triazol-3-one
Chemical Structure:
Empirical formula: C37H42F2N8O4
Molecular weight: 700.8.
Excipients: artificial cherry flavor purified water, citric acid monohydrate, glycerol, liquid glucose, 
polysorbate 80, simeticone, sodium benzoate (E211), sodium citrate dehydrate, titanium dioxide 
(E171), xanthan gum
 
 
04Q460


Product:  MK-5592 
87
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
[Description]
A white suspension; translucent to opaque white semi-solid particles may be observed.
[Indications]
1. Prophylaxis of Invasive Aspergillus and Candida Infections 
NOXAFIL® Oral Suspension is indicated for prophylaxis of invasive Aspergillus and Candida 
infections in patients, 13 years of age and older, who are at high risk of developing these infections 
due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) 
recipients with graftversus-host disease (GVHD) or those with hematologic malignancies with 
prolonged neutropenia from chemotherapy. 
2. Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to 
Itraconazole and/or Fluconazole 
NOXAFIL is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal 
candidiasis refractory to itraconazole and/or fluconazole.
[Strength]
Each ml of oral suspension contains 40 mg of posaconazole.
[Dosage & Administration]
1. Dosage
Table 1
Indication 
Dose and Duration of Therapy 
Prophylaxis of Invasive Fungal 
Infections 
200 mg (5 mL) three times a day. The duration of therapy is 
based on recovery from neutropenia or immunosuppression. 
Oropharyngeal Candidiasis 
Loading dose of 100 mg (2.5 mL) twice a day on the first day, 
then 100 mg (2.5 mL) once a day for 13 days. 
Oropharyngeal Candidiasis 
Refractory to itraconazole and/or 
fluconazole 
400 mg (10 mL) twice a day. Duration of therapy should be 
based on the severity of the patient’s underlying disease and 
clinical response. 
2. Administration Instructions
NOXAFIL Oral Suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant 
closures (NDC 0085-1328-01) containing 105 mL of suspension (40 mg of posaconazole per mL).
Shake NOXAFIL Oral Suspension well before use.
Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
It is recommended that the spoon is rinsed with water after each administration and before storage. 
 
 
04Q460


Product:  MK-5592 
88
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Each dose of NOXAFIL should be administered with a full meal or with a liquid nutritional 
supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal. 
To enhance the oral absorption of posaconazole and optimize plasma concentrations: 
1) Each dose of NOXAFIL should be administered during or immediately (i.e., within 20 minutes) 
following a full meal. In patients who cannot eat a full meal, each dose of NOXAFIL should be 
administered with a liquid nutritional supplement or an acidic carbonated beverage. For patients 
who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated 
beverage, alternative antifungal therapy should be considered or patients should be monitored 
closely for breakthrough fungal infections. 
2) Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough 
fungal infections. 
3) Coadministration of drugs that can decrease the plasma concentrations of posaconazole should 
generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients 
should be monitored closely for breakthrough fungal infections. 
3. Renal Insufficiency
Following single-dose administration of 400 mg of the oral suspension, there was no significant effect 
of mild (CLcr: 50-80 mL/min/1.73 m2, n=6) and moderate (CLcr: 20-49 mL/min/1.73 m2, n=6) renal 
insufficiency on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients 
with mild to moderate renal impairment. In subjects with severe renal insufficiency (CLcr: < 20 
mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal 
function (CLcr: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable 
(CV=96%) in these subjects with severe renal insufficiency as compared to that in the other renal 
impairment groups (CV< 40%). Due to the variability in exposure, patients with severe renal 
impairment should be monitored closely for breakthrough fungal infections. 
4. Hepatic Insufficiency
After a single oral dose of posaconazole 400 mg, the mean AUC was 43%, 27%, and 21% higher in 
subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), and severe 
(Child-Pugh Class C, N=6) hepatic insufficiency, respectively, compared to subjects with normal 
hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% 
higher, 40% higher, and 34% lower in subjects with mild, moderate, and severe hepatic insufficiency, 
respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in 
subjects with mild, moderate, and severe hepatic insufficiency, respectively, compared to subjects 
with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 
hours in subjects with normal hepatic function and mild, moderate, and severe hepatic insufficiency, 
respectively. 
It is recommended that no dose adjustment of NOXAFIL is needed in patients with mild to severe 
hepatic insufficiency (Child-Pugh Class A, B, and C) [see Precautions]. 
5. Gender
The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the 
dosage of NOXAFIL is necessary based on gender. 
 
 
04Q460


Product:  MK-5592 
89
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
6. Race
The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in 
the dosage of NOXAFIL is necessary based on race.
[Side Effects]
1. Serious and Other Important Adverse Reactions
The following serious and otherwise important adverse reactions are discussed in detail in another 
section of the labeling:
1) Hypersensitivity 
2) Arrhythmias and QT Prolongation 
3) Hepatic Toxicity 
2. Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed 
in clinical trials of NOXAFIL cannot be directly compared to rates in the clinical trials of another 
drug and may not reflect the rates observed in practice.
The safety of posaconazole therapy has been assessed in 1844 patients in clinical trials. This includes 
605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC 
studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This 
represents a heterogeneous population, including immunocompromised patients, e.g., patients with 
hematological malignancy, neutropenia post-chemotherapy, graft vs. host disease post hematopoietic 
stem cell transplant, and HIV infection, as well as non-neutropenic patients. This patient population 
was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥65 years of age 
and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 
14% black). Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients 
receiving posaconazole therapy for ≥12 months. Table 2 presents treatment-emergent adverse 
reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 3 presents 
treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC 
studies. 
Prophylaxis of Aspergillus and Candida: 
In the 2 randomized, comparative prophylaxis studies, the safety of posaconazole 200 mg three times 
a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely 
immunocompromised patients. 
The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, 
diarrhea and nausea. 
The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis 
studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic 
enzymes increased (2%).
 
 
04Q460


Product:  MK-5592 
90
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE 2: Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-
Emergent Adverse Reactions: Frequency of at Least 10% in the Posaconazole or Fluconazole 
Treatment Groups (Pooled Prophylaxis Safety Analysis)
Body System Preferred Term 
Posaconazole 
(n=605)
Fluconazole 
(n=539)
Itraconazole 
(n=58)
Subjects Reporting any Adverse Reaction 
595 (98)
531 (99)
58 (100)
Body as a Whole - General Disorders
Fever 
274 (45)
254 (47)
32 (55)
Headache 
171 (28)
141 (26)
23 (40)
Rigors 
122 (20)
87 (16)
17 (29)
Fatigue 
101 (17)
98 (18)
5 (9)
Edema Legs 
93 (15)
67 (12)
11 (19)
Anorexia 
92 (15)
94 (17)
16 (28)
Dizziness 
64 (11)
56 (10)
5 (9)
Edema 
54 (9)
68 (13)
8 (14)
Weakness 
51 (8)
52 (10)
2 (3)
Cardiovascular Disorders, General
Hypertension 
106 (18)
88 (16)
3 (5)
Hypotension 
83 (14)
79 (15)
10 (17)
Disorders of Blood and Lymphatic System
Anemia 
149 (25)
124 (23)
16 (28)
Neutropenia 
141 (23)
122 (23)
23 (40)
Febrile Neutropenia 
118 (20)
85 (16)
23 (40)
Disorders of the Reproductive System and Breast
Vaginal Hemorrhage* 
24 (10)
20 (9)
3 (12)
Gastrointestinal System Disorders
Diarrhea 
256 (42)
212 (39)
35 (60)
Nausea 
232 (38)
198 (37)
30 (52)
Vomiting 
174 (29)
173 (32)
24 (41)
Abdominal Pain 
161 (27)
147 (27)
21 (36)
Constipation 
126 (21)
94 (17)
10 (17)
Mucositis NOS 
105 (17)
68 (13)
15 (26)
Dyspepsia 
61 (10)
50 (9)
6 (10)
Heart Rate and Rhythm Disorders
Tachycardia 
72 (12)
75 (14)
3 (5)
Infection and Infestations
Bacteremia 
107 (18)
98 (18)
16 (28)
Herpes Simplex 
88 (15)
61 (11)
10 (17)
Cytomegalovirus Infection 
82 (14)
69 (13)
0
Pharyngitis 
71 (12)
60 (11)
12 (21)
Upper Respiratory Tract Infection 
44 (7)
54 (10)
5 (9)
Liver and Biliary System Disorders
Bilirubinemia 
59 (10)
51 (9)
11 (19)
Metabolic and Nutritional Disorders
Hypokalemia 
181 (30)
142 (26)
30 (52)
Hypomagnesemia 
110 (18)
84 (16)
11 (19)
Hyperglycemia 
68 (11)
76 (14)
2 (3)
Hypocalcemia 
56 (9)
55 (10)
5 (9)
Musculoskeletal System Disorders
Musculoskeletal Pain 
95 (16)
82 (15)
9 (16)
Arthralgia 
69 (11)
67 (12)
5 (9)
Back Pain 
63 (10)
66 (12)
4 (7)
Platelet, Bleeding and Clotting Disorders
Thrombocytopenia 
175 (29)
146 (27)
20 (34)
 
 
04Q460


Product:  MK-5592 
91
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Body System Preferred Term 
Posaconazole 
(n=605)
Fluconazole 
(n=539)
Itraconazole 
(n=58)
Petechiae 
64 (11)
54 (10)
9 (16)
Psychiatric Disorders
Insomnia 
103 (17)
92 (17)
11 (19)
Anxiety 
52 (9)
61 (11)
9 (16)
Respiratory System Disorders
Coughing 
146 (24)
130 (24)
14 (24)
Dyspnea 
121 (20)
116 (22)
15 (26)
Epistaxis 
82 (14)
73 (14)
12 (21)
Skin and Subcutaneous Tissue Disorders
Rash 
113 (19)
96 (18)
25 (43)
Pruritus 
69 (11)
62 (12)
11 (19)
* Percentages of sex-specific adverse reactions are based on the number of males/females.
NOS = not otherwise specified.
HIV Infected Subjects with OPC: 
In 2 randomized comparative studies in OPC, the safety of posaconazole at a dose of ≤400 mg QD in 
557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at 
a dose of 100 mg QD. 
An additional 239 HIV-infected patients with refractory OPC received posaconazole in 2 non-
comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose 
and the remainder received the ≤400-mg QD dose. 
In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, 
and vomiting. 
  The most common adverse reactions that led to treatment discontinuation of posaconazole in the 
Controlled OPC Pool included respiratory insufficiency (1%) and pneumonia (1%). In the refractory 
OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole 
were AIDS (7%) and respiratory insufficiency (3%). 
 
 
04Q460


Product:  MK-5592 
92
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE 3: Treatment-Emergent Adverse Reactions with Frequency of at Least 10% in OPC Studies 
(Treated Population)
Body System Preferred Term 
Number (%) of Subjects
Controlled OPC Pool
Refractory OPC 
Pool
Posaconazole
Fluconazole
Posaconazole
n=557
n=262
n=239
Subjects Reporting any Adverse Reaction* 
356 (64)
175 (67)
221 (92)
Body as a Whole – General Disorders
Fever 
34 (6)
22 (8)
82 (34)
Headache 
44 (8)
23 (9)
47 (20)
Anorexia 
10 (2)
4 (2)
46 (19)
Fatigue 
18 (3)
12 (5)
31 (13)
Asthenia 
9 (2)
5 (2)
31 (13)
Rigors 
2 (<1)
4 (2)
29 (12)
Pain 
4 (1)
2 (1)
27 (11)
Disorders of Blood and Lymphatic System
Neutropenia 
21 (4)
8 (3)
39 (16)
Anemia 
11 (2)
5 (2)
34 (14)
Gastrointestinal System Disorders
Diarrhea 
58 (10)
34 (13)
70 (29)
Nausea 
48 (9)
30 (11)
70 (29)
Vomiting 
37 (7)
18 (7)
67 (28)
Abdominal Pain 
27 (5)
17 (6)
43 (18)
Infection and Infestations
Candidiasis, Oral 
3 (1)
1 (<1)
28 (12)
Herpes Simplex 
16 (3)
8 (3)
26 (11)
Pneumonia 
17 (3)
6 (2)
25 (10)
Metabolic and Nutritional Disorders
Weight Decrease 
4 (1)
2 (1)
33 (14)
Dehydration 
4 (1)
7 (3)
27 (11)
Psychiatric Disorders
Insomnia 
8 (1)
3 (1)
39 (16)
Respiratory System Disorders
Coughing 
18 (3)
11 (4)
60 (25)
Dyspnea 
8 (1)
8 (3)
28 (12)
Skin and Subcutaneous Tissue Disorders
Rash 
15 (3)
10 (4)
36 (15)
Sweating Increased 
13 (2)
5 (2)
23 (10)
OPC=oropharyngeal candidiasis; SGOT=serum glutamic oxaloacetic transaminase (same as 
AST); SGPT=serum glutamic pyruvic transaminase (same as ALT). 
* Number of subjects reporting treatment-emergent adverse reactions at least once during the 
study, without regard to relationship to treatment. Subjects may have reported more than 1 event. 
Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among 
these highly immunocompromised patients with advanced HIV disease, serious adverse reactions 
(SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and 
neutropenia (10%). 
 
 
04Q460


Product:  MK-5592 
93
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Less Common Adverse Reactions: 

Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic 
thrombocytopenic purpura, neutropenia aggravated

Endocrine disorders: adrenal insufficiency

Nervous system disorders: paresthesia

Immune system disorders: allergic reaction

Cardiac disorders: Torsades depointes

Vascular disorders: pulmonary embolism

Liver and Biliary System Disorders: bilirubinemia, hepatic enzymes increased, hepatic 
function abnormal, hepatitis, hepatomegaly, jaundice, SGOT Increased, SGPT Increased

Metabolic and Nutritional Disorders: hypokalemia

Platelet, Bleeding, and Clotting Disorders: thrombocytopenia

Renal & Urinary System Disorders: renal failure acute
Clinical Laboratory Values: 
In healthy volunteers and patients, elevation of liver function test values did not appear to be 
associated with higher plasma concentrations of posaconazole. The majorities of abnormal liver 
function tests were minor, transient, and did not lead to discontinuation of therapy. 
For the prophylaxis studies, the number of patients with changes in liver function tests from Common 
Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in 
Table 4.
TABLE 4: Study 1 and Study 2. Changes in Liver Function test results from CTC Grade 0, 1 or 2 at 
Baseline to Grade 3 or 4
Number (%) of Patients With Change* 
Study 1
Laboratory Parameter 
Posaconazole 
n=301 
Fluconazole 
n=299 
AST 
11/266 (4) 
13/266 (5) 
ALT 
47/271 (17) 
39/272 (14) 
Bilirubin 
24/271 (9) 
20/275 (7) 
Alkaline Phosphatase 
9/271 (3) 
8/271 (3) 
Study 2
Laboratory Parameter 
Posaconazole 
(n=304) 
Fluconazole/Itraconazole 
(n=298) 
AST 
9/286 (3) 
5/280 (2) 
ALT 
18/289 (6) 
13/284 (5) 
Bilirubin 
20/290 (7) 
25/285 (9) 
Alkaline Phosphatase 
4/281 (1) 
1/276 (<1) 
*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. 
These data are presented in the form X/Y, where X represents the number 
of patients who met the criterion as indicated, and Y represents the 
number of patients who had a baseline observation and at least one post-
baseline observation. 
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; 
ALT= Alanine Aminotransferase. 
 
 
04Q460


Product:  MK-5592 
94
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
The number of patients treated for OPC with clinically significant liver function test (LFT) 
abnormalities at any time during the studies is provided in Table 5. (LFT abnormalities were present 
in some of these patients prior to initiation of the study drug). 
TABLE 5: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline Value
Laboratory Test 
Controlled 
Refractory 
Posaconazole 
Fluconazole 
Posaconazole 
n=557(%) 
n=262(%) 
n=239(%) 
ALT > 3.0 x ULN 
16/537 (3) 
13/254 (5) 
25/226 (11) 
AST > 3.0 x ULN 
33/537 (6) 
26/254 (10) 
39/223 (17) 
Total Bilirubin > 1.5 x ULN 
15/536 (3) 
5/254 (2) 
9/197 (5) 
Alkaline Phosphatase > 3.0 x ULN 
17/535 (3) 
15/253 (6) 
24/190 (13) 
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.
3．Postmarketing Experience
No clinically significant postmarketing adverse reactions were identified that have not previously 
been reported during clinical trials experience.
[Contraindications]
1．Hypersensitivity 
NOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole, any 
component of NOXAFIL, or other azole antifungal agents. 
2．Use with Sirolimus 
NOXAFIL is contraindicated with sirolimus. Concomitant administration of NOXAFIL with 
sirolimus increases the sirolimus blood concentrations by approximately 9 fold and can result in 
sirolimus toxicity. 
3．QT Prolongation with Concomitant Use with CYP3A4 Substrates 
NOXAFIL is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant 
administration of NOXAFIL with the CYP3A4 substrates, terfenadine, astemizole, cisapride, 
pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc 
prolongation and rare occurrences of torsades de pointes. 
4. HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4 
Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through 
CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma 
concentration of these drugs can lead to rhabdomyolysis. 
5．Use with Ergot Alkaloids 
Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and 
dihydroergotamine) which may lead to ergotism. Coadministration of posaconazole and ergot 
alkaloids is contraindicated.
 
 
04Q460


Product:  MK-5592 
95
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
[Precaution]
1．Calcineurin-Inhibitor Drug Interactions
Concomitant administration of NOXAFIL with cyclosporine or tacrolimus increases the whole blood 
trough concentrations of these calcineurin-inhibitors. Nephrotoxicity and leukoencephalopathy 
(including isolated deaths) have been reported in clinical efficacy studies in patients with elevated 
cyclosporine concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough 
concentrations should be performed during and at discontinuation of posaconazole treatment and the 
tacrolimus or cyclosporine dose adjusted accordingly. 
2．Arrhythmias and QT Prolongation
Some azoles, including posaconazole, have been associated with prolongation of the QT interval on 
the electrocardiogram. In addition, rare cases of torsades de pointes have been reported in patients 
taking posaconazole. 
Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase 
in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were 
recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of 
age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean 
QTc (Fridericia) interval change from baseline was –5 msec following administration of the 
recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small 
number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) 
interval change from baseline was < 0msec (–8msec). No healthy subject administered posaconazole 
had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline. 
Noxafil must not be administered with medicinal products that are substrates for CYP3A4 and are 
known to prolong the QTc interval.
Noxafil should be administered with caution to patients who probably with drug related arrhythmic.
Noxafil must be administered with caution to patients with pro-arrhythmic conditions such as: 

Congenital or acquired QTc prolongation

Cardiomyopathy, especially in the presence of cardiac failure

Sinus bradycardia

Existing symptomatic arrhythmias

Concomitant use with medicinal products known to prolong the QTc interval (other than 
those mentioned in Contraindications).
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should 
be monitored and corrected as necessary before and during posaconazole therapy.
Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during 
treatment with other medicinal products that are metabolised by CYP3A4 (see in Drug interactions).
3. Hepatic Toxicity
Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been 
reported in clinical trials. The elevations in liver function tests were generally reversible on 
discontinuation of therapy, and in some instances these tests normalized without drug interruption and 
rarely required drug discontinuation. Isolated cases of more severe hepatic reactions including 
cholestasis or hepatic failure including deaths have been reported in patients with serious underlying 
 
 
04Q460


Product:  MK-5592 
96
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe 
hepatic reactions were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg 
QID) in clinical trials. 
Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. 
Patients who develop abnormal liver function tests during posaconazole therapy should be monitored 
for the development of more severe hepatic injury. Patient management should include laboratory 
evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of 
posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop 
that may be attributable to posaconazole. 
4. Use with Midazolam
Concomitant administration of NOXAFIL with midazolam increases the midazolam plasma 
concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate 
and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects 
associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists 
must be available to reverse these effects.
5. Others
Hypersensitivity
There is no information regarding cross-sensitivity between posaconazole and other azole antifungal 
agents. Caution should be used when prescribing Noxafil to patients with hypersensitivity to other 
azoles.
Gastrointestinal dysfunction
There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as 
severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for 
breakthrough fungal infections.
Rifamycin 
antibacterials 
(rifampicin, 
rifabutin), 
certain 
anticonvulsants 
(phenytoin, 
carbamazepine, phenobarbital, primidone), efavirenz and cimetidine
Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use 
with posaconazole should be avoided unless the benefit to the patient outweighs the risk.
Excipients
This medicinal product contains approximately 1.75 g of glucose per 5 ml of suspension. Patients 
with glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines
No studies on the effects of posaconazole on the ability to drive and use machines have been 
performed. Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with 
posaconazole use, which potentially may affect driving/operating machinery, caution needs to be 
used.
[Pregnancy & Nursing Mothers]
Pregnancy Category C:
There are no adequate and well-controlled studies in pregnant women. NOXAFIL should be used in 
pregnancy only if the potential benefit outweighs the potential risk to the fetus. 
Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing 
ribs) in rats when given in doses ≥27 mg/kg (≥1.4 times the 400-mg BID regimen based on steady-
 
 
04Q460


Product:  MK-5592 
97
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in 
rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400-mg BID regimen. No 
malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 
mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 
400-mg BID regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in 
body weight gain of females and a reduction in litter size were seen. 
Nursing Mothers
Posaconazole is excreted in milk of lactating rats. It is not known whether NOXAFIL is excreted in 
human milk. Because of the potential for serious adverse reactions from NOXAFIL in nursing 
infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking 
into account the importance of the drug to the mother.
Fertility
Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 times the 400-mg 
BID regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a 
dose up to 45 mg/kg (2.2 times the 400-mg BID regimen). There is no clinical experience assessing 
the impact of posaconazole on fertility in humans.
[Pediatric Use]
The safety and effectiveness of posaconazole have been established in the age groups 13 to 17 years 
of age. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years 
have not been established. Use of posaconazole in these age groups is supported by evidence from 
adequate and well-controlled studies of posaconazole in adults with additional data. 
A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) for 
prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears 
similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric 
patients, the mean steady-state average posaconazole concentration (Cav) was similar between these 
patients and adults (≥18 years of age). 
A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg twice a day or 200 
mg four times a day) in a study for another indication. Based on pharmacokinetic data in 12 of these 
pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar 
between these patients and adults (≥18 years of age). 
In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was 
similar among ten adolescents (13 to 17 years of age) and adults (≥18 years of age). This is consistent 
with pharmacokinetic data from another study in which mean steady-state posaconazole Cav from 12 
adolescent patients (8-17 years of age) was similar to that in the adults (≥18 years of age).
[Use In the Elderly]
Of the 605 patients randomized to posaconazole in the prophylaxis clinical trials, 63 (10%) were 
≥65 years of age. In addition, 48 patients treated with ≥800-mg/day posaconazole in another 
indication were ≥65 years of age. No overall differences in safety were observed between the 
geriatric patients and younger patients; therefore, no dosage adjustment is recommended for 
geriatric patients. 
The pharmacokinetics of posaconazole are comparable in young and elderly subjects (≥65 years of 
age). No adjustment in the dosage of NOXAFIL is necessary in elderly patients (≥65 years of age) 
based on age. 
 
 
04Q460


Product:  MK-5592 
98
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
No overall differences in the pharmacokinetics and safety were observed between elderly and young 
subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.
[Drug Interactions]
Posaconazole is primarily metabolized via UDP glucuronidation and is a substrate of p-glycoprotein 
efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma 
concentrations. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations 
of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. 
1. Immunosuppressants Metabolized by CYP3A4
Sirolimus: Repeat dose administration of oral posaconazole (400 mg oral suspension twice daily for 
16 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 
8.9-fold, respectively, in healthy subjects. When initiating therapy in patients already taking sirolimus, 
the dose of sirolimus should be reduced (e.g., to about 1/10 of the current dose) with frequent 
monitoring of sirolimus whole blood trough concentrations. Sirolimus concentrations should be 
performed upon initiation, during coadministration, and at discontinuation of posaconazole treatment,
with sirolimus doses adjusted accordingly.
Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus
(0.05 mg/kg single dose) by 121% and 358%, respectively. At initiation of posaconazole treatment, 
reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of 
tacrolimus whole blood trough concentrations should be performed during and at discontinuation of 
posaconazole treatment and the tacrolimus dose adjusted accordingly. 
Cyclosporine: Posaconazole 200mg oral suspension once daily has been shown to increase 
cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole 
treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the 
original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole 
blood trough concentrations should be performed during and at discontinuation of posaconazole 
treatment and the cyclosporine dose adjusted accordingly. 
2. CYP3A4 Substrates 
Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and 
quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation 
and rare occurrences of torsades de pointes. Therefore, posaconazole is contraindicated with these 
drugs. 
3. HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4 
Repeat dose administration of oral posaconazole (50, 100, and 200 mg oral suspension once daily for 
13 days) increased the Cmax and AUC of simvastatin (40 mg single dose) an average of 7.4- to 11.4-
fold, and 5.7- to 10.6-fold, respectively. Increased HMG-CoA reductase inhibitor concentrations in 
plasma can be associated with rhabdomyolysis.   Coadministration of posaconazole and HMG-CoA 
reductase inhibitors primarily metabolized through CYP3A4 is contraindicated.
4. Ergot Alkaloids 
Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma 
concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. 
Therefore, posaconazole is contraindicated with ergot alkaloids. 
 
 
04Q460


Product:  MK-5592 
99
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
5. Benzodiazepines Metabolized by CYP3A4 
Concomitant administration of posaconazole with midazolam increases the midazolam plasma 
concentrations by approximately 5 fold. Repeat dose administration of oral posaconazole (200 mg 
oral suspension twice daily for 7 days) increased the Cmax and AUC of IV midazolam (0.4 mg single 
dose) an average of 1.3- and 4.6-fold, respectively; Posaconazole 400 mg oral suspension twice daily 
for 7 days increased the IV midazolam Cmax and AUC by 1.6 and 6.2-fold, respectively. Both doses of 
posaconazole increased Cmax and AUC of oral midazolam (2 mg single oral dose) by 2.2 and 4.5-
fold, respectively.  In addition, oral posaconazole (200 mg or 400 mg oral suspension) prolonged the 
mean terminal half-life of midazolam from approximately 3-4 hours to 8-10 hours during 
coadministration. Increased plasma midazolam concentrations could potentiate and prolong hypnotic 
and sedative effects. 
Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., 
alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. 
Patients must be monitored closely for adverse effects associated with high plasma concentrations of 
benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available 
to reverse these effects. It is recommended that dose adjustments of benzodiazepines, metabolized by 
CYP3A4, be considered during coadministration with posaconazole.
6. Anti-HIV Drugs 
As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase 
plasma levels of these antiretroviral agents. Repeat dose administration of oral posaconazole (400 mg 
oral suspension twice daily for 7 days) increased the Cmax and AUC of atazanavir (300 mg once a 
day for 7 days) an average of 2.6-fold and 3.7-fold, respectively, in healthy subjects.  Repeat dose 
administration of oral posaconazole (400 mg oral suspension twice daily for 7 days) increased the 
Cmax and AUC of atazanavir to a lesser extent when administered as a boosted regimen with ritonavir 
(300 mg atazanavir plus ritonavir 100 mg once a day for 7 days) with an average of 1.5-fold and 2.5-
fold, respectively, in healthy subjects. Frequent monitoring for adverse events and toxicity related to 
antiretroviral agents that are substrates of CYP3A4 is recommended during co-administration with 
posaconazole.
Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma 
concentrations. 400mg once a day decreased the Cmax and AUC of posaconazole by 45% and 50%, 
respectively. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the 
benefit outweighs the risks. 
Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole 
increases plasma concentrations of these drugs. Frequent monitoring of adverse effects and toxicity of 
ritonavir and atazanavir should be performed during coadministration with posaconazole. 
Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole 
plasma concentrations. If concomitant administration is required, close monitoring for breakthrough 
fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg BID x 10 
days) decreased the Cmax and AUC of posaconazole (200 mg oral suspension QD on the 1st day, 200 
mg oral suspension BID on the 2nd day, then 400 mg oral suspension BID x 8 Days) by 21% and 
23%, respectively.
7. Rifabutin 
Rifabutin induces UDP-glucuronidase, Rifabutin 300mg once a day decreased the Cmax and AUC of 
posaconazole by 43% and 49%, respectively. Rifabutin is also metabolized by CYP3A4. Therefore, 
coadministration of rifabutin with posaconazole increases the Cmax and AUC of rifabutin by 31% 
and 72%, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the 
 
 
04Q460


Product:  MK-5592 
100
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
benefit to the patient outweighs the risk. However, if concomitant administration is required, close 
monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and 
adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are 
recommended. 
8. Phenytoin 
Phenytoin induces UDP-glucuronidase, Phenytoin 200mg once a day decreased the Cmax and AUC of 
posaconazole by 41% and 50%, respectively. Phenytoin is also metabolized by CYP3A4. Therefore, 
coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations. 
Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient 
outweighs the risk. However, if concomitant administration is required, close monitoring for 
breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations 
should be performed while coadministered with posaconazole and dose reduction of phenytoin should 
be considered.
9. Gastric Acid Suppressors/Neutralizers 
Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) decrease 
posaconazole plasma concentrations. It is recommended to avoid concomitant use of cimetidine and 
esomeprazole with posaconazole unless the benefit outweighs the risks.
Posaconazole plasma concentrations (Cmax and AUC) were reduced by 39 % when posaconazole 
oral suspension was administered with cimetidine (400 mg twice a day) due to reduced absorption 
possibly secondary to a decrease in gastric acid production. Co-administration of posaconazole oral 
suspension with H2 receptor antagonists should be avoided if possible. 
Similarly, administration of 400 mg posaconazole oral suspension with esomeprazole (40 mg daily) 
decreased mean Cmax and AUC by 46 % and 32 %, respectively, compared to dosing with 400 mg 
posaconazole alone. Co-administration of posaconazole oral suspension with proton pump inhibitors 
should be avoided if possible.
However, if concomitant administration is required, close monitoring for breakthrough fungal 
infections is recommended. No clinically relevant effects were observed when posaconazole is 
concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage 
adjustment of posaconazole is required when posaconazole is concomitantly used with antacids and 
H2 receptor antagonists other than cimetidine.
10. Vinca Alkaloids 
Most of the vinca alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma 
concentrations of vinca alkaloids (e.g., vincristine and vinblastine) which may lead to neurotoxicity. 
Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered. 
11. Calcium Channel Blockers Metabolized by CYP3A4 
Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by 
CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for 
adverse reactions and toxicity related to calcium channel blockers is recommended during 
coadministration. Dose reduction of calcium channel blockers may be needed. 
12. Digoxin 
Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and 
posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during 
coadministration. 
 
 
04Q460


Product:  MK-5592 
101
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
13. Gastrointestinal Motility Agents 
Metoclopramide decreases posaconazole plasma concentrations. If metoclopramide is concomitantly 
administered, it is recommended to closely monitor for breakthrough fungal infections. 
Loperamide does not affect posaconazole plasma concentrations. No dosage adjustment of 
posaconazole is required when loperamide and posaconazole are used concomitantly. 
14. Glipizide 
10mg single dose had no clinically significant effect on posaconazole Cmax and AUC. Although no 
dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when 
posaconazole and glipizide are concomitantly used.
15. Zidovudine (AZT), lamivudine (3TC), indinavir
Clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, 
indinavir were observed when administered with posaconazole; therefore, no dose adjustments are 
required for these co-administered drugs.
[Overdosage]
During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse 
reactions noted that were different from the lower doses. In addition, accidental overdose was noted 
in one patient who took 1200 mg BID for 3 days. No related adverse reactions were noted by the 
investigator. 
Posaconazole is not removed by hemodialysis.
[Clinical Trial]
1. Prophylaxis of Aspergillus and Candida Infections 
Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the 
prevention of invasive fungal infections (IFIs) among patients at high risk due to severely 
compromised immune systems. 
The first study (Study 1) was a randomized, double-blind trial that compared posaconazole oral 
suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis 
against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients 
with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite 
endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may 
have met more than one of these criteria). Study 1 assessed all patients while on study therapy plus 7 
days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 
2 treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 6 contains the results from 
Study 1.
 
 
04Q460


Product:  MK-5592 
102
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE 6: Results from Blinded Clinical Study 1 in Prophylaxis of IFI in All Randomized Patients 
with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD)
Posaconazole 
n=301
Fluconazole 
n=299
On therapy plus 7 days
Clinical Failure*
50 (17%)
55 (18%)
Failure due to:
Proven/Probable IFI 
7 (2%)
22 (7%)
(Aspergillus) 
3 (1%)
17 (6%)
(Candida) 
1 (<1%)
3 (1%)
(Other) 
3 (1%)
2 (1%)
All Deaths
22 (7%)
24 (8%)
Proven/probable fungal infection prior to death
2 (<1%)
6 (2%)
SAF†
27 (9%)
25 (8%)
Through 16 weeks
Clinical Failure*,‡
99 (33%)
110 (37%)
Failure due to:
Proven/Probable IFI 
16 (5%)
27 (9%)
(Aspergillus) 
7 (2%)
21 (7%)
(Candida) 
4 (1%)
4 (1%)
(Other) 
5 (2%)
2 (1%)
All Deaths
58 (19%)
59 (20%)
Proven/probable fungal infection prior to death 
10 (3%)
16 (5%)
SAF†
26 (9%)
30 (10%)
Event free lost to follow-up§
24 (8%)
30 (10%)
* Patients may have met more than one criterion defining failure. 
† Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions 
(empiric/IFI usage >4 consecutive days). 
‡ 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%). 
§ Patients who are lost to follow-up (not observed for 112 days), and who did not meet 
another clinical failure endpoint. These patients were considered failures. 
The second study (Study 2) was a randomized, open-label study that compared posaconazole oral 
suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole 
oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were 
receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. As 
in Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, 
death, or treatment with systemic antifungal therapy (Patients might have met more than one of these 
criteria). Study 2 assessed patients while on treatment plus 7 days and 100 days postrandomization. 
The mean duration of therapy was comparable between the 2 treatment groups (29 days, 
posaconazole; 25 days, fluconazole or itraconazole). Table 7 contains the results from Study 2. 
 
 
04Q460


Product:  MK-5592 
103
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE 7: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized 
Patients with Hematologic Malignancy and Prolonged Neutropenia
Posaconazole
n=304
Fluconazole/Itraconazole
n=298
On therapy plus 7 days
Clinical Failure*,†
82 (27%)
126 (42%)
Failure due to:
Proven/Probable IFI 
7 (2%)
25 (8%)
(Aspergillus) 
2 (1%)
20 (7%)
(Candida) 
3 (1%)
2 (1%)
(Other) 
2 (1%)
3 (1%)
All Deaths
17 (6%)
25 (8%)
Proven/probable fungal 
infection prior to death 
1 (<1%)
2 (1%)
SAF‡
67 (22%)
98 (33%)
Through 100 days postrandomization
Clinical Failure†
158 (52%) 
191 (64%) 
Failure due to: 
Proven/Probable IFI 
14 (5%) 
33 (11%) 
(Aspergillus) 
2 (1%) 
26 (9%) 
(Candida) 
10 (3%) 
4 (1%) 
(Other) 
2 (1%) 
3 (1%) 
All Deaths
44 (14%)
64 (21%)
Proven/probable fungal 
infection prior to death 
2 (1%) 
16 (5%) 
SAF‡
98 (32%) 
125 (42%) 
Event free lost to follow-up§
34 (11%) 
24 (8%) 
* 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%). 
† Patients may have met more than one criterion defining failure.
‡ Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions 
(empiric/IFI usage >3 consecutive days).
§ Patients who are lost to follow-up (not observed for 100 days), and who did not meet 
another clinical failure endpoint. These patients were considered failures. 
In summary, 2 clinical studies of prophylaxis were conducted. As seen in the accompanying tables 
(Tables 6 and 7), clinical failure represented a composite endpoint of breakthrough IFI, mortality and 
use of systemic antifungal therapy. In Study 1 (Table 6), the clinical failure rate of posaconazole 
(33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% 
to 3.7%) while in Study 2 (Table 7) clinical failure was lower for patients treated with posaconazole 
(27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the 
difference posaconazole–comparator -22.9% to -7.8%). 
All-cause mortality was similar at 16 weeks for both treatment arms in Study 1 [POS 58/301 (19%) 
vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients 
in Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated substantially 
fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole
prophylaxis when compared to patients receiving fluconazole or itraconazole. 
2. Treatment of Oropharyngeal Candidiasis 
Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected patients with 
oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension 
 
 
04Q460


Product:  MK-5592 
104
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
(both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 
100 mg once a day for 13 days). 
Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the 
end of treatment. Patients who received at least 1 dose of study medication and had a positive oral 
swish culture of Candida species at baseline were included in the analyses (see Table 8). The majority 
of the subjects had C. albicans as the baseline pathogen. 
Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) 
and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks 
after the end of treatment were similar between the treatment arms (see Table 8). 
Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of 
therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also 
similar between the treatment arms (see Table 8).
TABLE 8: Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal 
Candidiasis
Posaconazole
Fluconazole
Clinical Success at End of Therapy (Day 14) 
155/169 (91.7%)
148/160 (92.5%)
Clinical Relapse (4 Weeks after End of Therapy) 
45/155 (29.0%)
52/148 (35.1%)
Mycological Eradication (absence of CFU) at End of 
Therapy (Day 14) 
88/169 (52.1%)
80/160 (50.0%)
Mycological Relapse (4 Weeks after End of Treatment) 
49/88 (55.6%)
51/80 (63.7%)
Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with 
≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, 
fluconazole 68.1%). The clinical significance of this finding is unknown. 
3. Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole 
or Itraconazole
Study 4 was a noncomparative study of posaconazole oral suspension in HIV-infected subjects with 
OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was 
considered refractory if there was failure to improve or worsening of OPC after a standard course of 
therapy with fluconazole ≥100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for 
at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been 
discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled 
in this study, 89 subjects met these strict criteria for refractory infection. 
Forty-five subjects with refractory OPC were treated with posaconazole 400 mg BID for 3 days, 
followed by 400 mg QD for 25 days with an option for further treatment during a 3-month 
maintenance period. Following a dosing amendment, a further 44 subjects were treated with 
posaconazole 400 mg BID for 28 days. The efficacy of posaconazole was assessed by the clinical 
success (cure or improvement) rate after 4 weeks of treatment. The clinical success rate was 74.2% 
(66/89). The clinical success rates for both the original and the amended dosing regimens were 
similar (73.3% and 75.0%, respectively).
 
 
04Q460


Product:  MK-5592 
105
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
[Pharmacology & Toxicology]
Pharmacology
Mechanism of Action
Posaconazole is a triazole antifungal agent. Posaconazole is a potent inhibitor of the enzyme 
lanosterol 14α-demethylase, which catalyses an essential step in ergosterol biosynthesis.
Posaconazole produce antifungal effect through the inhibition of lanosterol 14α-demethylase in the 
fungal cell membrane.
Microbiology
Posaconazole has been shown in vitro and in clinical infections to be active against the following 
micro-organisms: Aspergillus species (A. fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. 
ustus, A. ochraceus), Candida species (C. albicans, C. glabrata, C. krusei, C. parapsilosis), 
Cryptococcus neoformans, Coccidioides immitis, Fonsecaea pedrosoi, Histoplasma capsulatum, 
Pseudallescheria boydii and species of Alternaria, Exophiala, Fusarium, Ramichloridium, 
Rhizomucor, Mucor, and Rhizopus.
Posaconazole also exhibits in vitro activity against the following yeasts and moulds: Candida 
dubliniensis, C. famata, C. guilliermondii, C. lusitaniae, C. kefyr, C. rugosa, C. tropicalis, C. 
zeylanoides, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis, Cryptococcus 
laurentii, Kluyveromyces marxianus, Saccharomyces cerevisiae, Yarrowia lipolytica, species of 
Pichia, and Trichosporon, Aspergillus sydowii, Bjerkandera adusta, Blastomyces dermatitidis, 
Epidermophyton floccosum, Paracoccidioides brasiliensis, Scedosporium apiospermum, Sporothrix 
schenckii, Wangiella dermatitidis and species of Absidia, Apophysomyces, Bipolaris, Curvularia, 
Microsporum, Paecilomyces, Penicillium, and Trichophyton. However, the safety and effectiveness 
of posaconazole in treating clinical infections due to these microorganisms have not been established 
in clinical trials.
NOXAFIL* exhibits broad-spectrum antifungal activity against some yeasts and moulds not 
generally responsive to azoles, or resistant to other azoles:

species of Candida (including C. albicans isolates resistant to fluconazole, voriconazole and 
itraconazole, C. krusei and C. glabrata which are inherently less susceptible to fluconazole, 
C. lusitaniae which is inherently less susceptible to amphotericin B),

Aspergillus (including isolates resistant to fluconazole, voriconazole, itraconazole and 
amphotericin B)

organisms not previously regarded as being susceptible to azoles such as thezygomycetes 
(e.g. species of Absidia, Mucor, Rhizopus and Rhizomucor).
In vitro NOXAFIL* exhibited fungicidal activity against species of:

Aspergillus,

dimorphic fungi (Blastomyces dermatitidis, Histoplasma capsulatum, Penicillium marneffei, 
Coccidioides immitis)

some species of Candida.
In animal infection models NOXAFIL* was active against a wide variety of fungal infections caused 
by moulds or yeasts. However, there was no consistent correlation between minimum inhibitory 
concentration and efficacy.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should 
be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted 
 
 
04Q460


Product:  MK-5592 
106
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
before the results of the cultures and other laboratory studies are known. However, once these results 
become available, antifungal therapy should be adjusted accordingly.  Drug Resistance
C. albicans strains resistant to posaconazole could not be generated in the laboratory; spontaneous 
laboratory Aspergillus fumigatus mutants exhibiting a decrease in susceptibility to posaconazole arose 
at a frequency of 1x10-8 to 1x10-9. Clinical isolates of Candida albicans and Aspergillus fumigatus 
exhibiting significant decreases in posaconazole susceptibility are rare. In those rare instances where 
decreased susceptibility was noted, there was no clear correlation between decreased susceptibility 
and clinical failure. Clinical success has been observed in patients infected with organisms resistant to 
other azoles; consistent with these observations posaconazole was active in vitro against many 
Aspergillus and Candida strains that developed resistance to other azoles and/or amphotericin B. 
Breakpoints for posaconazole have not been established for any fungi.
ANTIFUNGAL MEDICINAL PRODUCT COMBINATIONS
When combinations of posaconazole with either amphotericin B or caspofungin were tested in vitro 
and in vivo there was little or no antagonism and in some instances there was an additive effect. The 
clinical significance of these results is unknown.
Toxicology
Genotoxicity:
Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a 
chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell 
mutagenicity study, and a mouse bone marrow micronucleus study.
Fertility:
Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400-mg BID 
regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up 
to 45 mg/kg (2.2 x the 400-mg BID regimen). 
Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing 
ribs) in rats when given in doses ≥27 mg/kg (≥1.4 times the 400-mg BID regimen based on steady-
state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in 
rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400-mg BID regimen. No 
malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 
mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 
400-mg BID regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in 
body weight gain of females and a reduction in litter size were seen.
Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower 
than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and 
malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal 
viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at 
therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were 
considered to be due to a treatment-related effect on steroidogenesis.
Carcinogenesis:
No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at 
doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole 
orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9 or 
3.5 times the exposure achieved with a 400-mg BID regimen, respectively, based on steady-state 
AUC in healthy volunteers administered a high-fat meal (400-mg BID regimen). In the mouse study, 
 
 
04Q460


Product:  MK-5592 
107
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
mice were treated at oral doses up to 60 mg/kg/day or 4.8 times the exposure achieved with a 400-mg 
BID regimen.
Others:
As observed with other azole antifungal agents, effects related to inhibition of steroid hormone 
synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects 
were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained 
at therapeutic doses in humans.
Neuronal phospholipidosis occurred in dogs dosed for ≥ 3 months at lower systemic exposures than 
those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one 
year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were 
observed on the central or peripheral nervous systems at systemic exposures greater than those 
achieved therapeutically.
Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 
2-year study in rats. These findings are not necessarily indicative of a potential for functional changes 
in humans.
No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety 
pharmacology study in monkeys at systemic exposures 4.6-fold greater than the exposures obtained at 
therapeutic doses in humans. Echocardiography revealed no indication of cardiac decompensation in 
a repeat dose safety pharmacology study in rats at a systemic exposure 1.4-fold greater than that 
achieved therapeutically. Increased systolic and arterial blood pressures (up to 29 mm-Hg) were seen 
in rats and monkeys at systemic exposures 1.4-fold and 4.6-fold greater, respectively, than those 
achieved with therapeutic doses.
[Pharmacokinetics]
Posaconazole is a triazole antifungal agent.
Exposure Response Relationship: In clinical studies of immunocompromised patients, a wide range of 
plasma exposures to posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis of 
patient data revealed an apparent association between average posaconazole concentrations (Cav) and 
prophylactic efficacy. A lower Cav may be associated with an increased risk of treatment failure 
[defined in the study as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), 
or invasive fungal infections (IFI)]. 
To enhance the oral absorption of posaconazole and optimize plasma concentrations: 
1) Each dose of NOXAFIL should be administered during or immediately (i.e., within 20 
minutes) following a full meal. In patients who cannot eat a full meal, each dose of 
NOXAFIL should be administered with a liquid nutritional supplement or an acidic 
carbonated beverage. For patients who cannot eat a full meal or tolerate an oral nutritional 
supplement or an acidic carbonated beverage, alternative antifungal therapy should be 
considered or patients should be monitored closely for breakthrough fungal infections. 
2) Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough 
fungal infections. 
3) Coadministration of drugs that can decrease the plasma concentrations of posaconazole 
should generally be avoided unless the benefit outweighs the risk. If such drugs are 
necessary, patients should be monitored closely for breakthrough fungal infections [see Drug 
Interactions].
 
 
04Q460


Product:  MK-5592 
108
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Absorption: 
In clinical studies of immunocompromised patients, a wide range of plasma exposures to 
posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an 
apparent association between average posaconazole concentrations (Cav) and prophylactic efficacy. 
A lower Cav may be associated with an increased risk of treatment failure [defined in the study as 
treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or invasive fungal 
infections (IFI)]. 
Posaconazole is absorbed with a median Tmax of ~3 to 5 hours. Dose proportional increases in plasma 
exposure (AUC) to posaconazole were observed following single oral doses from 50 mg to 800 mg 
and following multiple-dose administration from 50 mg BID to 400 mg BID. No further increases in 
exposure were observed when the dose was increased from 400 mg BID to 600 mg BID in febrile 
neutropenic patients or those with refractory invasive fungal infections. Steady-state plasma 
concentrations are attained at 7 to 10 days following multiple-dose administration. 
Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are 
approximately 3 times higher when administered with a nonfat meal and approximately 4 times 
higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following 
single-dose administration of 400 mg, the mean AUC and Cmax of posaconazole are approximately 3 
times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted 
state (see Table 9). In order to assure attainment of adequate plasma concentrations, it is 
recommended to administer posaconazole with food or a nutritional supplement. 
TABLE 9: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following 
Single-Dose Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions
Dose (mg)
Cmax 
(ng/mL)
Tmax * 
(hr)
AUC (I) 
(ng·hr/mL)
CL/F 
(L/hr)
t½
(hr)
200 mg fasted
(n=20)‡
132 (50) 
[45-267]
3.50 
[1.5-36†]
4179 (31) 
[2705-7269]
51 (25) 
[28-74]
23.5 (25) 
[15.3-33.7]
200 mg nonfat 
(n=20)‡
378 (43) 
[131-834]
4
[3-5]
10,753 (35) 
[4579-17,092]
21 (39) 
[12-44]
22.2 (18) 
[17.4-28.7]
200 mg high fat 
(54 gm fat) (n=20)‡
512 (34) 
[241-1016]
5
[4-5]
15,059 (26) 
[10,341-24,476]
14 (24) 
[8.2-19]
23.0 (19) 
[17.2-33.4]
400 mg fasted 
(n=23)§
121 (75) 
[27-366]
4
[2-12]
5258 (48) 
[2834-9567]
91 (40) 
[42-141]
27.3 (26) 
[16.8-38.9]
400 mg with liquid 
nutritional supplement 
(14 gm fat) (n=23)§
355 (43) 
[145-720]
5
[4-8]
11,295 (40) 
[3865-20,592]
43 (56) 
[19-103]
26.0 (19) 
[18.2-35.0]
* Median [min-max]. 
† The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL 
difference between 4 hrs and 36 hrs).
‡ n=15 for AUC (I), CL/F, and t ½
§ n=10 for AUC (I), CL/F, and t ½
 
 
04Q460


Product:  MK-5592 
109
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Table 10: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of 
Posaconazole in Healthy Volunteers
Study Description 
Administration Arms 
Change in Cmax
(ratio estimate**; 
90% CI of the 
ratio estimate) 
Change in AUC 
(ratio estimate**; 
90% CI of the ratio 
estimate) 
400-mg single dose with a high-fat 
meal relative to fasted state (n=12) 
5 minutes before high-fat 
meal 
↑96%
(1.96; 1.48-2.59)
↑111%
(2.11; 1.60-2.78)
During high-fat meal 
↑339%
(4.39; 3.32-5.80)
↑382%
(4.82; 3.66-6.35)
20 minutes after high-fat 
meal 
↑333%
(4.33; 3.28-5.73)
↑387%
(4.87; 3.70-6.42)
400 mg BID and 200 mg QID for 7 
days in fasted state and with liquid 
nutritional supplement (BOOST®) ( 
n=12) 
400 mg BID with BOOST 
↑65%
(1.65; 1.29-2.11)
↑66%
(1.66; 1.30-2.13)
200 mg QID with BOOST 
No Effect
No Effect
Divided daily dose from 400 mg 
BID to 200 mg QID for 7 days 
regardless of fasted conditions or 
with BOOST (n=12) 
Fasted state 
↑136%
(2.36; 1.84-3.02)
↑161%
(2.61; 2.04-3.35)
With BOOST 
↑137%
(2.37; 1.86-3.04)
↑157%
(2.57; 2.00-3.30)
400-mg single dose with carbonated 
acidic beverage (ginger ale) and/or 
proton pump inhibitor 
(esomeprazole) (n=12) 
Ginger ale 
↑92%
(1.92; 1.51-2.44)
↑70%
(1.70; 1.43-2.03)
Esomeprazole 
↓32%
(0.68; 0.53-0.86)
↓30%
(0.70; 0.59-0.83)
400-mg single dose with a 
prokinetic agent (metoclopramide 
10 mg TID for 2 days) + BOOST or 
a antikinetic agent (loperamide 4-
mg single dose) + BOOST (n=12) 
With metoclopramide + 
BOOST 
↓21%
(0.79; 0.72-0.87)
↓19%
(0.81; 0.72-0.91)
With loperamide + BOOST 
↓3%
(0.97; 0.88-1.07)
↑11%
(1.11; 0.99-1.25)
400-mg single dose either orally 
with BOOST or via an NG tube 
with BOOST (n=16) 
Via NG tube* 
↓19%
(0.81; 0.71-0.91)
↓23%
(0.77; 0.69-0.86)
*In 5 subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, 
respectively) when NOXAFIL was administered via an NG tube compared to when NOXAFIL was 
administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when 
NOXAFIL is administered via an NG tube because a lower plasma exposure may be associated with an increase 
risk of treatment failure.
**Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax
or AUC. 
The mean (%CV) [min-max] posaconazole average steady-state plasma concentrations (Cav) and 
steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 
mg BID of the oral suspension are provided in Table 11. 
 
 
04Q460


Product:  MK-5592 
110
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE 11: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in 
Patients Following Oral Administration of Posaconazole 200 mg TID and 400 mg BID
Dose*
Cav (ng/mL)
AUC|| 
(ng·hr/mL)
CL/F (L/hr)
V/F (L)
t½ (hr)
200 mg TID† (n=252) 
1103 (67) 
[21.5-3650]
ND¶
ND¶
ND¶
ND¶
200 mg TID‡ (n=215) 
583 (65) 
[89.7-2200]
15,900 (62) 
[4100-56,100]
51.2 (54) 
[10.7-146]
2425 (39) 
[828-5702]
37.2 (39) 
[19.1-148]
400 mg BID§ (n=23) 
723 (86) 
[6.70-2256]
9093 (80) 
[1564-26,794]
76.1 (78) 
[14.9-256]
3088 (84) 
[407-13,140]
31.7 (42) 
[12.4-67.3]
Note: Cav based on observed data; other pharmacokinetic parameters based on estimates from population 
pharmacokinetic analyses
* Oral suspension administration
† Allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease 
‡ Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or 
myelodysplastic syndromes
§ Febrile neutropenic patients or patients with refractory invasive fungal infections, Cav n=24 || AUC (0-24 
hr) for 200 mg TID and AUC (0-12 hr) for 400 mg BID
¶ Not done 
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in 
healthy subjects. 
Distribution:
Posaconazole has an apparent volume of distribution of 1774 L, suggesting extensive extravascular 
distribution and penetration into the body tissues. 
Posaconazole is highly protein bound (>98%), predominantly to albumin. 
Metabolism:
Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, 
the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). 
Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The 
excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate 
for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may 
affect posaconazole plasma concentrations. A summary of drugs studied clinically, which affect 
posaconazole concentrations, is provided in Table 12.
 
 
04Q460


Product:  MK-5592 
111
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE 12: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers
Coadministered Drug 
(Postulated Mechanism 
of Interaction)
Coadministered 
Drug 
Dose/Schedule 
Posaconazole 
Dose/Schedule 
Effect on Bioavailability of Posaconazole 
Change in Mean 
Cmax
(ratio estimate*; 
90% CI of the ratio 
estimate) 
Change in Mean 
AUC 
(ratio estimate*; 
90% CI of the ratio 
estimate) 
Efavirenz
(UDP-G Induction) 
400 mg QD × 10 and 
20 days
400 mg (oral 
suspension) BID 
× 10 and 20 days
↓45%
(0.55; 0.47-0.66)
↓ 50%
(0.50; 0.43-0.60)
Fosamprenavir (unknown 
mechanism)
700 mg BID x 10 
days
200 mg QD on 
the 1st day, 200 
mg BID on the 
2nd day, then 
400 mg BID x 8 
Days
↓ 21% 
0.79 (0.71-0.89)
↓ 23% 
0.77 (0.68-0.87)
Rifabutin
(UDP-G Induction) 
300 mg QD x 17 
days
200 mg (tablets) 
QD × 10 days
↓ 43%
(0.57; 0.43-0.75)
↓ 49%
(0.51; 0.37-0.71)
Phenytoin
(UDP-G Induction) 
200 mg QD x 10 
days
200 mg (tablets) 
QD × 10 days
↓ 41% 
(0.59; 0.44-0.79)
↓ 50% 
(0.50; 0.36-0.71)
Cimetidine
(Alteration of Gastric pH) 
400 mg BID × 10 
days
200 mg (tablets) 
QD × 10 days
↓ 39% 
(0.61; 0.53-0.70)
↓ 39% 
(0.61; 0.54-0.69)
Esomeprazole 
(Increase in gastric pH) 
40 mg QAM × 3 
days
400 mg (oral 
suspension) 
single dose
↓ 46% 
(0.54; 0.43-0.69)
↓ 32% 
(0.68; 0.57-0.81)
Metoclopramide 
(Increase in gastric 
motility) 
10 mg TID × 2 days
400 mg (oral 
suspension) 
single dose
↓ 21% 
(0.79; 0.72-0.87)
↓ 19% 
(0.81; 0.72-0.91)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax
or AUC.
In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an 
inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that 
posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. 
Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased 
by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were 
affected by posaconazole, is provided in Table 13. 
 
 
04Q460


Product:  MK-5592 
112
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
TABLE 13: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers 
and Patients
Coadministere
d Drug 
(Postulated 
Mechanism of 
Interaction is 
Inhibition of 
CYP3A4 by 
posaconazole) 
Coadministered 
Drug 
Dose/Schedule 
Posaconazole 
Dose/ Schedule 
Effect on Bioavailability of 
Coadministered Drugs 
Change in Mean 
Cmax
(ratio estimate*; 
90% CI of the ratio 
estimate) 
Change in Mean 
AUC 
(ratio estimate*; 
90% CI of the ratio 
estimate) 
Sirolimus 
2-mg single oral 
dose 
400 mg (oral 
suspension) BID x 
16 days 
↑ 572%
(6.72; 5.62-8.03)
↑ 788%
(8.88; 7.26-10.9)
Cyclosporin 
Stable maintenance 
dose in heart 
transplant recipients 
200 mg (tablets) 
QD x 10 days 
↑ cyclosporine whole blood trough 
concentrations 
Cyclosporine dose reductions of up to 
29% were required 
Tacrolimus 
0.05-mg/kg single 
oral dose 
400 mg (oral 
suspension) BID × 
7 days 
↑ 121%
(2.21; 2.01-2.42)
↑ 358%
(4.58; 4.03-5.19)
Simvastatin 
40-mg single oral 
dose 
100 mg (oral 
suspension) QD x 
13 days 
200 mg (oral 
suspension) QD x 
13 days
Simvastatin
↑ 841%
(9.41, 7.13-12.44) 
Simvastatin Acid
↑817%
(9.17, 7.36-11.43)
Simvastatin 
↑1041%
(11.41, 7.99-16.29) 
Simvastatin Acid 
↑851%
(9.51, 8.15-11.10)
Simvastatin
↑931%
(10.31, 8.40-12.67)
Simvastatin Acid 
↑634%
(7.34, 5.82-9.25)
Simvastatin 
↑960%
(10.60, 8.63-13.02)
Simvastatin Acid
↑748%
(8.48, 7.04-10.23)
Midazolam
0.4-mg single IV 
dose†
0.4-mg single IV 
dose†
2-mg single oral 
dose†
2-mg single oral 
dose†
200 mg (oral 
suspension) BID x 
7 days
400 mg (oral 
suspension) BID x 
7 days
200 mg (oral 
suspension) QD x 
7 days
400 mg (oral 
suspension) BID x 
7 days
↑30%
(1.3; 1.13-1.48)
↑62%
(1.62; 1.41-1.86)
↑169%
(2.69; 2.46-2.93)
↑138% 
(2.38; 2.13-2.66)
↑362%
(4.62; 4.02-5.3)
↑524%
(6.24; 5.43-7.16)
↑470%
(5.70; 4.82-6.74)
↑397%
(4.97; 4.46-5.54)
Rifabutin 
300 mg QD x 17 
days 
200 mg (tablets) 
QD × 10 days 
↑ 31%
(1.31; 1.10-1.57)
↑72% (1.72;1.51-
1.95)
Phenytoin 
200 mg QD PO x 
10 days 
200 mg (tablets) 
QD x 10 days 
↑ 16%
(1.16; 0.85-1.57)
↑16%
(1.16; 0.84-1.59)
Ritonavir 
100 mg QD x 14 
days 
400 mg (oral 
suspension) BID x 
7 days 
↑ 49%
(1.49; 1.04-2.15)
↑ 80%
(1.8;1.39-2.31)
 
 
04Q460


Product:  MK-5592 
113
Protocol/Amendment No.: 120-00 
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Coadministere
d Drug 
(Postulated 
Mechanism of 
Interaction is 
Inhibition of 
CYP3A4 by 
posaconazole) 
Coadministered 
Drug 
Dose/Schedule 
Posaconazole 
Dose/ Schedule 
Effect on Bioavailability of 
Coadministered Drugs 
Change in Mean 
Cmax
(ratio estimate*; 
90% CI of the ratio 
estimate) 
Change in Mean 
AUC 
(ratio estimate*; 
90% CI of the ratio 
estimate) 
Atazanavir 
Atazanavir/ 
ritonavir 
boosted 
regimen
300 mg QD x 14 
days 
300 mg/100 mg QD 
x14 days
400 mg (oral 
suspension) BID x 
7
400 mg (oral 
suspension) BID x 
7 days
↑155%
(2.55; 1.89-3.45)
↑53%
(1.53; 1.13-2.07)
↑268%
(3.68; 2.89-4.70)
↑146%
(2.46; 1.93-3.13)
*Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for 
Cmax or AUC.
† The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during 
coadministration with posaconazole. 
Additional clinical studies demonstrated that no clinically significant effects on zidovudine, 
lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; 
therefore, no dose adjustments are required for these coadministered drugs when coadministered with 
posaconazole 200 mg QD. 
Excretion: 
Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range: 20-66 hours) and a total 
body clearance (CL/F) of 32 L/hr. Posaconazole is predominantly eliminated in the feces (71% of the 
radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the 
radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled 
dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).
[Storage]
Store at 25°C; excursions permitted to 15°-30°C. Do not freeze.
[Package Material & Size]
105 ml of oral suspension in a 123 ml bottle (glass amber type IV) closed with a plastic child-resistant 
cap (polypropylene) and a measuring spoon (polystyrene) with 2 graduations: 2.5 ml and 5 ml.
1 bottle/box.
[Shelf Life]
Unopened container: 24 months
After first opening the container: 4 weeks
 
 
04Q460


Pr o d uct:   M K -5 5 9 2 
1 1 4
Pr ot oc ol/ A me n d me nt N o.: 1 2 0- 0 0 
M K - 5 5 9 2- 1 2 0- 0 0 Fi nal Pr ot oc ol
2 4- J ul- 2 0 1 7
C o nfi de ntial
[ A p pr o ve d S pecific ati o n] 
J X 2 0 0 7 0 1 2 8
[I m p ort Dr u g Lice nse N u m ber] 
H 2 0 1 5 0 0 6 5
[ C o m p a n y]
Tel N u m ber :
 
 
P P D
0 4 Q 4 6 0
C CI


Product:  MK-5592 
115
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
List of Abbreviations
12.11
Abbreviations
Definitions
AE 
Adverse event
ALT 
Alanine aminotransferase 
AMB
Amphotericin B
AML
Acute myelogenous leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
ASaT
All Subjects as Treated
AUC 
Area under the curve
AUC0-inf
Area under the plasma concentration-time curve from time 0 extrapolated to
infinity
AUC0-last
Area under the plasma concentration-time curve from time 0 to last measurable 
concentration
BMI
Body mass index
BP 
Blood pressure
bpm 
Beats per minute
Cmax
Maximum plasma concentration
CI 
Confidence interval
CFR
Code of Federal Regulations
CL
Clearance
CL/F
Apparent clearance
CRF 
Case report form
CSR 
Clinical study report
CYP
Cytochrome P-450
D5W
5% dextrose for injection
ECG 
Electrocardiogram
ECI
Event of Clinical Interest
EOT
End Of Trial
ERC
Ethical Review Committee
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FSH
Follicle stimulating hormone
GCP 
Good Clinical Practices
HIV
Human immunodeficiency virus
HSCT
Hematopoietic Stem Cell Transplantation
hr 
Hour
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registrationof Pharmaceuticals for Human Use
IEC
Independent Ethics Commitee
IFI
Invasive fungal infection
IRB
Institutional Review Board
IRBs/ERCs
Institutional Review Boards/ethics committees
IUD
Intrauterine device
IV
Intravenous
kg 
Kilogram
L 
Liter
MDS
Myelodysplastic syndrome
mg 
Milligrams
 
 
04Q460


Product:  MK-5592 
116
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
Abbreviations
Definitions
mL
Milliliter
NA
N/A Not applicable
NOAEL
No observable adverse effect level
NOEL
No observed effect level
PK/PD
Pharmacokinetic/Pharmacodynamic
POS
Posaconazole
PP
Per-Protocol
QD
Quaque die (once a day)
SAE 
Serious adverse event
SAP
Statistical Analysis Plan
SCH 
Schering-Plough identification number
SD 
Standard deviation
SOP 
Standard operating procedure
t1/2
Half-life
tmax
Time to reach maximum drug concentration
Vd
Volume of Distribution
ULN
Upper limit of normal
V/F
Volume of distribution as a function of bioavailability
WBC
White blood cell (count)
 
 
04Q460


Product:  MK-5592 
117
Protocol/Amendment No.: 120-00
MK-5592-120-00 Final Protocol
24-Jul-2017
Confidential
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 – 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
 
 
04Q460