A Randomized, Comparative, Open-label Study to Assess the Safety and Efficacy of MK-5592 Compared With Voriconazole in Japanese Subjects With Deep-seated Fungal Infection
Phase: PHASE3
Conditions: Aspergillosis
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02180165 
Document Date: 
27-Apr-2017
A Randomized, Comparative, Open-label Study to Assess the 
Safety and Efficacy of MK-5592 Compared with Voriconazole in 
Japanese Subjects with Deep-seated Fungal Infection

Product:  MK-5592 (SCH 56592)
1
Protocol/Amendment No.: 101-06
MK-5592-101-06 Final Protocol
27-Apr-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder.
TITLE:
A Randomized, Comparative, Open-label Study to Assess the Safety and Efficacy of MK-
5592 Compared with Voriconazole in Japanese Subjects with Deep-seated Fungal Infection 
  
EudraCT NUMBER:  [Not Applicable]
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
2.1
Trial Design ........................................................................................................... 14
2.2
Trial Diagram........................................................................................................ 14
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
3.1
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 15
4.0
BACKGROUND & RATIONALE.......................................................................... 16
4.1
Background ........................................................................................................... 16
Pharmaceutical and Therapeutic Background .................................................... 16
4.1.1
Clinical Trials...................................................................................................... 18
4.1.2
4.1.2.1
Treatment Study (P00041 Study) and Prophylaxis Study (P01899 and 
C/I98-316).................................................................................................... 18
4.1.2.2
PN067 Study................................................................................................ 19
4.1.2.3
P05520 Study............................................................................................... 20
4.1.2.4
P05615 Study............................................................................................... 22
Ongoing Clinical Trials....................................................................................... 24
4.1.3
4.1.3.1
PN069 .......................................................................................................... 24
4.1.3.2
PN101 cohort 1 (Preliminary data review).................................................. 24
4.2
Rationale................................................................................................................ 25
Rationale for the Trial and Selected Subject Population .................................... 25
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 26
4.2.2
Rationale for Endpoints ...................................................................................... 28
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 29
4.2.3.2
Safety Endpoints .......................................................................................... 32
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 32
4.2.3.4
Future Biomedical Research........................................................................ 33
5.0
METHODOLOGY ................................................................................................... 33
5.1
Entry Criteria........................................................................................................ 33
 
 
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Diagnosis/Condition for Entry Into the Trial...................................................... 33
5.1.1
Subject Inclusion Criteria.................................................................................... 34
5.1.2
Subject Exclusion Criteria .................................................................................. 38
5.1.3
5.2
Trial Treatments................................................................................................... 41
Dose Selection/Modification .............................................................................. 41
5.2.1
5.2.1.1
Dose Selection ............................................................................................. 41
5.2.1.1.1
MK-5592 IV Solution........................................................................... 42
5.2.1.1.2
MK-5592 Solid Oral Tablet.................................................................. 43
5.2.1.1.3
Voriconazole IV.................................................................................... 44
5.2.1.1.4
Voriconazole Oral Tablet...................................................................... 45
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 46
5.2.1.3
Treatment Duration...................................................................................... 46
Timing of Dose Administration .......................................................................... 47
5.2.2
Trial Blinding/Masking....................................................................................... 47
5.2.3
5.3
Randomization or Treatment Allocation............................................................ 47
5.4
Stratification.......................................................................................................... 47
5.5
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 47
Concomitant Medications, Supplements, and Other Substances Allowed 
5.5.1
During the Trial................................................................................................... 48
Other Treatments ................................................................................................ 49
5.5.2
5.6
Rescue Medications & Supportive Care............................................................. 49
5.7
Diet/Activity/Other Considerations..................................................................... 50
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 50
5.9
Subject Replacement Strategy............................................................................. 50
5.10
Beginning and End of the Trial ........................................................................... 51
5.11
Clinical Criteria for Early Trial Termination ................................................... 51
6.0
TRIAL FLOW CHART ........................................................................................... 52
7.0
TRIAL PROCEDURES ........................................................................................... 55
7.1
Trial Procedures ................................................................................................... 55
Administrative Procedures.................................................................................. 55
7.1.1
7.1.1.1
Informed Consent......................................................................................... 55
7.1.1.1.1
General Informed Consent.................................................................... 55
 
 
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7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 56
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 56
7.1.1.3
Subject Identification Card .......................................................................... 56
7.1.1.4
Medical History ........................................................................................... 56
7.1.1.5
Prior and Concomitant Medications Review ............................................... 56
7.1.1.5.1
Prior Medications.................................................................................. 56
7.1.1.5.2
Concomitant Medications..................................................................... 56
7.1.1.6
Assignment of Screening Number............................................................... 56
7.1.1.7
Assignment of Randomization Number....................................................... 57
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 57
Clinical Procedures/Assessments........................................................................ 57
7.1.2
7.1.2.1
Physical Examination................................................................................... 57
7.1.2.2
Clinical Signs and Symptoms of Deep-Seated Fungal Infection................. 57
7.1.2.3
Vital Signs.................................................................................................... 58
7.1.2.4
12-Lead Electrocardiogram ......................................................................... 58
7.1.2.5
Diagnostic Imaging...................................................................................... 58
7.1.2.6
Mycology Testing........................................................................................ 59
7.1.2.7
Serology Testing (Aspergillus Antigen, Aspergillus Antibody and β-D-
Glucan)......................................................................................................... 59
7.1.2.8
Sample Collection for Plasma Concentration of MK-5592 (MK-5592 
Treatment Arm) ........................................................................................... 59
7.1.2.9
Evaluation for Overall Response ................................................................. 60
7.1.2.10 Guidance for Treatment of adverse event.................................................... 60
7.1.2.11 Domiciling ................................................................................................... 61
Laboratory Procedures/Assessments .................................................................. 61
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 61
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 62
7.1.3.2.1
Blood Collection for Plasma MK-5592................................................ 62
7.1.3.3
Future Biomedical Research........................................................................ 63
Other Procedures................................................................................................. 63
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 63
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 63
 
 
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7.1.4.2
Blinding/Unblinding .................................................................................... 63
Visit Requirements.............................................................................................. 63
7.1.5
7.1.5.1
Procedure of MK-5592 Treatment for Subjects in case That 
Zygomycete are Observed During the Treatment Period in 
Voriconazole Treatment Arm ...................................................................... 64
7.2
Assessing and Recording Adverse Events .......................................................... 64
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 65
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 65
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 66
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 66
7.2.3.2
Events of Clinical Interest............................................................................ 67
Evaluating Adverse Events ................................................................................. 67
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 70
7.2.5
7.3
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 70
Clinical Adjudication Committee ....................................................................... 70
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 70
8.1
Statistical Analysis Plan Summary ..................................................................... 70
Efficacy Analyses ............................................................................................... 70
8.1.1
Safety Analyses................................................................................................... 71
8.1.2
Power and Sample Size....................................................................................... 71
8.1.3
Interim Analyses ................................................................................................. 71
8.1.4
8.2
Statistical Analysis Plan ....................................................................................... 72
Responsibility for Analyses/In-House Blinding ................................................. 72
8.2.1
Hypotheses/Estimation ....................................................................................... 72
8.2.2
Analysis Endpoints ............................................................................................. 72
8.2.3
8.2.3.1
Efficacy Endpoints....................................................................................... 72
8.2.3.1.1
Primary Efficacy Endpoint ................................................................... 72
8.2.3.1.2
Secondary Efficacy Endpoints.............................................................. 72
8.2.3.1.3
Exploratory Efficacy Endpoints............................................................ 73
8.2.3.2
Safety Endpoints .......................................................................................... 73
8.2.3.3
Derivations of Efficacy Endpoints............................................................... 73
Analysis Populations........................................................................................... 74
8.2.4
 
 
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8.2.4.1
Efficacy Analysis Populations ..................................................................... 74
8.2.4.2
Safety Analysis Populations ........................................................................ 75
Statistical Methods.............................................................................................. 75
8.2.5
8.2.5.1
Statistical Methods for Efficacy................................................................... 75
8.2.5.1.1
Primary Efficacy Analysis .................................................................... 75
8.2.5.1.2
Secondary Efficacy Analysis ................................................................ 76
8.2.5.1.3
Other Secondary and Exploratory Efficacy Analyses .......................... 77
8.2.5.1.4
Accounting for Missing Data................................................................ 77
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 77
8.2.5.3
Summary of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 78
Multiplicity ......................................................................................................... 78
8.2.6
Sample Size and Power Calculations.................................................................. 78
8.2.7
Subgroup Analyses and Effect of Baseline Factors ............................................ 80
8.2.8
Interim Analysis.................................................................................................. 80
8.2.9
Compliance (Medication Adherence) ................................................................. 80
8.2.10
8.2.10.1 IV Route....................................................................................................... 80
8.2.10.2 Oral Therapy ................................................................................................ 81
Extent of Exposure.............................................................................................. 81
8.2.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 81
9.1
Investigational Product ........................................................................................ 81
9.2
Packaging and Labeling Information ................................................................. 82
9.3
Clinical Supplies Disclosure................................................................................. 82
9.4
Storage and Handling Requirements.................................................................. 82
9.5
Returns and Reconciliation.................................................................................. 82
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 82
10.1
Confidentiality....................................................................................................... 82
Confidentiality of Data ....................................................................................... 82
10.1.1
Confidentiality of Subject Records ..................................................................... 83
10.1.2
Confidentiality of Investigator Information........................................................ 83
10.1.3
Confidentiality of IRB/IEC Information............................................................. 84
10.1.4
 
 
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10.2
Compliance With Financial Disclosure Requirements...................................... 84
10.3
Compliance With Law, Audit and Debarment .................................................. 84
10.4
Compliance With Trial Registration and Results Posting Requirements....... 86
10.5
Quality Management System............................................................................... 86
10.6
Data Management................................................................................................. 87
10.7
Publications ........................................................................................................... 87
11.0
LIST OF REFERENCES......................................................................................... 88
12.0
APPENDICES........................................................................................................... 90
12.1
Merck Code of Conduct for Clinical Trials........................................................ 90
 
12.3
Pharmacogenetics Informational Brochure for IRBs/IECs & 
Investigational Site Staff ...................................................................................... 98
12.5
Clinical Study Conduct System ......................................................................... 108
13.0
SIGNATURES......................................................................................................... 109
13.1
Sponsor's Representative ................................................................................... 109
13.2
Investigator.......................................................................................................... 109
 
 
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LIST OF TABLES
Table 1
Correlation Between Efficacy (Treatment or Prophylaxis for Invasive Fungal 
Infection) and Mean Exposure (Cavg).................................................................. 19
Table 2
Assessment of Similarity of Pharmacokinetic Parameters Following 30-
Minute Constant Infusion of MK-5592 IV Solution at a Dose of 300 mg 
Between Healthy, Japanese Male subjects and Healthy, Non-Japanese Male 
and Female Subjects ............................................................................................. 20
Table 3
Assessment of Similarity of Pharmacokinetic Parameters at Steady-State 
Following Once Daily Oral Administration of MK-5592 Solid Oral Tablet at 
a Dose of 200 mg and 400 mg to Healthy, Japanese Male Subjects, or 
Healthy, Non-Japanese Male and Female Subjects.............................................. 20
Table 4
Mean Pharmacokinetic Parameters of MK-5592 After Administration of IV 
Solution 200 or 300 mg BID (Day 1), Followed by 200 or 300 mg QD in 
High Risk Patients  (Results of P05520)............................................................... 21
Table 5
Mean Pharmacokinetic Parameters After Repeated Administration of the 
Solid Oral Tablet in High Risk Patients (Results of Parts 1 and 2, P05615)........ 23
Table 6
Estimated Cavg (pCavg) After Repeated Administration of 300 mg QD in 
High Risk Patients (Comparison of Results by Target Patients in Part 1B and 
Part 2, P05615)...................................................................................................... 23
Table 7
Criteria for Clinical Response............................................................................... 29
Table 8
Criteria for the Radiological Response................................................................. 30
Table 9
Criteria for Mycological Response....................................................................... 30
Table 10
Overall Response Criteria for Invasive Aspergillosis, Zygomycosis and 
Fusariosis .............................................................................................................. 31
Table 11
Overall Response Criteria for Chronic Pulmonary Aspergillosis......................... 31
Table 12
Overall Response Criteria for in Case of Zygomycosis and Fusariosis 
Without Imaging................................................................................................... 32
Table 13
Prohibited Medications......................................................................................... 39
Table 14
Trial Treatment ..................................................................................................... 41
Table 15
Dosing for MK-5592 IV Therapy for Cohort 2 .................................................... 43
Table 16 Dosing for MK-5592 Oral Therapy for Cohort 2 ................................................. 44
Table 17
Dosing for Voriconazole IV Therapy ................................................................... 45
Table 18
Dosing for Voriconazole Oral Tablet ................................................................... 45
Table 19
Allowed Concomitant Medications and Recommendations................................. 48
Table 20
Laboratory Tests (Hematology)............................................................................ 61
Table 21
Laboratory Tests (Blood Chemistry) .................................................................... 62
Table 22 Laboratory Test (Other)........................................................................................ 62
Table 23
Evaluating Adverse Events................................................................................... 68
Table 24
Analysis Strategy for Primary Efficacy Endpoint ................................................ 71
Table 25
The Data for Assessing the Overall Response and Criteria of Efficacy 
Judgment............................................................................................................... 74
Table 26
Analysis Strategy for Key Efficacy Variables...................................................... 76
Table 27
Analysis Strategy for Safety Parameters............................................................... 78
 
 
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Table 28
95% Confidence Interval for Difference of the Incidence Rates for Adverse
Events.................................................................................................................... 79
Table 29
Product Descriptions............................................................................................. 81
 
 
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LIST OF FIGURES
Figure 1
Outline of Trial Design and Therapeutic Regimen for Cohort 2........................ 15
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
This amendment is only applicable to 
. Primary reason for this amendment is 
to change the maximum treatment duration for the specific subjects with zygomycosis. Zygomycosis is a severe infection and 
amphotericin B formulation is an only option for the treatment in Japan at the moment. However, MK-5592 therapy would benefit the 
patients who cannot use these treatments. Therefore, MK-5592 therapy could be continued after finishing 84 day maximum treatment 
period in those patients with prior approval from Sponsor. During the study treatment over 84 days, adverse events should be 
monitored, and the information of study medication and adverse events should be recorded in the source documents and CRF(Routine 
safety laboratory should be also monitored and recorded in the source document). The study treatment period over 84 days in those 
zygomycosis subjects will be considered as extension period. All objectives in Section 3 will be performed for Cohort 2 only and
. Data from extension period will be excluded from the analysis.
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
5.2.1.3
TRIAL SUMMARY 
Trial Design
Treatment Duration
Added the possibility to join the 
extension period after main study 
period 
for 
the 
subject 
with 
zygomycosis.
Zygomycosis is a severe infection 
and amphotericin B formulation is an 
only option for the treatment in Japan 
at the moment. There is no option for 
the patients who cannot use these 
treatments. 
1.0
2.1
3.0
8.1
8.2
TRIAL SUMMARY
Trial Design
OBJECTIVE(S) & HYPOTHESIS(ES)
Statistical Analysis Plan Summary
Statistical Analysis Plan
Added to exclude data for 
extension period from the analysis 
for the subject with zygomycosis.
MK-5592 administration during the 
extension period for the subject with 
zygomycosis is an exceptional use, 
therefore the data is excluded from 
the analysis.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.2.3.3
6.0     
Pharmacokinetic Endpoints
TRIAL FLOW CHART (footnote 9)
Added and clarified not to collect 
the PK sampling during the 
extension period.
MK-5592 administration data and 
safety data is only collected during 
the extension period.
5.2.1.1
5.2.1.3
6.0
Dose Selection
Treatment Duration
TRIAL FLOW CHART (footnote 11)
Added to be able to switch the both 
formulation interactively (IV ↔
PO) during the extension period.
Zygomycosis is a severe infection 
and amphotericin B formulation is an 
only option for the treatment in Japan 
at the moment. There is no option for
the patients who cannot use these 
treatments. In those cases,
continuation of MK-5592 therapy 
would benefit the patients.
6.0
TRIAL FLOW CHART (footnote 13, 17)
Added and clarified the procedure 
during the extension period.
After the main study period, MK-
5592 administration is for the 
exceptional use, therefore, MK-5592 
administration data and safety data is 
only collected and procedures during 
the extension period are simplified.
7.1.2.9
Evaluation for Overall Response
Clarified not to evaluate the overall 
response during the extension 
period.
After the main study period, MK-
5592 administration is for the 
exceptional use, therefore, MK-5592 
administration data and safety data is 
only collected and procedures during 
the extension period are simplified.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-5592 Phase III study for treatment of deep-seated fungal infection in 
Japanese subjects.
Trial Phase
Phase III
Clinical Indication
Treatment of deep-seated fungal infection
Trial Type
Interventional
Type of control
Active control with Voriconazole
Route of administration
Intravenous or Oral (or both)
Trial Blinding
Unblinded Open-label
Treatment Groups 
MK-5592 treatment arm or Voriconazole treatment arm
Number of trial subjects
Approximately 112(Cohort 1: 22 subjects enrolled under protocol 
amendment 00-03, Cohort 2: 90 subjects enrolled under protocol 
amendment 04 and any subsequent amendment) subjects will be 
enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 45
months(may extend due to zygomycosis subjects who join the extension 
period) from the time the first subject signs the informed consent until 
the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial for approximately 15 weeks at a 
maximum, from the time the subject signs the Informed Consent Form 
(ICF) through the final contact.  After a screening phase of 1 week, each 
subject will be receiving assigned treatment for approximately 12 weeks.  
After the end of treatment each subject will be followed for 14 days.
However, if the subject is a patient with zygomycosis and joins the 
extension period, study period may be extended by necessary duration 
for the subject.
Randomization Ratio
A total of 112 subjects with Aspergillosis (approximately 112) will be 
randomized to MK-5592 treatment arm (approximately 75) or 
Voriconazole treatment arm (approximately 37) in a 2:1 ratio. 
 
 
nd a new Cohort 
2 which will include 90 patients with body weight ≥45 kg to receive 300 
mg QD of MK-5592. Subject with invasive aspergillosis will be 
randomized to MK-5592 treatment arm or Voriconazole treatment arm in 
a 2:1 ratio using a classification (proven and probable / possible) at the 
randomization as a stratification factor. Subject with chronic pulmonary 
aspergillosis will be randomized to MK-5592 treatment arm or 
voriconazole treatment arm in a 2:1 ratio without stratification. Subject 
with fusariosis or zygomycosis will be assigned to MK-5592 treatment 
arm only.
All objective in Section 3 will be performed for Cohort 2 only and
 
. Data from extension period will be excluded from 
the analysis of Cohort 2.
 
 
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2.0 TRIAL DESIGN
2.1
Trial Design
This is a randomized, active-controlled, parallel-group, multi-site, open-label trial of MK-
5592 versus Voriconazole in Japanese subjects with deep-seated fungal infection to be 
conducted in conformance with Good Clinical Practices. Subjects with Fusariosis or 
Zygomycosis will be assigned to the MK-5592 treatment arm; approximately 112 subjects 
with Aspergillosis will be randomized to MK-5592 (approximately 75 subjects) or 
Voriconazole (approximately 37 subjects) in a 2:1 ratio. Subject with invasive aspergillosis 
will be randomized to MK-5592 treatment arm or Voriconazole treatment arm in a 2:1 ratio 
using a classification (proven and probable / possible) at randomization as a stratification 
factor. Subject with chronic pulmonary aspergillosis will be randomized to MK-5592 
treatment arm or voriconazole treatment arm in a 2:1 ratio without stratification. 
Approximately 15 subjects with invasive aspergillosis as a target number will be enrolled. 
The target number of subjects is not set in the subjects with Fusariosis or Zygomycosis, and 
there will not be comparator arm for these subjects, because Fusarium and Zygomycota are 
rare fungi. MK-5592 or Voriconazole will be administered by oral and/or intravenous 
injection for 84 days as a general rule. After the end of treatment each subject will be 
followed for 14 days. The initial formulation will be selected based on the subjects’ 
condition. For the voriconazole treatment arm, subjects for whom zygomycota is detected 
after voriconazole is initiated may be transitioned to MK-5592 treatment arm at the 
investigator’s discretion after discontinuation of voriconazole treatment and completion of all 
applicable activities scheduled for the end of treatment visit. For the subjects with 
zygomycosis, restart of the study therapy after finishing 84 day maximum treatment period or
extension of treatment period could be done under the extension period with the prior
approval from the Sponsor and obtaining the signing of a new informed consent from the 
subject.
 
 and additional 90 subjects who will be enrolled into updated version of the protocol 
(from version 04) are treated as cohort 2. Cohort 2 is the main cohort in this study and all 
objectives in Section 3 will be performed for Cohort 2 only
 
. Data from extension period will be excluded from 
the analysis of Cohort 2.
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.
2.2
Trial Diagram
The trial design is provided in Figure 1.
 
 
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IV: 300 mg BID
OR
Oral Tab : 300 mg BID
IV: 300 mg QD
OR
Oral Tab : 300 mg QD
IV : 6 mg/kg BID
OR
Oral Tab : 300 mg BID 
IV : 4 mg/kg BID
OR
Oral Tab : 200 mg BID 
Screening
Follow up 14 days
Randomization
(approximately 90 subjects with 
Aspergillosis)
MK-5592 treatment arm
(approximately 60 subjects)
Voriconazole treatment arm
(approximaltey 30 subjects)
Day 1
Day 2-84
IV: 300 mg BID
OR
Oral Tab : 300 mg BID
IV: 300 mg QD
OR
Oral Tab : 300 mg QD
MK-5592 treatment arm
(Fusariosis or Zygomycosis)
1. In the event that additional work-up does not result in a proven or probable IA diagnosis within 7 days of randomization, 
subjects should continue participation in the trial with possible IA.
2. 22 subjects already enrolled is treated as cohort 1. Additional 90 subjects will be newly enrolled as cohort 2.
Figure 1 Outline of Trial Design and Therapeutic Regimen for Cohort 2
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
1) Objective: To assess and compare the safety of MK-5592 and Voriconazole in 
Japanese subjects with Aspergillosis [Invasive aspergillosis and Chronic pulmonary 
aspergillosis (Chronic progressive pulmonary aspergillosis and Simple pulmonary 
aspergilloma)]
3.2
Secondary Objective(s) & Hypothesis(es)
1) Objective: To assess the overall response on Day 42 of MK-5592 and Voriconazole 
in Japanese subjects with Invasive aspergillosis.
2) Objective: To assess the overall response on Day 84 of MK-5592 and Voriconazole 
in Japanese subjects with Chronic pulmonary aspergillosis (chronic progressive 
pulmonary aspergillosis and simple pulmonary aspergilloma)
 
 
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3) Objective: To assess the overall response at EOT of MK-5592 and Voriconazole in 
Japanese subjects with Aspergillosis [Invasive aspergillosis or Chronic pulmonary 
aspergillosis (Chronic progressive pulmonary aspergillosis and simple pulmonary 
aspergilloma)]
4) Objective: To assess the safety and efficacy of MK-5592 in Japanese subjects with 
fusariosis and zygomycosis
5) Objective: To assess the pharmacokinetic profile of MK-5592 in Japanese subjects 
with deep-seated fungal infection.
An overall response criterion is defined in Section 4.2.3.1.  Also, all objectives in Section 3 
will be performed for Cohort 2 only 
 
4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-5592.
Pharmaceutical and Therapeutic Background
4.1.1
Fungal infections are classified as superficial mycoses due to dermatophyte and deep-seated 
fungal infections, as represented by Candida spp. and Aspergillus spp.  Deep-seated fungal 
infections are recognized in patients in a broad area such as hematology, respiratory 
medicine, pediatrics and obstetrics and gynecology. The morbidity of deep-seated fungal 
infections is variable. There are some risk factors for deep-seated fungal infections such as 
latent or apparent infection due to highly infectious fungus and opportunistic infection under 
immuno-compromised conditions.  The latter accounts for the overwhelmingly majority of 
cases in Japan [1] and most of the cases led to a poor prognosis.  The important factors 
causing deep-seated fungal infections are neutropenia, immunosuppressive treatment, long-
term steroid administration, indwelling of CV catheters, complication of graft versus host 
disease (GVHD), long-term antibiotics administration, diabetes and HIV et. Al [2].  The 
more usage of immunosuppressive treatment for organ or bone marrow transplantation, 
change of medical condition emerging antibody drug and immune compromised in aging 
patients are increasing [3], the higher the risk is for deep-seated fungal infections. 
The fungi causing deep-seated fungal infection are eukaryotic organism existing in the body 
and environment, including Candida spp., Aspergillus spp. Cryptococcus spp and 
Zygomycetes spp.  Since there is no comprehensive surveillance system regarding a deep-
seated fungal infection, an epidemiological status of deep-seated fungal infection is mostly 
inferred by the information of pathology autopsy in Japan. According to the estimated 
number of deceased leukemic with deep-seated fungal infection, 20.9% of deceased leukemic 
have been infected by some fungi, in which majority of fungi is Aspergillus spp. (52.4%) and 
then Candida spp. (14.2%) and Zygomycetes spp. (12.0%). The rate of deep-seated fungal 
patients leading to serious medical conditions is 63.9% and the rate of serious medical 
 
 
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conditions in Zygomycetes spp., Aspergillus spp. and Candida spp. are 81.8%, 65.6% and 
57.8%, respectively.  Recently, fungal infection of Zygomycetes spp. is increasing [4] and it 
is reported that some patients displayed unfavorable response to conventional medications [5, 
6].  Therefore there are high medical needs to develop an antifungal agent with broad 
spectrum against fungi.  
Debridement therapy and treatment of antifungal agents for deep-seated fungal infection are 
generally performed and antifungal agent therapy are utilized as prophylactic for the onset of 
deep-seated mycosis.  Amphotericin B has a broad spectrum against fungi, strong antifungal 
activity and acts in sterilization against Candida spp., Aspergillus spp. and Zygomycetes spp.  
However sufficient doses of amphotericin B are unable to be administrated due to adverse 
effects.  Azole antifungal agents such as fluconazole are safer than amphotericin B but the 
azole class does not have necessarily satisfactory efficacy from the aspect of antifungal 
spectrum and pharmacokinetics. Voriconazole, approved in 2005, is effective against 
Aspergillus spp. and Candida spp with resistance to fluconazole and has broad spectrum 
activity against fungi. In Japan, a Phase III study showed that the efficacy of voriconazole for 
Japanese subjects with deep-seated fungal infection was 27/39 (69.2%) for Aspergillosis. 
Voriconazole is utilized as a first line of empirical therapy and target therapy for Aspergillus 
infection and is more effective as compared to amphotericin B [7]. Photophobia, vision 
blurred and visual impairment related to voriconazole administration are observed with high-
frequency. In some cases breakthrough infection due to Zygomycetes spp. during 
voriconazole administration were observed [8, 9]. At present, only amphotericin B is 
effective in both highly lethal Aspergillus infection and Zygomycetes infection. 
Conventional antifungal agent does not meet the medical needs so development of antifungal 
agents which have an effective broad spectrum and safer is needed. 
MK-5592 is an antifungal agent in the azole class and inhibits ergosterol biosynthesis, the 
main component of fungal cell membrane by affecting the enzyme lanosterol 14-alpha 
demethylase (CYP51), which is the same mechanism as other azoles [10-12].  As a result, 
depletion of ergosterol and the accumulation of methylated intermediates occurs. This leads 
to the inhibition of growth of the fungal cell or cell death and show antifungal activity. 
Clinical studies targeting patients with deep-seated fungal infections demonstrated that MK-
5592 oral suspension was effective against aspergillosis, candidiasis, pulmonary 
cryptococcosis, fusariosis, coccidioidomycosis, chromoblastomycosis and mycetoma and 
zygomycosis. Furthermore MK-5592 showed efficacy in zygomycosis patients with 
infections refractory or intolerant of the other antifungal treatments [5, 6].  In clinical studies 
targeting acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) patients 
with neutropenia and patients with GVHD MK-5592 showed superiority or non-inferiority 
efficacy in reducing the incidence of deep-seated fungal infections as compared to
itraconazole or fluconazole.  For safety, specific adverse drug reactions are reported but 
generally well tolerated. 
In the EU MK-5592 (oral suspension) was first approved in October 2005 and is currently 
registered and approved in more than 80 countries, such as the US, EU and Australia. MK-
5592 is indicated for the treatment of invasive aspergillosis with disease that is refractory or 
intolerant of other antifungal agents, treatment of fusariosis, coccidioidomycosis, 
 
 
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chromoblastomycosis and mycetoma, treatment of oropharyngeal candidiasis and 
prophylaxis of invasive fungal infections.  In addition MK-5592 has the indication for the 
treatment of zygomycosis in Australia. In Japan MK-5592 is expected to be effective for 
these fungal infections [13].  Thus, MK-5592 is an important alternative option for the 
treatment of deep-seated fungal infections as an antifungal agent with broad spectrum against 
fungi. The profile of MK-5592 oral suspension which is widely used in ex-Japan 
demonstrates that the pharmacokinetics of MK-5592 is affected by food and absorption is 
saturated at the highest dose. On the other hand, the formulation of MK-5592 which will be 
used in Japan (as of May 1st 2015, solid oral tablet is approved in US, EU, Canada, Australia, 
New Zealand, Switzerland, Taiwan and Korea, IV solution is approved in  US, EU, Canada 
and Australia), has an improved pharmacokinetic profile compared to the oral suspension. 
MK-5592 solid oral tablet and IV solution ensures sufficient exposure regardless of food. 
MK-5592 PK parameter is similar between Japanese and non-Japanese when single doses of 
MK-5592 solid oral tablet and IV solution and multiple doses of MK-5592 solid oral tablet 
are administered.
Therefore, in Japan, the Sponsor has decided to develop the MK-5592 solid oral tablet and 
IV solution which is thought to be an important alternative option for the treatment of 
Japanese patients with deep-seated fungal infections.
Clinical Trials
4.1.2
4.1.2.1
Treatment Study (P00041 Study) and Prophylaxis Study (P01899 and C/I98-
316)
Merck has analyzed the correlation between the efficacy and exposure of MK-5592 oral 
suspension in clinical trials conducted in overseas (P00041, P01899 and C/I98-316 study) 
(Table 1). As a result, efficacy of lowest quartile was lower than that of control and efficacy 
was becoming almost constant to ~2500 ng/mL.  Safety profile was similar within the 
exposure which was observed in clinical trial.  From the efficacy and safety point of view, it 
was suggested that 500~2500 ng/mL of Cavg was targeted.
 
 
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Table 1
Correlation Between Efficacy (Treatment or Prophylaxis for Invasive Fungal 
Infection) and Mean Exposure (Cavg)
P00041
(Aspergillosis)
P01899
(AML/MDS)
C/I98-316
(GVHD)
Range of Cavg
(ng/mL)
Response 
N(%)
Range of Cavg
(ng/mL)
Response 
N (%)
Range of Cavg
(ng/mL)
Response 
N (%)
MK-5592
55-277
24(4/17)
90-322
45.3(24/53)
22-557
55.6(35/63)
290-544
53(9/17)
322-490
63.0(34/54)
557-915
79.4(50/63)
550-861
53(9/17)
490-734
53.7(29/54)
915-1563
82.5(52/63)
877-2010
71(11/16)
734-2200
72.2(39/54)
1563-3650
82.5(52/63)
P00041 study : Treatment of invasive fungal infection (IFI) as an endpoint. Success is defined complete response  and 
partial response at the end of treatment using overall response 
P01899 study : Prophylaxis of IFI as an endpoint, AML/MDS subjects as a target population
C/I98-316 study : Prophylaxis of IFI as an endpoint,  GVHD subjects as a target population
P01899 and C/I98-316 study: Failure is defined occurrence of a proven or probable IFI, use of empiric antifungal 
therapy treatment with a systemic antifungal other than study treatment for 5 days or more and death from all causes 
and/or premature discontinuation of study treatment. Success is defined other than failure.
 
 
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4.1.2.3
P05520 Study
P05520 study was conducted to evaluate the pharmacokinetics and safety in non-Japanese 
patients with acute myeloid leukaemia, myelodysplastic syndrome, and post allogeneic-
HSCT patients when 200 mg or 300 mg of MK-5592 IV solution was administered via 
central vein. This study consisted of 4 cohorts (Cohorts 0, 1, 2, 3).
Overall, 94% (46/49) of subjects had Cavg values between 500 to 2500 ng/mL, meeting the 
PK exposure target specified in P05520 study. In Cohort 0, a single dose of MK-5592 IV 
solution 200 mg or placebo was administered via a central vein and its pharmacokinetic 
profile was evaluated in 21 subjects.
 
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In Cohort 2, MK-5592 IV solution 300 mg was administered twice a day via a central vein on 
Day 1, once a day on Days 2 to 14, and MK-5592 oral suspension 400 mg was orally 
administered twice a day on Days 15 to 28 in 24 subjects with AML/MDS. Data (steady 
state) from 19 PK-evaluable subjects on Day 14 showed that mean Cavg of MK-5592 was 
1410 ng/mL and Cavg of 95% (18/19) of subjects was within target exposure (500 to 2500 
ng/mL), but Cavg of 5% (1/19) subjects was 2910 ng/mL (Table 4). Similar to the safety of 
MK-5592 IV solution 200 mg dose / MK-5592 oral suspension 400 mg dose, the safety of 
MK-5592 IV solution 300 mg dose / MK-5592 oral suspension 400 mg dose was also 
favorable at this dose. There is no new safety concern due to dose escalation of MK-5592. 
The Sponsor considered that a higher exposure is desirable in order to have enough efficacy 
and judged that 300 mg is the most appropriate dose for the IV solution in Cohort 3.
In Cohort 3, MK-5592 IV solution 300 mg was administered twice a day via a central vein on 
Day 1 and once a day on subsequent days for at least 4 days in 213 subjects with 
AML/MDS/HSCT to evaluate the safety, tolerability, and pharmacokientics of the IV 
solution in a wider range of patients. From the point where the subject was judged eligible 
for oral administration up to Day 28, MK-5592 oral suspension was orally administered at 
400 mg twice a day or 200 mg three times a day. Data from 31 serial PK-evaluable subjects 
receiving 300 mg of MK-5592 IV solution showed that mean Cavg in steady state was 1566
ng/mL on Day 10 and Cavg of 93% (28/30) of subjects was within the target exposure (500-
2500 ng/mL), but Cavg of 7% (2/30) of subjects was between 2500 and less than 3650 
ng/mL. Only one subject was above 3650 ng/mL. This subject was excluded from the 
analysis because this subject was dosed and the PK sample was collected through the same 
catheter. The mean Cavg at steady state from MK-5592 IV solution 300 mg dose for the 
pooled data from Cohorts 2 and 3 was 1500 ng/mL. 
Table 4
Mean Pharmacokinetic Parameters of MK-5592 After Administration of IV 
Solution 200 or 300 mg BID (Day 1), Followed by 200 or 300 mg QD in High 
Risk Patients (Results of P05520)
Cohort
Dose (mg)
Day
n†
AUC(τ)
(ng•hr /mL)
Cavg§
(ng/mL)
n (%) of subjects Cavg
≥500 ng/mL and <2500
%
subjects／n
1
200 QD
14
15
28200 (51)
1180 (51)
94
14/15
2
300 QD
14
19
33800 (42)
1410 (42)
95
18/19
3
300QD
10
30
37600 (31)
1566 (31)
93
28/30
2+3
300QD
10, 14
49
36100 (35)
1500 (35)
94
46/49
† PK-evaluable subject
§ Cavg= AUC(interval) at steady state/dosing interval
 
 
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4.1.2.4
P05615 Study
A repeat dose study of the solid oral tablets 200 mg and 300 mg in non-Japanese patients 
with neutropenia or non-Japanese HSCT patients was conducted to evaluate the safety and 
pharmacokinetics of the solid oral tablet in patients (P05615). This study consisted of 3 parts 
(Part 1A, Part 1B, Part 2).
The pre-defined exposure target range was achieved at the 300 mg dose level.
In Part 1A, MK-5592 solid oral tablet 200 mg was orally administered twice a day on Day 1 
and once a day on Days 2 to 28 in 20 AML or MDS patients with neutropenia. Data (steady 
state) from 18 serial PK-evaluable subjects showed that mean Cavg on Day 8 was 981 ng/mL 
and Cavg of 83% (15/18) of subjects was within target exposure (500-2500 ng/mL), but 17% 
(3/18) of subjects could not achieve the target exposure and their Cavg were between 200 to 
500 ng/mL (Table 5).
In Part 1B, MK-5592 solid oral tablet 300 mg was administered in the same manner in 34 
patients with patient characteristics similar to those in Part 1A, and in Part 2, MK-5592 solid 
oral tablet 300 mg was orally administered twice a day on Day 1 and once a day on Days 2 to 
28 in 176 AML or MDS patients with neutropenia and HSCT patients, and the 
pharmacokinetics and safety were evaluated in a greater number of subjects. Based on Day 8 
data (steady state) from serial PK-evaluable subjects with AML/MDS (33 patients) and 
HSCT (17 patients) receiving MK-5592 solid oral tablet 300 mg, Cavg were 1440 ng/mL and 
1870 ng/mL, respectively and Cavg in HSCT serial PK-evaluable subjects was slightly higher 
than in the AML/MDS serial PK-evaluable subjects. AML/MDS and HSCT patients with 
Cavg between 500 ng/mL and 2500 ng/mL were 97% (32/33) and 76% (13/17), respectively. 
AML/MDS and HSCT patients with Cavg between 2500 ng/mL and 3750 ng/mL were 3% 
(1/33) and 24% (4/17), respectively. Based on the pooled data from part 1B and part 2, Cavg
at steady state from MK-5592 solid oral tablet 300 mg dose was 1580 ng/mL and 90% 
(45/50) of patients attained Cavg between 500 ng/mL and 2500 ng/mL.
A linear regression model was created from the Cmin obtained in Part 1A, 1B and Part 2. An 
estimated Cavg (pCavg) was calculated using this model and the results are shown in Table 6. 
Among 186 Cmin PK-evaluable subjects with AML/MDS and HSCT subjects, the percentage 
of subjects with a steady-state pCavg within target exposure (500-2500 ng/mL) were 90% 
(96/107) for AML/MDS subjects and 70% (55/79) for HSCT subjects. The percentage of 
subjects with a steady-state pCavg within 2500 to 3750 ng/mL was 8% (9/107) for AML/MDS 
subejcts and 23% (18/79) for HSCT subjects. HSCT subjects treated with MK-5592 solid 
oral tablet 300 mg attained somewhat higher concentrations as compared to AML/MDS
patients.
With respect to the safety of MK-5592 solid oral tablet 300 mg in Part 1B and Part 2, the 
most frequently observed adverse events were gastrointestinal adverse reactions reported in 
148 (70%) patients. Of those 148 subjects with events they were assessed as adverse drug 
reactions in 54 patients (26%), but no new safety concern was observed compared to 
administration at 200 mg. Results were generally comparable to those in the major overseas 
 
 
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studies of the oral suspension (oral suspension: P00041, P01899, C/I98-316), and increased 
exposure observed in this study was suggested to have no significant impact on the safety 
profile. This increased exposure will not affect the tendency of frequency of adverse events.
Table 5
Mean Pharmacokinetic Parameters After Repeated Administration of the Solid 
Oral Tablet in High Risk Patients (Results of Parts 1 and 2, P05615)
Part
Dose(mg)
Day
n
Disease
AUC(τ)
(ng•hr /mL)
Cavg§
(ng/mL)
n (%) of subjects Cavg
≥500 ng/mL and <2500
%
subject／n
1A
200 QD
8
18
AML/MDS
23500 (49)
981 (48)
83
15/18
1B
300 QD
8
33
AML/MDS
34300 (36)
1440 (36)
97
32/33
2
300 QD
8
17
HSCT
44800 (45)
1870 (45)
76
13/17
1B+2
300 QD
8
50
AML/MDS
+HSCT
37900 (42)
1580 (42)
90
45/50
§ Cavg = AUC(interval) at steady state/dosing interval
Table 6
Estimated Cavg (pCavg) After Repeated Administration of 300 mg QD in High 
Risk Patients (Comparison of Results by Target Patients in Part 1B and Part 2, 
P05615)
pCavg a (ng/mL)
AML/MDS+HSCT
AML/MDS
HSCT
N
186
107
79
Arithmeric Mean (%CV)
1970 (56)
1680 (41)
2370 (60)
Range
442-9520
442-3970
680-9520
n (%) of subjects pCavg
≥200 ng/mL and <500 ng/mL
1 (0.5%)
1 (1%)
0 (0%)
n (%) of subjects pCavg
≥500 ng/mL and <2500 ng/mL
151 (81%)
96 (90%)
55 (70%)
n (%) of subjects pCavg
≥2500 ng/mL and <3750 ng/mL
27 (15%)
9 (8%)
18 (23%)
n (%) of subjects pCavg
≥3750 ng/mL
7 (4%)
1 (1%)
6 (8%)
a:
pCavg was derived from linear regression model using observed Cmin on Day 8 from P05615 Parts 1
and 2 (pCavg= 228 +1.02·Avg_Cmin)
 
 
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Ongoing Clinical Trials
4.1.3
4.1.3.1
PN069
PN069 is a randomized, double-blind phase III study to evaluate the efficacy, safety and 
tolerability of MK-5592 IV solution and solid oral tablet (300 mg QD, 300 mg BID on Day 1 
only) versus voriconazole IV and solid oral formulation [IV: 6 mg/kg BID for loading dose 
and 4 mg/kg BID for maintenance dose, solid oral formulation: 300 mg BID for loading dose 
and 200 mg BID for maintenance dose] for the treatment of invasive aspergillosis in adults;
 
 
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).
4.2
Rationale
Rationale for the Trial and Selected Subject Population
4.2.1
The diagnosis of invasive fungal infections (IFI) is generally difficult and most of patients 
with IFI have serious underlying diseases.  In most of cases the therapy for IFI is initiated 
prior to the diagnosis of IFI because the condition of patient is critical.   The antifungal 
agents approved in Japan are not always effective depending on the IFI morbidity and it is 
reported that some patients displayed unfavorable response to the conventional medication.  
Therefore there are high medical needs to develop safe and effective antifungal agent with 
broad spectrum against fungi.  
Amphotericin B has broad spectrum activity against fungi and has a strong antifungal 
activity, many adverse effects are observed due to strong toxicity.  Antifungal agents such as 
azoles and echinocandins are superior to amphotericin B with regards to safety and 
pharmacokinetics profile, but antifungal spectrum is not entirely satisfactory. 
MK-5592 is an antifungal agent in the azole class that inhibits ergosterol biosynthesis, a in 
the main component of the fungal cell membrane, by affecting the enzyme lanosterol 14-
alpha demethylase (CYP51).  Nonclinical and clinical studies (MK-5592 oral suspension) 
indicate that MK-5592 is effective against broad fungus including zygomycota that is 
refractory to voriconazole in addition to aspergillus. In safety profile, azole specific ADRs 
were observed, but well tolerated.
Based on the above, MK-5592 is expected to be safe and efficacious in the treatment of 
broad deep-seated fungal infections and should be considered as one option for the treatment 
of these deep-seated fungal infections to meet the current medical needs. This Phase 3 study
is planned to assess the safety and efficacy of MK-5592 in patients with proven or probable 
deep-seated fungal infections in Japan using the criteria and endpoints referred to in the 
EORTC/MSG criteria [14, 15], endpoints of MK-5592 clinical study conducted outside 
Japan, endpoints of clinical study for chronic pulmonary aspergillosis conducted in and 
outside Japan [16, 17], and the guideline as antifungal drugs evaluation committee by Japan 
chemotherapy association March 2012 [18].
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.
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.
 
 
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Rationale for Dose Selection/Regimen/Modification
4.2.2
1) Rationale for MK-5592 dosage and administration
 
 
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For Cohort 2
2) Rationale for Voriconazole Dosage and Administration
Dosage of Voriconazole was chosen based on approved dosage of treatment for deep-seated 
fungal infection in Japan. Oral administration is 200 mg BID (300 mg BID on Day 1), IV
infusion is 4 mg/kg BID (6 mg/kg BID on Day 1). 
 
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In JPC of voriconazole, ‘it is recommended that plasma concentration of voriconazole should 
be monitored during the treatment’ is stated.  From the both efficacy and safety aspects, 
dosing adjustment based on the result of therapeutic drug monitoring (TDM)
is 
recommended for voriconazole in Japan. Therefore, in this study, adjustment of voriconazole 
dosing should be performed based on the result of TDM, with the dose modified at the 
investigator’s discretion.  The frequency of blood sampling for TDM is also left to the 
investigator’s discretion.
Rationale for Endpoints
4.2.3
Safety and efficacy endpoints in this study are based on the EORTC/MSG criteria [14, 15], 
endpoints of MK-5592 clinical study conducted outside Japan, endpoints of clinical study for 
chronic pulmonary aspergillosis conducted in and outside Japan [16, 17], and the guideline as 
antifungal drugs evaluation committee by Japan chemotherapy association March 2012 [18].
Deep-seated fungal infection is usually manifested in immunocompromised subjects with 
serious underlying diseases (such as HIV, organ transplantation, and cancer).  For such 
infections, the assessment of efficacy usually takes into consideration a number of key 
variables, including the response to clinical signs and symptoms (Clinical Response), the 
response to mycological measures of the infection (Mycological Response), and the response 
to radiological evidence of the infection (Radiological Response).  Therefore, an overall 
response, which encompasses many of these individual components, is routinely applied to 
the assessment of efficacy in these types of infections. Overall response criteria for invasive 
aspergillosis is set in 5 levels (complete response, partial response, stable response, 
progressive disease and unable to determine). Success is defined as complete response and 
partial response. Failure is defined as stable response, progressive disease and unable to 
determine. Overall response criteria for chronic pulmonary aspergillosis is set in 4 levels 
(favorable response, stable response, progressive disease and unable to determine). Success is 
defined as favorable response. Failure is defined as stable response, progressive disease and 
unable to determine. For chronic pulmonary aspergillosis, it is rare that ‘finding of imaging’
are resolved. Complete response and partial response are not set but favorable response is set 
in overall response. The overall response is evaluated by the investigator or sub-investigator 
according to the criteria. The overall response is finally evaluated by the clinical adjudication 
committee.
For subject with IA, we set the endpoint at Day 42 same as global study (069 study) in order 
to be able to confirm the efficacy between 101 and 069 study. For subject with CPA, we set 
the endpoint at Day 84 same as registration clinical studies conducted with using other anti-
fungal drugs in the subject with CPA in Japan. 
Pharmacokinetics endpoints were chosen to evaluate MK-5592 PK profile and will be able to 
compare to other clinical trials. 
 
 
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4.2.3.1 Efficacy Endpoints
(1) Invasive aspergillosis 
Overall response for efficacy is evaluated based on clinical response, radiological
response and mycological response.
(2) Chronic pulmonary aspergillosis (chronic progressive pulmonary aspergillosis and simple 
pulmonary aspergilloma)
Overall response for efficacy is evaluated based on clinical response, radiological
response.
(3) Fusariosis and Zygomycosis
Overall response for efficacy is evaluated based on clinical response, radiological
response and mycological response.
(4) Antifungal susceptibility testing
Minimum inhibitory concentration (MIC) of MK-5592, voriconazole and representative 
anti-mycosis drugs will be measured in the isolated causative fungus from the subjects 
(pre-treatment, post-treatment).  
Individual evaluation criteria and overall response criteria is defined as follows;
Criteria for Each Evaluation Element
Table 7
Criteria for Clinical Response
Response
Definition
Resolution†
Resolution of attributable signs and symptoms of disease
Improvement
Improvement of attributable signs and symptoms of disease‡
Stabilization
No change or minor improvement of attributable signs and symptoms of 
disease
Worsening
Worsening of attributable signs and symptoms of disease
Unable to Determine
Unable to determine
Clinical response is evaluated based on the clinical signs and symptoms related to mycosis (cough, dyspnea, 
sputum, hemoptysis, bloody sputum, pain, pyrexia and weight loss etc), with vital sign and shift of clinical 
laboratory (CRP etc) for reference during the trial.
†: It does not use for chronic pulmonary aspergillosis
‡: “Resolution or Improvement of attributable signs and symptoms of disease” for chronic pulmonary 
aspergillosis
 
 
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Table 8
Criteria for the Radiological Response
Response
Definition
Resolution†
Resolution of radiological lesions
Improvement‡
Major reduction of size of radiological lesions§
Stabilization
No change or minor reduction of size of radiological lesions
Worsening
Increase of size of existing lesion or new site with fungal infection
Unable to Determine
Unable to Determine
Imaging findings caused by fungus is evaluated.
†:
It does not use for chronic pulmonary aspergillosis
‡:
In the case of invasive aspergillosis, fusariosis, and mucormycosis, reduction of the longest diameter of 
lesions on imaging by 25% or more; for chronic pulmonary aspergillosis, whether lesions have been 
improved or not is judged by considering change in size and quality of lesions on imaging 
comprehensively.
§:
“Resolution or improvement of radiological lesions” for chronic pulmonary aspergillosis
Table 9
Criteria for Mycological Response 
Response
Definition
Eradication
Fungus detected from culture or microscopy at the screening is eradicated 
at the time of evaluation(including presumed eradication†)
Stabilization
“Fungus detected from culture or microscopy at the screening is detected at 
the time of evaluation” or “Fungus at the screening is not detected at the 
time of screening and evaluation”
Worsening
Fungus is not detected at the screening but fungus or newly infected site is 
detected at the time of evaluation.
Unable to Determine
Unable to determine
†:
It is difficult to obtain the sample due to eradication of infection site (etc.) but it is clinically judged to 
eradicate the infected fungus.
 
 
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Criteria for Overall Response
Table 10 Overall Response Criteria for Invasive Aspergillosis, Zygomycosis and Fusariosis 
Clinical Response
Resolution
Improvement
Stabilization
Worsening
Unable to 
determine
Radiological Response
Resolution
Comlete 
Response
Partial 
Response
Partial 
Response
Progressive 
Disease
Unable to 
determine
Improvement
Partial 
Response
Partial 
Response
Partial 
Response
Progressive 
Disease
Unable to 
determine
Stabilization
Partial 
Response
Partial 
Response†
／Stable 
response†
Stable 
Response
Progressive 
Disease
Unable to 
determine
Worsening
Progressive 
Disease
Progressive 
Disease
Progressive 
Disease
Progressive 
Disease
Progressive 
Disease
Unable to 
determine
Unable to 
determine
Unable to 
determine
Unable to 
determine
Progressive 
Disease
Unable to 
determine
†: Assessment based on the Mycological Response in below

In case of ‘’Detected at Screening’’ and ‘’Undetected at the Evaluation’’, Mycological Response and 
Overall Response are ‘’Resolution’’ and ‘’Partial Response’’, respectively.

In case of ‘’Undetected at Screening’’ and ‘’Undetected at the Evaluation’’, Mycological Response 
and Overall Response are ‘’Stabilization’’ and ‘’Stable Response’’, respectively.

In case of ‘’Detected at Screening’’ and ‘’Detected at the Evaluation’’, Mycological Response and 
Overall Response are ‘’Stabilization’’ and ‘’Stable Response’’, respectively.

In case of ‘’Undetected at Screening’’ and ‘’Detected at the Evaluation’’, Mycological Response and 
Overall Response are ‘’Worsening’’ and ‘’Stable Response’’, respectively.
Table 11 Overall Response Criteria for Chronic Pulmonary Aspergillosis
Clinical Response
Improvement
Stabilization
Worsening
Unable to determine
Radiological 
Response
Improvement
Favorable Response
Favorable Response
Progressive 
Disease
Unable to determine
Stabilization
Favorable Response
Stable Response
Progressive 
Disease
Unable to determine
Worsening
Progressive Disease
Progressive Disease
Progressive 
Disease
Progressive Disease
Unable to 
determine
Unable to determine
Unable to determine
Progressive 
Disease
Unable to determine
 
 
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Table 12 Overall Response Criteria for in Case of Zygomycosis and Fusariosis Without 
Imaging 
Clinical Response
Resolution
Improvement
Stabilization
Worsening
Unable to 
determine
Mycological 
Response
Eradication
Complete 
Response
Partial 
Response
Stable 
Response
Progressive 
Disease
Unable to 
determine
Stabilization
Partial 
Response
Stable 
Response
Stable 
Response
Progressive 
Disease
Unable to 
determine
Worsening
Progressive 
Disease
Progressive 
Disease
Progressive 
Disease
Progressive 
Disease
Progressive 
Disease
Unable to 
determine
Unable to 
determine
Unable to 
determine
Unable to 
determine
Progressive 
Disease
Unable to 
determine
4.2.3.2
Safety Endpoints
Safety endpoints are evaluated based on physical findings, clinical symptoms and signs, vital 
signs, 12-lead ECG and laboratory measurements. Adverse events are collected through the 
study duration from the subjects.
4.2.3.3
Pharmacokinetic Endpoints
Steady-state pharmacokinetic profile of MK-5592 in Japanese patients with mycosis will be 
explored using population PK approach. The PPK analysis plan will be prepared separately. 
For MK-5592 treatment arm, plasma samples for PK evaluation will be collected at the 
following time points:
For IV administration: Thirty minutes before the treatment, just before the end of first 
infusion, 6 to 10 hours after the initiation of the infusion and just before the treatment of 
second infusion on Day 1[Blood sampling after the first dosing on Day 1 (or second dosing) 
should be performed at least 3 hours apart among these sampling points (6 to 10 hours after 
the treatment and just before the second treatment)]. Thirty minutes before the treatment on 
Day 3, 14, 28, 42 and end of treatmenta, b. Thirty minutes before the treatment, just before the 
end of the infusion, 2 to 3 hours after the initiation of infusion, 8 to 10 hours after the 
initiation of infusion on Day 8 and thirty minutes before the treatment of the next day (on 
Day 9).
For oral administration: Thirty minutes before the treatment, 2 to 4 hours after the first 
treatment, 6 to 10 hours after the treatment and just before the second treatment on Day
1[Blood sampling after the first dosing on Day 1 (or second dosing) should be performed at 
least 3 hours apart among these sampling points (6 to 10 hours after the treatment and just 
before the second treatment)]. Thirty minutes before the treatment on Day 3, 14, 28, 42 and 
end of treatmenta, b. 30 minutes before the treatment and 2 to 6 hours after the treatment on 
after 7 days of switching formulation (Only for the subjects who switch from IV to orala). 
Thirty minutes before the treatment, 2 to 3 hours after the treatment, 4 to 6 hours after the 
treatment, 8 to 10 hours after the treatment on Day 8 and 30 minutes before the treatment of 
the next day (on Day 9).
 
 
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For both formulations: At the time of interruptiona or discontinuationa due to adverse events, 
or at the incidence of serious adverse eventsa by MK-5592 administration.
a: The plasma samples for PK evaluation in the subjects with zygomycosis during the 
extension period will not be needed.
b: The plasma samples for PK evaluation in the subjects with zygomycosis must be collected 
at EOT before the transition to the extension period.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA (blood) specimens collected 
during this clinical trial.
5.0 METHODOLOGY
5.1
Entry Criteria
Diagnosis/Condition for Entry Into the Trial
5.1.1
Male/Female subjects with deep-seated mycosis of at least 18 years of age will be enrolled in 
this trial.
 
 
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Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. The subject whose written consent is obtained prior to the study. If the subjects is
incompetent, the written consent of an appropriate attorney* must be obtained. If the 
subject is infancy, the written consent/assent of a subject and an appropriate attorney*
must be obtained. The subject may also provide consent/assent for Future Biomedical 
Research.  However, the subject may participate in the main trial without 
participating in Future Biomedical Research.
* Appropriate attorney includes those persons who can consider the best benefit of
the subject judging from the livelihood or mental relationships with the subject, such 
as a spouse, parent, legal guardian or other person pursuant to those persons.
2. Male or female Japanese subject aged 18 years and over at the time when informed 
consent is obtained, and subject with body weight greater than or equal to 45 kg at the 
randomization.
3. The subject who can take investigational medical products [he/she can take tablet via 
oral or he/she can take IV formulation via central vein (he/she has central venous 
catheter or he/she can obtain a central venous catheter)]
4. The subject (only female) who has a negative pregnancy test at screening visit. 
Female subjects of child-bearing potential who agree to continue using proper 
combination of barrier method of birth control (e.g. condom, pessary, oral 
contraceptive, intrauterine device (IUD), hormonal implant, vasectomy) during the 
study period. Female subjects of non-child-bearing potential are defined as having 
none of following three items.
(1) 12 months of spontaneous amenorrhea with no alternative medical cause
(2) 6 month or more post surgical bilateral oophorectomy with or without 
hysterectomy
(3) Bilateral tubal ligation
5. As a result of screening test within 7 days prior to Day 1, subject met the following 
criteria for 1 of the 4 listed fungal infections. 
(1) Invasive Aspergillosis
Subject meets the following criteria for proven, probable or possible IA
(a) Proven IA: the subject meets the following criteria 1) or 2)
 
 
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1)
Tissue 
histopathologic, 
cytopathologic*, 
or 
direct 
microscopic 
examination of a needle aspiration or biopsy specimen obtained within 14
days prior to Day 1 showing hyphal forms with evidence of associated 
tissue damage (either microscopically or as an infiltrate or lesion by
imaging)
*:  tissue and cells submitted for histopathology or cytopathology should 
be stained by Grocott-Gomori methenamine silver stain or by periodic 
acid Schiff stain to facilitate inspection of fungal structures. Where 
possible, wet mounts of specimens from foci related to invasive fungal 
infectious disease should be stained with a fluorescent dye (e.g., 
calcofluor or Blankophor).
2)
Recovery of Aspergillus species by culture from a sample obtained by a 
sterile procedure from a normally sterile and clinically or radiologically 
abnormal site consistent with an infectious disease process obtained 
within 14 days prior to Day 1, excluding BAL, cranial sinus cavity, and 
urine.
(b) Probable IA: the subject meets one host factor, one clinical criteria and one
mycological criteria, respectively
1)
Host factors*
i. Recent history of neutropenia (0.5 x 109 neutrophils/L [<500 
neutrophils/mm3] for >10 days) temporally related to the onset of 
fungal disease
ii. Receipt of an allogeneic HSCT
iii. Treatment with other recognized T-cell immune suppressants, such as 
cyclosporine, TNF-α blockers, specific monoclonal antibodies (such as 
alemtuzumab), or nucleoside analogues during the past 90 days.
iv. Prolonged use corticosteroid (excluding among patients with allergic 
bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 
mg/kg/day of prednisone equivalent for >3 weeks.
v. Inherited severe immunodeficiency (such as chronic granulomatous 
disease or several combined immunodeficiency)
vi. Host factor which matches to develop invasive aspergillosis (In this 
case the pre-approval of the sponsor is required and subject meets one 
clinical criteria and one mycological criteria)
*: Host factors are not synonymous with risk factors and are 
characteristics by which individuals predisposed to invasive fungal 
 
 
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diseases can be recognized. They are intended primarily to apply to 
patients given treatment for malignant disease and to recipients of 
allogeneic hematopoietic stem cell and solid-organ transplants. 
These host factors are also applicable to patients who receive 
corticosteroids and other T cell suppressants as well as to patients 
with primary immunodeficiencies.
2)
Clinical criteria*
i. For lower respiratory tract fungal disease**, the presence of 1 of 
following  3 signs:  1) dense, well-circumscribed lesions(s) with or 
without a halo sign, 2) air-crescent sign or 3) cavity on CT
ii. For 
tracheobronchitis, 
tracheobronchial 
ulceration, 
nodule, 
pseudomembrane, plaque, or eschar seen on bronchoscopic analysis
iii. For sinonasal infection, Imaging showing sinusitis plus at least 1 of the 
following 3 signs: 1) Acute localized pain (including pain radiating to 
the eye), 2) Nasal ulcer with black eschar or 3) Extension from the 
paranasal sinus across bony barriers, including into the orbit
iv. CNS infection 1 of the following 2 signs: 1) Focal lesions on imaging, 
2) Meningeal enhancement on MRI or CT
*  : Must be consistent with the mycological findings, if any, and must 
be temporally related to current episode.
**: Every reasonable attempt should be made to exclude an alternative 
etiology.
3)
Mycological criteria
i. For direct test (cytology, direct microscopy, or culture), Mold in 
sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus 
aspirate samples obtained within 14 days prior to Day 1, indicated by 1 
of the following: 1) Presence of fungal elements indicating a mold or 
2) Recovery by culture of a mold (e.g., Aspergillus species)
ii. For indirect tests (detection of antigen or cell-wall constituents), 
Galactomannan antigen detected in serum or bronchoalveolar lavage 
(BAL) fluid [a positive test result defined as a cut-off index ≥1.0 
(single result from serum or BAL) or  ≥0.5 (2 consecutive results from 
serum samples)]
(c) Possible IA: the subject meets one host factor (vi is not applicable for this 
criteria) and one clinical criteria, respectively. Of the subject who is enrolled 
as possible IA, if the subject meets the criteria for proven IA or probable IA 
 
 
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within 7 days of randomization, it is treated as proven IA or probable IA 
respectively.
(2) Chronic pulmonary aspergillosis (chronic progressive pulmonary aspergillosis or 
simple pulmonary aspergilloma)
The subject meets host factor, clinical criteria and mycological criteria with 
active chronic pulmonary aspergillosis.
(a) Host factors: 
The subject has one of the risk factor of chronic pulmonary aspergillosis 
(chronic 
progressive 
pulmonary 
aspergillosis 
or 
simple 
pulmonary 
aspergilloma) (obsolete pulmonary tuberculosis, COPD, bronchiectasis, cavity 
formulation including cyst, pulmonary nontuberculous mycobacteriosis,
interstitial pneumonia or history of chest surgery etc)
(b) Clinical criteria: subject meets the all of following criteria
1)
The subject has attributable chronic signs and symptoms [e.g. cough, 
sputum (bloody sputum or hemoptysis etc), dyspnea, pyrexia, weight 
decrease etc]
2)
The subject has a shadow [enhancement of cavity, thickness of cavity 
wall (enhancement of cavity consolidation), fungus ball-like shadow, 
progression of pleural thickening or niveau etc.] by chest imaging (CT) 
and it is judged that other causes are negative.
(c) Mycological criteria: the subject meets one of following criteria by 
mycological testing or serological testing
1)
Fungal element of Aspergillus species is detected by direct microscopy in  
biopsy specimen (bronchial mucosa or lung etc.), BAL, sputum, sputum 
with transtracheal aspiration, pleural effusion or a sample obtained within 
14 days prior to Day 1 using any other appropriate method, or recovery of 
Aspergillus species by culture of samples obtained within 14 days prior to 
Day 1 (Proven case)
2)
Aspergillus species is detected by histpathological testing of samples 
obtained within 14 days prior to Day 1 (Proven case)
3)
Galactomannan antigen is detected in serum or bronchoalveolar lavage 
(BAL) fluid [a positive test result defined as a cut-off index ≥1.0 (single 
result from serum or BAL) or ≥0.5 (2 consecutive results from serum 
samples)], or aspergillus antibody is detected in serum or BAL (Probable 
case) Aspergillus antibody within 28 days before the initiation of study 
therapy, it can be used as a screening result.
 
 
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(3) Zygomycosis (The subject is assigned to the MK-5592 treatment arm); Fungal 
infection is strongly suspected based on clinical symptom and/or characteristic
imaging findings and meets at least one of the following criteria: If data of (a) 
and (b) comes from within 14 days before initiation of study therapy, it can be 
used as a screening result.
(a) Fungal elements of Zygomycota spp (Rhizopus, Absidia, Rhizomucor, Mucor, 
Cunninghamella, etc.) mold in biopsy sample (bronchial mucosa, lung etc.), 
broncho-aleveolar lavage fluid, sputum, sputum with transtracheal aspiration, 
pleural effusion, blood and any other appropriate sample by direct microscopy 
or Zygomycota spp. are observed by culture test.
(b) Zygomycota spp. is detected by histopathologic test.
(4) Fusariosis (The subject is assigned to the MK-5592 treatment arm); Fungal 
infection is strongly suspected based on clinical symptom and/or characteristic
imaging findings etc. and met at least one of the following criteria: If data of (a) 
and (b) comes from within 14 days before initiation of study therapy, it can be 
used as a screening result.
(a) Fungal elements of Fusarium spp. mold in biopsy sample (bronchial mucosa, 
lung etc.), broncho-aleveolar lavage fluid, sputum, sputum with transtracheal 
aspiration, pleural effusion, blood and any other appropriate sample by direct 
microscopy or Fusarium spp. are observed by culture test.
(b) Fusarium spp. is detected by histopathologic test.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. The 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 the trial. 
2. The subject has fungal infection other than Aspergilus spp., Zygomycetes (including 
Mucor spp.) and Fusarium spp. infection.
3. The subject has allergic bronchopulmonary aspergillosis, allergic sinusitis of 
aspergillosis or aspergillosis of the eye.
4. The subject with long-term inactive aspergilloma which are not expected to develop 
the radiological response and clinical response by investigational product.
5. The subject is not expected to survive for this study duration.
 
 
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6. The subject with an underlying disease, complication(e.g. bacterial pneumonia which 
is difficult to be distinguished from study target infection or aspiration pneumonia) or 
systemic condition which makes it difficult to evaluate the efficacy and safety of the 
study drug.
7. The subject has received any systemic antifungal therapy for the treatment of this 
infection who cannot discontinue this treatment or has improve/tend improve for this 
infection (The subject whose fungal infection does not improve/tend to improve can 
switch from existing medication to study drug).
8. The subject is expected to need prohibited medications in the following durations.
Table 13 Prohibited Medications
Prohibited Medications
Duration
Systemic antifungal therapy (oral, intravenous or inhaled) for treatment of this 
infection.
Note that new antifungal therapy must not be started during the study medication 
for this infection.
Randomization to 
end of treatment
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.
Prior 28 days of Day 
1 to end of treatment
Prophylaxis of deep-seated fungal infection with systemic antifungal drugs.
Randomization to 
end of treatment
Medications that are known to interact with azole and may lead to life-threatening 
side effects (QT prolongation, ventricular arrhythmia including torsades de pointes 
etc.) : ebastine, pimozide and quinidine.
Prior 24 hours of Day
1 to end of treatment
Ergot alcaloids (ergotamine, dihydrogergotamine or other licensed or 
investigational members of this class).
Prior 2 days of Day 1 
to end of treatment
Medications that are known to result in a false positive galactomannan EIA 
(Aspergillus antigen) result:  amoxicillin/clavulanate
From the date of 
informed consent to 
end of treatment
Medications known to lower the serum concentration/efficacy of azole 
antifungals: barbituratesa, carbamazepine, isoniazid, phenytoin, rifabutin, 
rifampicinb, and St John’s Worta (hypericum perforatum).
Prior 24 hours of Day 
1 to end of treatment
Cyclophosphamide
Prior 24 hours of Day 
1 to end of treatment
Ritonavira and efavirenz
Prior 24 hours of Day 
1 to end of treatment
Vinca Alkaloids
Prior 24 hours of Day 
1 to end of treatment
Triazolam a
Prior 24 hours of Day 
1 to end of treatment 
HMG-CoA reductase inhibitors metabolized via CYP3A4c
Prior 24 hours of Day 
1 to end of treatment
a:
After randomization, it is applicable to only the subject assigned to voriconazole treatment arm.
b:
After randomization, it is applicable to the subject assigned to voriconazole treatment arm, but in case of co-
administration in subject assigned to MK-5592 treatment arm, refer to the recommendation (Section 5.5.1).
c:
After randomization, it is applicable to the subeject assigned to MK-5592 treatment arm, but in case of co-
administration in subject assigned to voriconazole treatment arm, refer to the recommendation (Section 5.5.1)
 
 
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9. The subject meet the following criteria;
(1) The subject has received MK-5592. 
(2) The subject has received voriconazole* for this infection in the past, and has 
deep-seated fungal infection which is not effective for this treatment. 
(3) The subject has intolerance for azole fungal treatment. 
(4) The subject who is receiving two or more systemic antifungal combination 
therapy for chronic pulmonary aspergillosis at the time when informed consent is 
obtained.
10. The subject has known hypersensitivity including serious drug allergy, shock or 
anaphylaxis to any medication [including hypersensitivity to azole agents or rash 
(regardless of seriousness) caused by these agents].
11. The subject has any known history of Torsade de Pointes, a history of recent 
myocardial infarction within 90 days of study entry, or subject has a congenital or 
acquired long QT interval syndrome (including administration of drug which 
prolongs QT interval) or have a unstable cardiac arrhythmia.
12. The subject has QTc interval ≥ 450 msec on electrocardiogram performed at
screening.
13. The subject has significant liver dysfunction (defined as total bilirubin > 1.5 times
upper limit of normal AND AST or ALT > 3 times upper limit of normal on 
screening labs) at the time of randomization.
14. The subject has liver cirrhosis or cholestasis at the time of randomization.
15. The subject has renal insufficiency (estimated creatinine clearance <30 mL/min.) or 
on hemodialysis at the time of randomization or is likely to require dialysis during the 
study.
In subject with estimated creatinine clearance of 30~50 mL/min and who receive IV 
formulation of MK-5592 or voriconazole, serum creatinine is carefully monitored. If 
serum creatinine is increased, switching to the oral therapy should be considered. 
Worsening of renal impairment may be occur due to accumulation of sulfobutylether-
beta-cyclodextrine sodium.(creatinine clearance should be calculated by using 
Cockcroft-Gault Equation)
16. The subject has a known hereditary problem of galactose intolerance, Lapp lactase 
deficiency, or glucose-galactose malabsorption*.
17. The subject has acute symptomatic pancreatitis within 6 months of study entry or has 
a diagnosis of chronic pancreatitis at the time of randomization*.
 
 
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18. The subject has an active skin lesion consistent with squamous cell carcinoma or
melanoma at the time of randomization or a prior history of malignant melanoma
within 5 year of study entry*.
19. A subject has known or suspected Gilbert’s disease at the time of randomization*.
20. The female subject is pregnant, intends to become pregnant during 14 days from the 
end of study treatment, or is nursing at the time of randomization.
21. The subject has previously enrolled in this study.
22. The subject in the judgment of the investigator/sub investigator, is unfit for entry into 
this study.
*: It is not applicable to the subject with zygomycosis or fusariosis.
5.2
Trial Treatments
The treatments to be used in this trial are outlined below in Table 14.
Table 14 Trial Treatment
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
MK-5592 (any one of oral tablet or IV solution must be selected)
oral tablet
300 mg
QD
(BID on Day 
1)
Oral
84 days as a general rule
deep-seated 
fungal 
infection
IV solution
300 mg
QD
(BID on Day 
1)
Central 
intravenous
deep-seated 
fungal 
infection
Voriconazole (any one of oral tablet or IV formulation must be selected)
oral tablet
200 mg (300 mg on 
Day 1)
BID
Oral
84 days as a general rule
deep-seated 
fungal 
infection
IV formulation
4 mg/kg(6 mg/kg on 
Day 1)
BID
intravenous
deep-seated 
fungal 
infection
If formulation is switched during the study, loading dose must not be administered again. From the date of switching 
formulation, maintenance dose administration should be continued.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated/assigned.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection
Investigator / sub-investigator will select the initial formulation according to the subject’s 
condition. Subjects who have central intravenous catheter or are judged to be able to 
administer via central venous at the timing of randomization by investigator will start with 
MK-5592 IV solution or voriconazole IV. Administration of MK-5592 IV solution or 
 
 
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voriconazole IV need to be considered for the subjects who present with or are expected to 
have intolerance to oral study drug administration (e.g. conditions which may interfere with 
oral intake or absorption of study drug such as vomiting or oral mucosal disorders). Subjects 
who are judged to be able to take the tablet at the timing of randomization by investigator 
will start with MK-5592 solid oral tablet or voriconazole tablet. 
After the initiation of the IV formulation, transition from IV to oral therapy on or after Day 9 
may occur when the subject is considered clinically stable and able to take oral 
administration by investigator’s discretion. When switching the formulation, the investigator 
must evaluate the overall response. In case that subject who started using oral formulation 
cannot continue to receive the oral formulation during the treatment, investigator must 
evaluate the overall response at that time and conduct the discontinuation procedure. Data 
gathered on the day of switching formulation or preceding day can be used as an overall 
response at the switching formulation [However, if the subject is a patient with zygomycosis 
and joins the extension period, the switch of the formulation(iv↔tablet) could be done based 
on the subject’s condition but dose modification of MK-5592 must not be allowed and the 
investigator does not need to evaluate the overall response at the timing of switching the 
formulation].
For subjects with estimated creatinine clearance of 30~50 mL/min who receive IV 
formulation of MK-5592 or voriconazole, serum creatinine is carefully monitored. If serum 
creatinine is increased, switching to the oral therapy should be considered. Worsening of 
renal impairment may occur due to accumulation of sulfobutylether-beta-cyclodextrine 
sodium.
5.2.1.1.1 MK-5592 IV Solution
Table 15 provides the dosing of MK-5592 for subjects randomized to the MK-5592 treatment 
arm if on IV therapy.
MK-5592 IV infusions will be prepared in 5% dextrose in water or saline.  See the procedure 
separately for detail of MK-5592 IV formulation preparation.  MK-5592 IV infusion is 
prepared as the time of use, but if necessary, the IV infusions may be prepared up to 18 hours 
prior to administration and stored at 2°C to 8°C refrigerated. The IV infusions should return 
to room temperature prior to administration.
MK-5592 IV will be given every 12 hours on Day 1, with infusions being not less than 9
hours or no more than 15 hours apart.  The subsequent MK-5592 IV infusions will be 
administered once daily at approximately the same time every day with 24 hours apart, with 
infusions being not less than 21 hours or no more than 27 hours apart(infusions on Day 2 
should not be less than 9 hours or no more than 15 hours apart). IV infusions should be 
administered for approximately 1.5 hours via a peripherally inserted central catheter or a 
dedicated lumen of a central venous catheter. Starting and stopping time of every infusion 
must be correctly recorded. Before and after infusion, investigator/sub-investigator will 
observe at the subject’s infusion site.
 
 
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If the dosing of study medication is delayed, the dose should be administered as soon as 
possible.  Regarding the dose on or after Day 2, if it is more than 6 hours since the missed 
dose, the missed dose should be skipped and the next dose should be administered at the 
regularly scheduled time. Any missed doses should be properly documented in the subject's 
source documentation and eCRF.
Exceptionally, first dose could be in the night on Day 1. In case that the first dose is in the 
night, second dose could be in the morning on Day 2 approximately 12 hours apart from the 
first dose, third dose could be in the night on Day 2 approximately 12 hours apart from the 
second dose, and following doses from Day 3 could be in the night at approximately the 
same time every day with 24 hours apart with dosing being not less than 21 hours or no more 
than 27 hours apart.  Also, if the dosing time need to be changed due to subject’s schedule or 
operational handling (e.g., from QD dosing in pm to QD dosing in am), the dosing time could 
be adjusted within the range of allowance (scheduled time -/+3 hours). However, 
approximate dosing time needs to be fixed by Day 5(e.g. QD dosing is done at approximately 
9:00am every day from Day 5).
Table 15 Dosing for MK-5592 IV Therapy for Cohort 2
Day 1
Day 2-84*
Dose
300 mg BID
300 mg QD
Volume
250 mL (150 mL can be acceptable as needed)
Infusion duration
1.5 hr
*: It should be conducted on or after Day 9 if subject need to switch the formulation of study drug.
5.2.1.1.2 MK-5592 Solid Oral Tablet
Table 16 provides the dosing of MK-5592 for subjects randomized to the MK-5592 treatment 
arm if on oral therapy.  
MK-5592 oral tablet will be given every 12 hours on Day 1, with being not less than 9 hours 
or no more than 15 hours apart, and will be given once daily at approximately the same time 
every day with 24 hours apart on or after Day 2, with doses being not less than 21 hours or 
no more than 27 hours apart (doses on Day 2 should not be less than 9 hours or no more than 
15 hours apart).  MK-5592 solid oral tablet can be administered with or without the food, 
investigator instructs that all cases should be properly documented in the administration diary 
(dosage amount, and food intake data within 2 hours before or within 1 hour after taking 
study drug etc.).
If the dosing of study medication is delayed, the dose should be taken as soon as possible.  
Regarding the dose on or after Day 2, if it is more than 12 hours since the missed dose, the 
missed dose should be skipped and the next dose should be administered at the regularly 
scheduled time. If a subject vomits within 15 minutes of MK-5592 solid oral administration, 
the dosing should be repeated as soon as possible, following appropriate antiemetic 
treatment.  Any missed doses should be properly documented in the subject's source 
documentation and eCRF.
 
 
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Exceptionally, first dose could be in the night on Day1, In case that the first dose is in the 
night, second dose could be in the morning on Day 2 approximately 12 hours apart from the 
first dose, third dose could be in the night on Day 2 approximately 12 hours apart from the 
second dose, and following doses from Day 3 could be in the night at approximately the 
same time every day with 24 hours apart with dosing being not less than 21 hours or no more 
than 27 hours apart.  Also, if the dosing time need to be changed due to subject’s schedule or 
operational handling (e.g., from QD dosing in pm to QD dosing in am), the dosing time could 
be adjusted within the range of allowance (scheduled time -/+3 hours). However, 
approximate dosing time needs to be fixed by Day 5(e.g. QD dosing is done at approximately 
9:00am every day from Day 5).
Table 16 Dosing for MK-5592 Oral Therapy for Cohort 2
Day 1 
Day 2-84 
Dose
300 mg(3 tablets) BID
300 mg(3 tablets) QD
5.2.1.1.3 Voriconazole IV
Table 17 provides the dosing of voriconazole for subjects randomized to the Voriconazole 
treatment arm if on IV therapy.  
Voriconazole IV infusions will be prepared in 5% dextrose in water or saline.  See the procedure 
separately for detail of Voriconazole IV formulation preparation.  Voriconazole IV infusion is 
prepared at the time of use, and it should be administered promptly after the preparation. 
Initial dosage is decided based on the weight on the day of registration. Voriconazole IV will 
be administered 6 mg/kg BID on Day 1 (approximately 12 hour intervals with being not less 
than 9 hours or no more than 15 hours apart) and followed by 4 mg/kg BID (at approximately 
the same time every day with 12 hours apart with approximately 12 hour intervals being not 
less than 9 hours or no more than 15 hours apart). The infusions should not run faster than 3 
mg/kg/hr. Starting and stopping time of every infusion must be correctly recorded. Before 
and after infusion, investigator/sub-investigator will observe at the subject’s infusion site.
If the dosing of study medication is delayed, the dose should be administered as soon as 
possible.  If it is more than 6 hours since the missed dose, the missed dose should be skipped 
and the next dose should be administered at the regularly scheduled time.  Any missed doses
should be properly documented in the subject's source documentation and eCRF.
Exceptionally, first dose could be in the night on Day 1. In case that the first dose is in the 
night, second dose could be in the morning on Day 2 approximately 12 hours apart from the 
first dose, third dose could be in the night on Day 2 approximately 12 hours apart from the 
second dose, and following BID doses from Day 3 could be in the morning and night at 
approximately the same time every day with 12 hours apart with dosing being not less than 9
hours or no more than 15 hours apart.  Also, if the dosing time need to be changed due to 
subject’s schedule or operational handling, the dosing time could be adjusted within the 
range of allowance (scheduled time -/+3 hours). However, approximate dosing time needs to 
be fixed by Day 5.
 
 
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Table 17 Dosing for Voriconazole IV Therapy
Day 1
Day 2-84*
Dose
6 mg/kg BID
4 mg/kg BID
Volume
The final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL
Infusion duration
The infusion should not run faster than 3 mg/kg/hr.
* : It should be conducted on or after Day 9 if subject need to switch the formulation of study drug. Dose adjustment may be 
performed based on the trough concentration of voriconazole.
5.2.1.1.4 Voriconazole Oral Tablet
Table 18 provides the dosing of voriconazole for subjects randomized to the Voriconazole 
treatment arm if on oral therapy.
Voriconazole tablets will be administered as a 300 mg dose BID on Day 1 (approximately 12 
hour intervals with being not less than 9 hours or no more than 15 hours apart) and followed 
by 200 mg dose BID (at approximately the same time every day with approximately 12 hour 
intervals being not less than 9 hours or no more than 15 hours apart).  Voriconazole oral 
tablets SHOULD NOT BE TAKEN WITH A MEAL, and all cases should be taken at least 
one hour before or one hour following a meal.  Investigator should instruct subject that all 
doses should be properly documented in the administration diary (dosage amount, and food 
intake data within 1 hour before or within 1 hour after taking study drug etc.). If the dosing of 
study medication is delayed, the dose should be taken as soon as possible at least one hour 
before or one hour following a meal. If it is more than 6 hours since the missed dose, the 
missed dose should be skipped and the next dose should be administered at the regularly 
scheduled time.
If a subject vomits within 15 minutes of Voriconazole oral administration, the dosing should 
be repeated as soon as possible, following appropriate antiemetic treatment.  Any missed 
doses should be properly documented in the subject's source documentation and eCRF.
Exceptionally, first dose could be in the night on Day 1. In case that the first dose is in the 
night, second dose could be in the morning on Day 2 approximately 12 hours apart from the 
first dose, third dose could be in the night on Day 2 approximately 12 hours apart from the 
second dose, and following BID doses from Day 3 could be in the morning and night at 
approximately the same time every day with 12 hours apart with dosing being not less than 9
hours or no more than 15 hours apart.  Also, if the dosing time need to be changed due to 
subject’s schedule or operational handling, the dosing time could be adjusted within the 
range of allowance (scheduled time -/+3 hours). However, approximate dosing time needs to 
be fixed by Day 5.
Table 18 Dosing for Voriconazole Oral Tablet
Day 1
Day 2-84*
Dose
300 mg (6 tablets) BID
200 mg (4 tablets) BID
* : Dose adjustment may be performed based on the trough concentration of voriconazole.
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other)
Dose modification of MK-5592 must not be allowed. On the other hand, during the study 
treatment, measurement of voriconazole concentration in plasma and subsequent TDM is 
recommended to be performed. The frequency of blood sampling for TDM is judged by the 
investigator’s discretion. Based on the result of voriconazole concentration in plasma, in case 
of concern about safety and efficacy, dose adjustment of voriconazole should be performed 
based on the result of TDM, with the dose modified at the investigator’s discretion. In case of 
adjustment of dosage, TDM must be performed. Voriconazole concentration in plasma is 
recommended between 1-2 μg/mL and 4-5 μg/mL from efficacy and safety point of view.  
In this case, upper limit of dosing is 6 mg/kg BID for IV formulation and 300 mg BID for 
oral formulation. If dose adjustment is performed, voriconazole concentration in plasma
should be appropriately monitored after the dose adjustment. Any dose adjustment and 
voriconazole concentration in plasma should be properly documented in the subject’s source 
documentation and eCRF.
In case of interruption due to adverse event, a temporary interruption of no more than 3 
sequential days without study medication will be allowed with resumption of treatment.
5.2.1.3
Treatment Duration
As a general rule, the treatment duration of all diseases is 84 days (77-84 days with 
considering the final treatment allowance). [However, for the subjects with zygomycosis, 
restart of the study therapy after finishing 84 day maximum treatment period or extension of 
treatment period could be done under the extension period with the prior approval from the 
Sponsor and obtaining the signing of a new informed consent from the only subject who have 
responded to the study therapy without intolerant toxicity if the investigator thinks that
continuation of MK-5592 therapy would benefit the subjects with ample consideration of the 
MK-5592 profile and no alternative treatment in Japan (e.g. failure or intolerant to
amphotericin B formulation). In addition to the above, in case of restart of the study therapy 
after the finishing 84 days, it can be done for the only subjects with same zygomycosis 
episode from the main study therapy (not new episode). The switch of the formulation 
(iv↔tablet) could be done based on the subject’s condition during the extension period but 
dose modification of MK-5592 must not be allowed. However, the study therapy must be 
discontinued when MK-5592 is marketed or the development of MK-5592 is discontinued in
Japan. As a general rule, study medication information and adverse events are recorded 
(routine safety laboratory should be also monitored and recorded in the source document) 
during the study treatment over 84 days but refer to the specific procedure relating this matter
including the details of information that should be recorded in CRF.] However, the treatment 
may be completed earlier if the subject does not need the therapy any longer by the 
investigator’s discretion (e.g. cure of the target infection). The therapy may also be 
discontinued prematurely if the investigator decides that the patient is not capable of 
receiving further therapy (e.g. adverse event) although the investigator feels that the patient 
requires further treatment for the condition under study (refer to section 5.8 for 
discontinuation criteria).
 
 
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In the event that the additional work-up does not result in a proven or probable IA diagnosis 
within 7 days of randomization, subjects should continue participation in the trial with 
possible IA.
Timing of Dose Administration
5.2.2
MK-5592 will be administered twice a day (12 hours interval) on Day 1 and will be 
administered every 24 hours on or after Day 2. Voriconazole will be administered twice a 
day (12 hours interval), however, voriconazole oral tablet should be taken at least one hour 
before (or at least more than one hour after) a meal.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
Randomization will occur centrally using an treatment registration center. There are 2
treatment arms.  Subjects will be assigned randomized treatment in an 2:1 ratio to MK-5592 
treatment arm and Voriconazole treatment arm, respectively. Subjects with fusariosis or 
zygomycosis will be assigned to the MK-5592 treatment arm. Recruitment is completed 
when 112 subjects’ are randomized (excluding subjects with fusariosis or zygomycosis).
Approximately 15 subjects with invasive aspergillosis as a target number will be enrolled.
5.4
Stratification
Randomization will be stratified according to the subject’s disease status at the time of 
randomization following three categories:
1. Proven/probable Invasive aspergillosis at randomization
2. Possible Invasive aspergillosis at randomization
3. Chronic pulmonary aspergillosis at randomization
Within each of these three categories of disease status, subject will be randomized in a 2:1 
ratio to the MK-5592 and Voriconazole treatment arms, respectively.  Note that chronic 
pulmonary aspergillosis includes subjects with chronic progressive pulmonary aspergillosis 
and subjects with simple pulmonary aspergilloma.
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in exclusion criterion 8 are not allowed 
during the specified period during the trial.  Listed below are some specific restrictions for 
concomitant therapy or vaccination during the course of the trial.  If there is a clinical 
indication for one of these or other medications or vaccinations specifically prohibited during 
 
 
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the trial, discontinuation from trial therapy or vaccination may be required.  The investigator 
should discuss any questions regarding this with the local Clinical Monitor.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician.  However, the decision to continue the subject on trial therapy or 
vaccination schedule requires the mutual agreement of the investigator, the Sponsor and the 
subject.
Concomitant Medications, Supplements, and Other Substances Allowed During 
5.5.1
the Trial
Both MK-5592 and voriconazole are potent inhibitors of CYP3A4.  Coadminstration of MK-
5592 or voriconazole with CYP3A4 substrates may result in large increases in exposure of 
CYP3A4 substrates.  Caution is advised during coadministration of MK-5592/voriconazole
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.
Voriconazole is also metabolized by CYP2C19, CYP2C9, and CYP3A4.  Inhibitors or 
inducers of these enzymes may increase or decrease Voriconazole exposure, respectively.
Note that the use of any concomitant medication must relate to the documented medical 
history, prophylaxis, or an adverse event of the subject.
The following medications, supplements, and other substances are allowed during the trial; 
however, caution is advised during co-administration.
Table 19 Allowed Concomitant Medications and Recommendations
Drug/Drug Class
Recommendations for Drug Dosage Adjustment/Comments
Cyclosporine
Tacrolimus
When initiating therapy with study drug follow with monitoring 
of blood levels of these drugs.  Blood level of these drug will be 
increased when coadministered with MK-5592 or voriconazole. 
Nephrotoxicity and leukoencephalopathy (including death) have 
been reported due to elevation of these drugs’ concentration in 
blood. When study drug is discontinued, concentrations must be 
frequently monitored and the dose adjusted as necessary.
Temsirolimus
When initiating therapy with study drug follow with monitoring
of blood levels of this drug. When study drug is discontinued, 
concentrations must be frequently monitored and the dose 
adjusted as necessary.
Methadone 
Monitoring for adverse events and toxicity related to methadone 
is recommended during coadministration. Dose reduction of 
methadone may be needed.
Fentanyl a
Oxycodone a
Reduction in the dose of fentanyl and other long-acting opiates 
metabolized by CYP3A4 should be considered when 
coadministered with study drug. Extended and monitoring for 
opiate associated adverse events may be necessary.
NSAIDs including. ibuprofen and 
diclofenaca
Monitoring for adverse events and toxicity related to NSAIDs. 
Dose reduction of NSAIDs may be needed. 
 
 
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Drug/Drug Class
Recommendations for Drug Dosage Adjustment/Comments
Oral Contraceptives containing 
ethinyl estradiol and norethisteronea
Monitoring for adverse events related to oral contraceptives is 
recommended during coadministration.  If oral contraceptives are 
used, an additional form of contraception should be used.
Warfarina
Monitor PT or other suitable anticoagulation tests. Adjustment of 
warfarin dosage may be needed.
Omeprazolea
Monitoring for adverse events is recommended during 
coadministation.
Antiretroviral therapy other than 
ritonavir and efavirenz (e.g., 
fosaprenavir, NNRTIs a,b)
Monitoring for adverse events and toxicity related to 
antiretroviral therapy. Adjustment of antiretroviral therapy
dosage may be needed.
Benzodiazepines
Monitoring for adverse events and toxicity (i.e., prolonged 
sedation) related to benzodiazepines metabolized by CYP3A4 
(e.g., midazolam, alprazolam, diazepam a). Adjustment of 
benzodiazepine dosage may be needed.
Calcium Channel Blockers
Monitoring for adverse events and toxicity related to calcium 
channel blockers. Adjustment of calcium channel blocker dosage 
may be needed.
Oral hypoglycemicsa
Monitoring of blood glucose and for signs and symptoms of 
hypoglycemia. Adjustment of oral hypoglycemic drug dosage 
may be needed.
HMG-CoA reductase inhibitors 
metabolized via CYP3A4c
Monitoring for adverse events and toxicity related to HMG-CoA 
reductase inhibitors metabolized by CYP3A4. Adjustment of 
HMG-CoA reductase inhibitors dosage may be needed.
Zorpidema
Monitoring for adverse events and toxicity related to zorpidem. 
Adjustment of zorpidem dosage may be needed.
Digoxin
Monitoring for adverse events and toxicity related to digoxin. 
Adjustment of digoxin dosage may be needed.
Theophylline
Monitoring for adverse events and toxicity related to 
theophylline. Adjustment of theophylline dosage may be needed.
Rifampicind
Carefully monitoring for patient condition because plasma 
concentration of MK-5592 may be decreased.
a
It is applicable to the subject who is randomized to voriconazole treatment arm
b
Non-Nucleoside Reverse Transcriptase Inhibitors
c
It is applicable to the subject who is randomized to voriconazole treatment arm. It is a prohibited medication to the MK-5592 
treatment arm.
d
It is applicable to the subject who is assigned (or transitioned) to MK-5592 treatment arm. It is a prohibited medication to the 
voriconazole treatment arm.
Other Treatments
5.5.2
Clinical and/or QTc monitoring is recommended when the study drug is coadministered 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.
5.6
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
 
 
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5.7
Diet/Activity/Other Considerations
Diet
Voriconazole tablet should not be taken with a meal, therefore taking a meal should be 
completed at least one hour before or at least one hour following a dosing.
5.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
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.

Subject with a prolonged QTc interval of their post baseline ECG: greater than 500 
msec. 

Subject who develops clinically indicated visual problems (Grade 3 or more)

Subject who develops an exfoliative cutaneous reaction, develops a skin lesion 
consistent with squamous cell carcinoma or melanoma.   

Subject who, during the course of the study, is determined to have an infection caused 
by an organism that may be insufficiently covered by the current study therapy or 
some other appropriate concomitant medications.    

Subject who cannot (or don’t need to) continue the study therapy (e.g. pregnancy).

Subject who develop the grade 4 AE with causality related to the study drugs.

Subject who
experiences adrenal insufficiency with associated electrolyte 
disturbances and related blood pressure grading
5.9
Subject Replacement Strategy
A subject that discontinues from the trial will not be replaced.
 
 
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5.10 Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
5.11 Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screen-
ing
Treatment
Post-treatment
Extension 17
In-patient16
In-patient/Out-patient
In-patient/
Out-patient
Visit Number/Title:
1
Screen-
ing
2
Day 1
3
Day 3
4
Day 8
5-8
After
Day 8
9
Day 42
10, 11
After
Day 42
12
End of 
treatment or 
discon13
X
Day  of 
formulation 
switch
13
14 days after 
end of treatment
X
Scheduled Day.:
-7 to -1
1
3
8
14, 21,
28, 35
42
56, 70
84
X
14
X
Scheduling Window Days
-
-
+2
+/-1
+/-3
-3 to +7
+/-6
+2
-1
+7
-
Administrative Procedures
Informed Consent
x14
Informed Consent for Future Biomedical 
Research
x
Subject Identification Card 
x
Inclusion/Exclusion Criteria
x
Medical History
x
Prior and Concomitant Medication 
Review
x
Physical Examination (clinical finding)
x
x1
x
x
x
x
x
x
x
x
Assessment of Clinical signs and symptom 
of deep-seated mycosis
x
x1
x
x
x
x
x
x
x
Vital signs and weight
x
x1, 12
x
x
x
x
x
x
x
x
Height 
x
12-Lead Electrocardiogram2
x
x
x
x
x
x
x
x
Diagnostic imaging (CT, MRI etc.)
x4
x
x
x
Mycology test (culture testing, direct 
microscopy or histopathological 
examination etc.) 3
x4
x
x
x
Serology testing 3
x4
x5
x
x
x
Hematology
x
x1
x
x
x
x
x
x
x
x
Serum Chemistry
x
x1
x
x
x
x
x
x
x
x
Serum Pregnancy testing (only for potency 
of child-bearing female)
x15
x
x
Treatment Allocation/Randomization
x1, 12 
Collection of sample to measure MK-5592 
plasma concentration (MK-5592 treatment 
arm) 6,7,8,9
x
x
x
x
x
x
x7
Blood for Future Biomedical Research 10
x
MK-5592, Voriconazole Administration
x
Switching the formulation of study drug11
x
Continuing to confirm
Everyday
 
 
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Trial Period:
Screen-
ing
Treatment
Post-treatment
Extension 17
In-patient16
In-patient/Out-patient
In-patient/
Out-patient
Visit Number/Title:
1
Screen-
ing
2
Day 1
3
Day 3
4
Day 8
5-8
After
Day 8
9
Day 42
10, 11
After
Day 42
12
End of 
treatment or 
discon13
X
Day  of 
formulation 
switch
13
14 days after 
end of treatment
X
Scheduled Day.:
-7 to -1
1
3
8
14, 21,
28, 35
42
56, 70
84
X
14
X
Scheduling Window Days
-
-
+2
+/-1
+/-3
-3 to +7
+/-6
+2
-1
+7
-
Dispensing and collecting of study drug, 
confirmation for number of study drug
x
x
x
Issuing, collecting and confirming the 
medication diary (oral administration)
x
x
x
Assessment of overall response (including 
clinical response, radiological response, 
and mycological response)11
xx
x
xx
x
x
Adverse Events Monitoring
x
x: must be done
xx: will be done as needed
1. Procedure must be done before the initiation of study therapy. If conducted on a same date, measurement and evaluation is not needed 2 times.
2.
12-lead ECG is tried to perform at the timing of maximum serum drug concentration. Recommended timing is as follows;
・
MK-5592 IV solution: just after the end of treatment
・
MK-5592 solid oral tablet: 3 to 5 hours after the treatment
・
Voriconazole IV: just after the end of treatment
・
Voriconazole oral tablet: 1 to 2 hours after the treatment
3. Subjects enrolled with a part of these testings, mycology testing and mycological serology testing (aspergillus antigen, antibody and β-D-glucan) must be performed. Mycological
testings must be performed during the treatment and EOT excluding eradication of the sample enable to collect. Aspergillus antibody is performed for the subject with chronic 
pulmonary aspergillosis and is performed at the screening only. Serology testing is no need for subjects with Zygomycosis and Fusariosis
4.   Data comes from within 7 days before initiation of study therapy, it can be used as a screening result. For the mycology test (culture testing, direct microscopy or histopathological 
examination etc.), data comes from within 14 days before initiation of study therapy can be used as a screening result. Aspergillus antibody testing, data comes from within 28 days 
before initiation of study therapy can be used as a screening result. Mycology test shroud be done by following 7.1.2.6 Mycology Testing and the isolated fungus should be provided to 
the central laboratory.
5.
Only for the subject with invasive aspergillosis.
6. Intravenous treatment (The plasma samples for PK evaluation in the subjects with zygomycosis during the extension period will not be needed)
a: Day 1;30 minutes before the treatment, just before the first treatment, 6 to 10 hours after the initiation of the infusion and just before the treatment of second infusion. Blood sampling
after the treatment on Day 1 (just before the end of first infusion, 6 to 10 hours after the initiation of the infusion and just before the treatment of second infusion) can be performed 
after the second dosing if it is difficult to perform the blood sampling after the first dosing.
b: Day 3, Day 14, Day 28, Day 42 and end of treatment; 30 minutes before the treatment
c: Day 8; 30 minutes before the treatment, just before the end of infusion, 2 to 3 hours after the initiation of infusion, 8 to 10 hour after the initiation of treatment and 30 minutes before 
the next day treatment.
d: At the time of interruption or discontinuation due to adverse events, or at the incidence of serious adverse events by MK-5592 administration.
Continuing to confirm
 
 
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7.   Oral administration (The plasma samples for PK evaluation in the subjects with zygomycosis during the extension period will not be needed)
a: Day 1; 30 minutes before the treatment, 2 to 4 hour after the first treatment, 6 to 10 hours after the treatment and just before the second treatment. Blood sampling after the treatment 
on Day 1 (2 to 4 hours after the first treatment, 6 to 10 hours after the treatment and just before the second treatment) can be performed after the second dosing if it is difficult to 
perform the blood sampling after the first dosing
b: Day 3, Day 14, Day 28, Day 42 and end of treatment; 30 minutes before the treatment
c: Day 8; 30 minutes before the treatment, 2 to 3 hour after the treatment, 4 to 6 hours after the treatment, 8 to 10 hour after the treatment and 30 minutes before the next day treatment.
d: At the time of interruption or discontinuation due to adverse events, or at the incidence of serious adverse events by MK-5592 administration.
e: After 7 days of switching formulation; 30 minutes before the treatment and 2 to 6 hour after the treatment (only for the subject who switch from IV to oral)
8. Early discontinuation subjects who has discontinued this study before Day 8 or Day 9 PK sample collection, PK sample should have collected regulation point Day 8 and/or Day 9 
sample on study discontinuation if possible (Oral administration; 30 minutes before the treatment, 2 to 3 hour after the treatment, 4 to 6 hours after the treatment, 8 to 10 hour after the 
treatment and 30 minutes before the next day treatment., intravenous administration; 30 minutes before the treatment, just before the end of infusion, 2 to 3 after the initiation of 
infusion, 8 to 10 hour after the initiation of treatment and 30 minutes before the next day treatment.).
9. Early discontinuation subject cannot collect sample of 30 minutes before the final treatment, PK sample should be collected on as at discontinuation if possible. If PK sample collected 
on discontinuation day, the other PK sample does not require. Also, PK sample should be collected on day of interruption due to adverse events or at the incidence of serious adverse 
events by MK-5592 administration, but if PK sample are collected on the same day, the other PK sample for interruption or serious adverse events is not required (However, the 
plasma samples for PK evaluation in the subjects with zygomycosis during the extension period will not be needed).
10. Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 (or with the next 
scheduled blood draw), as the last sample drawn, on randomized subjects only, or at a later date as soon as the informed consent is obtained.
11. At the switching formulation (from IV to PO), investigator must evaluate the overall response (including clinical response, radiological response, and mycological response). Data 
conducted on the day of switching formulation or preceding day can be used as an overall response at the switching formulation. In case that subject who started using oral formulation 
cannot continue to receive the oral formulation during the treatment, investigator must evaluate the overall response at that time and conduct the discontinuation procedure [However, 
if the subject is a patient with zygomycosis and joins the extension period, the switch of the formulation(iv↔tablet) could be done based on the subject’s condition but dose 
modification of MK-5592 must not be allowed and the investigator does not need to evaluate the overall response at the timing of switching the formulation].
12. Weight measurement and Treatment Allocation may be conducted between Day -1 and Day 1. Treatment allocation and weight measurement should be conducted on the same date. 
Weight used for treatment allocation should be considered as basis of the dosing calculation. When conducting the Visit 2 weight measurement on Day -1, weight measurement does 
not need to be repeated on Day 1.
13. As a general rule, treatment duration of all disease is 84 days (77-84 days with considering the treatment allowance). At the EOT (completion and discontinuation) visit before the 
transition to the extension period, procedure other than dose administration should be conducted within EOT +2 days. At the end of treatment or discontinuation, procedure at EOT 
should be conducted before starting other systemic antifungal therapy[However, if the subject is a patient with zygomycosis and joins the extension period, procedure at visit 12/EOT 
does not need to be conducted at the last dose of MK-5592 therapy in the extension period].
14. Informed Consent could be obtained prior 28 days of Day 1.
15. Urine pregnancy testing can be conducted. Even though urine pregnancy testing is conducted, serum pregnancy testing should be conducted as a screening testing.
16. Hospitalization is required until all procedures other than study drug administration are completed on Day 9 (9 days and 8 nights after the initiation of study drug). To closely monitor 
the subject’s safety especially at the beginning of the study in addition to the all study periods.  At the discretion of the investigator, subjects may be requested in remain in the 
investigator’s site longer.
17. I
 
 
 
 
 
 
 
 
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
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 must obtain documented consent from each potential subject 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.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
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. Diagnosing the deep-seated fungal infection 
and identifying the infected site will be appropriately recorded in the source document and 
eCRF.
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 after the subject provides written 
informed consent.
7.1.1.4
Medical History
A medical history will be obtained and recorded 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, including any 
protocol-specified washout requirement, and record the anti-fungal drug taken by the subject 
within 30 days before starting the study treatment, anti-bacterial drug taken by the subject 
within 14 days before starting the study treatment and record any other prior medication 
taken by the subject within 3 days before starting the study treatment.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
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 treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
 
 
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for different subjects.  Any subject who is screened multiple times will retain the original 
screening number assigned at the initial screening visit.
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated to trial treatment and will receive a 
randomization number.  The randomization number identifies the subject for all procedures 
occurring after randomization.  Once a randomization number is assigned to a subject, it can 
never be re-assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for 4 days
require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
In case of administration of trial medication (IV formulation), administration will be 
witnessed by the investigator and/or trial staff.
In case of administration of trial medication (oral formulation), the way of the administration 
of trial medication will be informed to the subjects by the investigator and/or designee.  The 
investigator and/or designee provides the direction that trial medication and meal should be 
recorded in the medication diary.  The subjects bring the medication diary when subjects visit 
the hospital, and the medication diary will be confirmed by the investigator and/or designee. 
The medication diary is stored at the study site after the clinical trial. All the information of 
trial medication and meal should be recorded in the source document and eCRF.
Clinical Procedures/Assessments
7.1.2
In order to minimize variability, it is preferred that the same individuals perform the same 
procedures/evaluations for all subjects at each trial site.
7.1.2.1
Physical Examination
Physical examination is performed at the specified visit and recorded in the source document. 
In case of abnormal physical findings compared to the baseline after the initiation of study 
treatment, the investigator/sub-investigator assesses and records whether the physical 
findings are adverse event, or not in the source document and eCRF.
7.1.2.2
Clinical Signs and Symptoms of Deep-Seated Fungal Infection
Attributable clinical signs and symptoms of deep-seated fungal infection [cough, dyspnea, 
sputum, bloody sputum, hemoptysis, pain, pyrexia and weight decreased etc.] are identified, 
and assessed through the existence and severity of vital signs and shifts of clinical laboratory 
 
 
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values (CRP etc.) for reference and recorded in the source document and eCRF at the 
scheduled visit. Intensity is evaluated in the following criteria.
Absense:
There is no symptom or observation.
Mild:
Grade 1 symptom or observation defined by the CTCAE grading (version 4.0). 
Moderate: Grade 2 symptom or observation defined by the CTCAE grading (version 4.0).
Severe:
Grade 3(or more) symptom or observation defined by the CTCAE grading 
(version 4.0).
7.1.2.3
Vital Signs
Temperature (oral, axilla or archo), pulse, blood pressure, weight and SpO2 will be measured 
and recorded in the source document and eCRF at the scheduled visit.  If it is difficult to 
measure these testing based on the subject’s condition, it may not be done. Temperature 
recorded should be highest (maximum temperature) in each day. In principle, measuring 
method is same throughout the study. If the temperature is measured other than scheduled 
visit during the study, all of these data should be recorded in the source document and eCRF.
7.1.2.4
12-Lead Electrocardiogram
12-lead electrocardiogram is performed using standard equipment that can be measured for 
ventricular rate, RR, PR, QRS, QT and QTc interval. 12-lead electrocardiogram is performed 
at the scheduled or unscheduled visit and tried to measure at the time of the highest plasma 
concentration.  Serum electrolytes (K, Ca, Mg) must be measured on the same day and 
recorded in the source document and eCRF, in case an
unscheduled 12-lead 
electrocardiogram is performed. Clinically abnormal findings in the electrocardiogram will 
be followed up until recovering to the baseline value or stabilization appropriately.  If QTc 
interval is greater than 500 msec, study treatment must be discontinued.
7.1.2.5
Diagnostic Imaging
The type of imaging used (e.g. CT or MRI) will depend on the site of infection. For 
pulmonary sites of infection, CT scanning is required. Each site of infection identified during 
screening should be followed throughout the study by repeating the same type of scan and 
the same imaging modality.  Imaging must be performed at the scheduled visit and all 
imaging must be recoded and stored at the study site appropriately, and masked imaging is 
provided to the sponsor or the designated imaging facility. In case of performing imaging at 
the unscheduled visit, the masked imaging may be provided to the sponsor or the designated 
imaging facility by the direction of clinical adjudication committee or trial physician for the 
assessment. The imaging at the unscheduled visit also must be recoded and stored at the 
study site appropriately. In addition, imaging performed in the time when the subject 
condition was good and antifungal treatment was not needed may be provided to the sponsor 
or the designated imaging facility after being masked by the direction of clinical adjudication 
committee or trial physicians for the assessment.
 
 
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7.1.2.6
Mycology Testing
Mycology testing is performed and fungal infection is observed by using the appropriate 
method. Even if causative fungus is identified by mycological serology testing, direct 
microscopy or histopathological examination, culture testing must be performed. Causative 
fungus is isolated from culture sample and its genus is identified at the study site. Fungal 
infection is followed throughout the trial by repeating the same mycology testing based on 
subjects’ condition in principle. The fungus isolated by culture testing is provided to the 
central laboratory and its species is identified and minimum inhibitory concentration (MIC) 
testing is performed at the central laboratory.  At the study site, isolated fungus is 
appropriately stored until identification of species.  If the fungus isolated by culture testing 
done at the time other than the specified visit in the protocol, this is also provided to the 
central laboratory and isolated fungus is appropriately stored at the study site until 
identification of species.
If the microorganisms other than fungus are isolated by culture testing, all of these data 
should be recorded in the source document and eCRF appropriately.
7.1.2.7
Serology Testing (Aspergillus Antigen, Aspergillus Antibody and β-D-Glucan)
Aspergillus antigen, antibody and β-D-glucan are measured at the scheduled visit and their 
result is recorded in the source document and eCRF appropriately. Aspergillus antibody is 
measured at the screening only. If the aspergillus antigen and β-D-glucan are measured at the 
unscheduled visit, all of these data should be recorded in the source document and eCRF 
appropriately. This testing does not need to be measured for the subjects with fusariosis and 
zygomycosis.
7.1.2.8
Sample Collection for Plasma Concentration of MK-5592 (MK-5592 Treatment 
Arm)
Blood sample for plasma concentration of MK-5592 is collected on the scheduled visit. 
Volume of the blood sampling is 2 mL/time. Blood sampling must be collected via other 
location different from the location of study administration. Regarding the sampling points of 
just before the end of first infusion on Day 1 and 8 for MK-5592 IV solution, blood sampling 
should be done before flushing. From the feasibility point of view, blood sampling after the 
treatment on Day 1 (IV solution: just before the end of first infusion, 6 to 10 hours after the 
initiation of the infusion and just before the treatment of second infusion, solid oral tablet: 2 
to 4 hours after the first treatment, 6 to 10 hours after the treatment and just before the second 
treatment) can be performed after the second dosing if it is difficult to perform the blood 
sampling after the first dosing (e.g. in case that the first dose is in the night). If it is difficult 
to perform the blood sampling at the just before the second treatment/infusion, it may not be 
done but the reason for not performing the blood sampling must be recorded in the source 
document and eCRF. Blood sampling after the first dosing on Day 1 (or second dosing) 
should be performed at least 3 hours apart among these sampling points (IV solution: 6 to 10 
hours after the initiation of the infusion and just before the treatment of second infusion, solid 
 
 
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oral tablet: 6 to 10 hours after the treatment and just before the second treatment). Sampling 
date and time must be correctly recorded in the source document and eCRF.
7.1.2.9
Evaluation for Overall Response
The individual response assessment (Clinical Response, Radiological Response, Mycological 
Response and Clinical Laboratory Response) in subjects with deep-seated fungal infection
will be evaluated at Day 42, EOT(before the transition to the extension period) and switching 
formulation according to the criteria described in 4.2.3.1, and Overall Response is assessed 
based on these individual responses (However, if the subject is a patient with zygomycosis 
and joins the extension period, the individual response assessment at switching formulation
or the last dose of MK-5592 therapy in the extension period does not need to be done).
Overall response assessed by investigator and information are provided to the Clinical 
adjudication committee. CAC assessed the overall response according to the same criteria. 
The assessment by CAC is used as a Primary efficacy endpoint.
7.1.2.10 Guidance for Treatment of adverse event
When a subject shows an adverse event, the investigators should always consider the 
necessity of treatment of adverse events as soon as possible regardless of the relationship to 
study drugs. The investigators should carefully monitor all testing results including those that 
are not usually done in the routine medical examination in the sites and treat the adverse 
events as soon as possible before they have an effect on subjects or lead to study 
discontinuations. Considering the safety profile of the study drugs, the following treatment 
may be considered but not limited to these adverse events or treatments. It is always 
important to consider the treatment of adverse events first. 

Pyrexia
Most of these adverse events reported in previous clinical studies were mild to moderate 
and reversible. Pyrexia is one of the major signs of infection, and it is important to 
identify the cause of pyrexia. Thus, if pyrexia is not related to target infection of the 
study, any clinical testing and assessment need to be attempted to identify the cause of 
pyrexia such as bacterial infection. Antibacterials, antipyretics or any other appropriate 
treatment should be considered based on the clinical testing.

Gastrointestinal events (nausea, vomiting, abdominal pain or diarrhea)
Most of these adverse events reported in previous clinical studies were mild to moderate 
and reversible. Appropriate antiemetic or antiflatulent treatment should be considered. 

Hepatic events (including asymptomatic elevations in transaminases and/or bilirubin)
Most of hepatic adverse events reported in previous clinical studies were mild to 
moderate and reversible. Interruption of suspicious concomitant drugs and/or adding 
hepatic function improving drugs should be considered. 
 
 
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
Visual disturbance
Most of these adverse events reported in previous clinical studies were mild to moderate 
and reversible without treatment.
If adverse events relate to study medication and they become a major issue in spite of the 
above attempt, interruption of study drugs should be considered before study drug 
discontinuation.
7.1.2.11 Domiciling
Hospitalization is required until all procedures other than study drug administration are
completed on Day 9 (9 days and 8 nights after the initiation of study drug). At the discretion 
of the investigator, subjects may be requested in remain in the investigator’s site longer.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory testing is performed in the local laboratory (or its outsourcing). 
Laboratory testing is performed at the timing of dosage in scheduled visit.  The total amount 
of blood to be drawn/collected over the course of the trial (from pre-trial to post-trial visits), 
including approximate blood volumes drawn/collected by visit and by sample type per 
subject can be found in Section 12.4.  If abnormal laboratory findings are observed, its 
abnormality is appropriately followed up until stabilization or recovery to baseline.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry are specified in Table 20 to Table 22.
Table 20 Laboratory Tests (Hematology)
Red blood cell count (RBC)
Hemoglobin
Hematocrit
Platelet count
White blood cell count (WBC)
WBC differential (neutrophil, eosinophil, basophil, lymphocyte, 
monocyte)
 
 
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Table 21 Laboratory Tests (Blood Chemistry)
Total protein
Blood Urea Nitrogen
Albumin
Creatinine
Aspartate aminotransferase (AST)
Uric acid
Alanine aminotransferase (ALT)
CRP
Alkaline phosphatase
Calcium
LDH
Chloride
Total Bilirubin  
Potassium
Direct Bilirubin
Sodium
Magnesium
Table 22 Laboratory Test (Other)
Serum hCG (Total hCG or β-hCG): female subjects of childbearing potential
Aspergillus antibody (only for subject with Chronic pulmonary aspergillosis): perform at 
Screening visit only
Galactomannan antigen (ELISA): perform for the subject with aspergillosis only
β-D-Glucan: perform for the subject with aspergillosis only
Serum electrolytes (K, Ca, Mg) must be measured on the same day and recorded in the 
source document and eCRF, in case an unscheduled 12-lead electrocardiogram is performed.  
In case adrenal insufficiency is observed, serum electrolytes (K, Ca, Mg) must be measured, 
evaluated and recorded in the source documents and eCRF.
If CRP is measured at the unscheduled visit, all of these data are recorded in the source 
document and eCRF appropriately.
Urine pregnancy testing can be conducted for confirmation of subject eligibility and it is not 
required to record in the eCRF. Even though urine pregnancy testing is conducted, serum 
pregnancy testing should be conducted as a screening testing and it is recorded in the source 
document and eCRF appropriately.  
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
Measurement for PK analysis will be performed in collected samples.
7.1.3.2.1 Blood Collection for Plasma MK-5592
Sample collection, storage and shipment instructions for plasma samples will be provided 
separately. 
 
 
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7.1.3.3
Future Biomedical Research
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  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
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for 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.
 
 
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7.1.5.1
Procedure of MK-5592 Treatment for Subjects in case That Zygomycete are 
Observed During the Treatment Period in Voriconazole Treatment Arm
Subjects in whom zygomycetes are detected during the treatment period in the voriconazole 
treatment arm can receive the MK-5592 by investigator’s discretion after the discontinuation 
of voriconazole treatment.  MK-5592 dosing can be initiated after performing all 
observations, testing and evaluations at the end of treatment and the signing of a new
informed consent.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable 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.
All adverse events 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. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
 
 
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Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than the dose below for cohort 2.
MK-5592 solid oral tablet and IV solution: 300 mg/time and 300 mg/day (600 mg/day on 
Day 1).
Voriconazole IV: 6 mg/kg/time and 12 mg/kg/day on Day 1, 4 mg/kg/time and 8 mg/kg/day 
after Day 1
Voriconazole oral tablet: 300 mg/time and 600 mg/day on Day 1, 200 mg/time and 
400 mg/day after Day 1
In case of higher than the above criteria, overdose is not applicable when the voriconazole 
dosage is adjusted based on the TDM, however overdose is any higher than 6 mg/kg for IV 
and 300 mg for oral tablet as a single dose.
In case of higher than the above criteria, overdose is not applicable when the MK-5592 and 
voriconazole daily dosage is exceeded according to the allowance of dosing interval by 
Day 5.
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 within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder.
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 or within 14 days of completing 
the trial.  All subjects who become pregnant 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 
 
 
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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.  Sponsor Contact information can be found in the Investigator Trial File Binder.
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 23 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 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
 
 
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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 recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor either by electronic media or paper.  Sponsor Contact 
information can be found in the Investigator Trial File Binder.
Events of clinical interest for this trial include:
a.
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. 
b. 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 may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder.
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.
 
 
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Table 23 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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); 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) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical 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 
test drug 
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
 
 
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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 U.S. CLINICAL 
MONITOR 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 there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
7.3
TRIAL GOVERNANCE AND OVERSIGHT
Clinical Adjudication Committee
7.3.1
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 8.0 – Statistical Analysis 
Plan.
1) Diagnosis of deep-seated fungal infection [For subjects with all queries closed, 
validity of deep-seated fungal infection diagnosed by investigators is assessed]
2) Overall Response [For subjects with all queries closed, validity of Overall Response 
assessed by investigator is assessed (Overall Response, Clinical Response, 
Radiological Response, Mycological Response)]
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial.  Specific details regarding endpoint definitions can be found in the 
Adjudication Charter.
8.0 STATISTICAL ANALYSIS PLAN
8.1
Statistical Analysis Plan Summary
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).
The primary population of statistical analysis is cohort 2 and the analysis plan described in 
this section will be conducted in cohort 2. Data from extension period will be excluded from 
the analyses of Cohort 2.  
 
  
Efficacy Analyses
8.1.1
The primary endpoints, primary analysis population, and statistical method that will be 
employed for the efficacy analyses are presented in Table 24 below.
The primary efficacy endpoint is the overall response assessed by CAC. The overall response 
rates (the proportion of subjects with “success” assessment [see Section 8.2.3.3]) for invasive 
aspergillosis at Day 42 and for chronic pulmonary aspergillosis (chronic progressive 
pulmonary aspergillosis and simple pulmonary aspergilloma) at Day 84 and their 95% 
confidence intervals will be computed by treatment. Subjects with solid oral tablet, IV 
solution and switch from IV solution to solid oral tablet for the MK-5592 treatment arm will 
 
 
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be pooled for the analyses due to the fact that it reflects clinical practice and the different 
routes of administration achieve targeted plasma concentration level of MK-5592. Likewise, 
subjects with oral tablet, IV solution and switch from IV solution to oral tablet for the 
Voriconazole treatment arm will be pooled for the analyses.
The overall response for the subjects with fusariosis and zygomycosis will be listed for MK-
5592 treatment arm since the enrollment of these infections will be very limited.
Table 24 Analysis Strategy for Primary Efficacy Endpoint
Endpoint/Variable
(Description, Timepoint)
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Overall response rates for 
invasive aspergillosis at Day 
42 and for chronic 
pulmonary aspergillosis at 
Day 84
95% CI with 
Clopper-
Pearson Exact 
Method
FAS
Carry Forward
Safety Analyses
8.1.2
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized patients who received at least 
one dose of study treatment.  Invasive aspergillosis and chronic pulmonary aspergillosis will 
be pooled for the analyses but subject with fusariosis and zygomycosis will be separately 
evaluated. In this study, the prespecfied events of interest (Tier-1 events) are not defined.
Power and Sample Size
8.1.3
This study initially planned to enroll a total of 90 subjects but due to the modification in 
protocol such as inclusion and exclusion criteria, an additional 90 subjects will be enrolled as 
cohort 2, 
  The cohort 2 will enroll 
subjects as initially planned for this protocol:
This study will randomize 60 subjects into the MK-5592 treatment arm and 30 into the 
Voriconazle treatment arm. A total number of 90 subjects were set with consideration of 
recruitment feasibility based on the past experiences (See Section 8.2.7 for details). A total of 
90 subjects include those with all aspergillosis for safety analyses, and among them 15 
subjects with invasive aspergillosis as a target number will be enrolled.  Subjects with 
fusariosis and zygomycosis will be assigned to the MK-5592 treatment arm and their target 
number of recruitment is not set.
Interim Analyses
8.1.4
Formal interim analyses are not planned in this study. Safety and PK data will be reviewed 
by the sponsor on an ongoing basis.  No alpha adjustment is needed since no hypothesis is 
tested in this study.
 
 
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8.2
Statistical Analysis Plan
The primary population of statistical analysis is cohort 2 and the analysis plan described 
below will be conducted in cohort 2. Data from extension period will be excluded from the 
analyses of Cohort 2.  Safety and PK data in cohort 1 will be separately summarized from 
cohort 2.
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label study, i.e., patients, investigators, and 
SPONSOR personnel will be aware of patient treatment assignments after each patient is 
enrolled and treatment is assigned.
The Clinical Biostatistics department or designee will generate the randomized allocation 
schedule for study treatment assignment. Randomization will be implemented by registration 
center.
This trial is being conducted as an open-label study but the diagnosis and overall response 
will be assessed by CAC in a blinded manner based on data with masked information such as 
treatment assignment.
Hypotheses/Estimation
8.2.2
Objectives and hypotheses of the study are stated in Section 3.0.  The hypothesis is not set 
since the main objective of this study is safety assessment.
Analysis Endpoints
8.2.3
Efficacy and safety endpoints are listed below.
8.2.3.1
Efficacy Endpoints
8.2.3.1.1 Primary Efficacy Endpoint
The Primary efficacy endpoint is the overall response for invasive aspergillosis at Day 42 and 
for chronic pulmonary aspergillosis at Day 84 assessed by CAC. 
8.2.3.1.2 Secondary Efficacy Endpoints
The following endpoints assessed by CAC will be secondary efficacy endpoints:

Overall response for invasive aspergillosis at Day 84

Overall response for chronic pulmonary aspergillosis (chronic progressive pulmonary 
aspergillosis and simple pulmonary aspergilloma) at Day 42
 
 
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
Overall response for all aspergillosis [invasive aspergillosis and chronic pulmonary 
aspergillosis (chronic progressive pulmonary aspergillosis and simple pulmonary 
aspergilloma)] at EOT

Overall response for fusariosis and zygomycosis at  Day 42 and Day 84

Clinical response for invasive aspergillosis and chronic pulmonary aspergillosis 
(chronic progressive pulmonary aspergillosis and simple pulmonary aspergilloma) at 
Day 42 and Day 84

Radiological response for invasive aspergillosis and chronic pulmonary aspergillosis 
(chronic progressive pulmonary aspergillosis and simple pulmonary aspergilloma) at 
Day 42 and Day 84

Mycological response for invasive aspergillosis and chronic pulmonary aspergillosis 
(chronic progressive pulmonary aspergillosis and simple pulmonary aspergilloma) at 
Day 42 and Day 84
In addition, overall response for invasive aspergillosis at Day 42 and for chronic pulmonary
aspergillosis at Day 84 assessed by investigators/sub-investigators will be evaluated as a 
secondary efficacy endpoint.
8.2.3.2
Safety Endpoints
Refer to Section 7.0 for safety endpoints.
8.2.3.3
Derivations of Efficacy Endpoints
The overall response will be assessed by CAC using clinical, radiological and mycological
response data.  The data for assessing the overall response and criteria of efficacy judgment 
are presented in the Table 25 and criteria for overall response is presented in Section 4.2.3.1.
Data will be submitted to CAC with masked Information such as treatment assignment and 
CAC will assess the overall response in a blinded manner.
 
 
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Table 25 The Data for Assessing the Overall Response and Criteria of Efficacy Judgment
Disease Category
Information for 
assessing the overall 
response
Efficacy Assessment
Success
Failure
Invasive aspergillosis†
Clinical response
Radiological response
Mycological response
Complete Response
Partial Response
Stable Response
Progression of disease
Unable to determine
Chronic pulmonary 
aspergillosis (chronic 
progressive pulmonary 
aspergillosis and simple 
pulmonary aspergilloma)
Clinical response 
Radiological response
Favorable Response
Stable Response
Progression of disease
Unable to determine
Fusariosis and zygomycosis
Clinical response, 
Radiological response and 
Mycological response
Or
Clinical response and 
Mycological response
Complete Response
Partial Response
Stable Response
Progression of disease
Unable to determine
†Subjects with possible invasive aspergillosis may also be enrolled into the study with further evaluation of proven or probable invasive 
aspergillosis, which must be confirmed by 7 days post-randomization to be included in the FAS analysis.
Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis
of efficacy data in this study.  The FAS for a given endpoint consists of all randomized
subjects in cohort 2 who: 

Diagnosed as target disease (proven or probable) by CAC

Receive at least one dose of study treatment

Have a baseline observation for the analysis endpoint
Subjects with possible invasive aspergillosis may also be enrolled into the study with further 
evaluation of proven or probable invasive aspergillosis, which must be confirmed by 7 days 
post-randomization to be included in the FAS analysis.
An Intention To Treat (ITT) population is defined as all randomized subjects in cohort 2 who 
received at least one dose of study treatment, and the analysis of the primary efficacy 
endpoint will be performed.
A supportive analysis using the Per-Protocol population in cohort 2 will be also performed 
for the primary efficacy endpoint.  The Per-Protocol population excludes patients due to 
important deviations from the protocol that may substantially affect the results of the primary 
efficacy endpoint. Potential violations that may result in the exclusion of a patient from the 
Per-Protocol population include:

Subjects with cases that affect the results of the primary efficacy endpoint, confirmed 
by CAC
 
 
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The final determination on protocol violations, and thereby the composition of the Per-
Protocol population, will be made prior to the final lock of the database and will be 
documented in a separate memo.
Patients will be included in the treatment group to which they are randomized for the analysis 
of efficacy data using both the FAS, ITT and Per-Protocol populations.  Details on the 
approach to handling missing data are provided in Section 8.2.5.1.4.
8.2.4.2
Safety Analysis Populations
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this study. 
Randomized subjects with invasive aspergillosis and chronic pulmonary 
aspergillosis (chronic progressive pulmonary aspergillosis
and simple pulmonary 
aspergilloma) will be pooled for the analyses but subjects with fusariosis and zygomycosis, 
not randomized subjects, will be separately evaluated. The ASaT population consists of all 
randomized subjects in cohort 2 who received at least one dose of study treatment. Subjects
will be included in the treatment group corresponding to the study treatment they actually 
received for the analysis of safety data using the ASaT population.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
8.2.5
The main objective of this study is assessment of safety and the formal hypothesis testing for 
efficacy endpoints will not be conducted. Nominal p-values and confidence intervals will be 
presented at the α=0.05 (2-sided) level.
8.2.5.1
Statistical Methods for Efficacy
8.2.5.1.1 Primary Efficacy Analysis
The primary efficacy endpoint is the overall response assessed by CAC. The overall response 
rates (the proportion of subjects with “success” assessment) for invasive aspergillosis at Day 
42 and for chronic pulmonary aspergillosis (chronic progressive pulmonary aspergillosis and 
simple pulmonary aspergilloma) at Day 84 and their 95% confidence intervals will be 
computed by treatment. Subjects with solid oral tablet, IV solution and switch from IV 
solution to solid oral tablet for the MK-5592 treatment arm will be pooled for the analyses 
due to the fact that it reflects clinical practice and the different routes of administration 
achieve targeted plasma concentration level of MK-5592. Likewise, subjects with oral tablet, 
IV solution and switch from IV solution to oral tablet for the Voriconazole treatment arm 
will be pooled for the analyses. The 95% confidence intervals will be estimated with the 
Clopper-Pearson method.
 
 
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8.2.5.1.2 Secondary Efficacy Analysis
The overall response rates for invasive aspergillosis at Day 84 and for chronic pulmonary 
aspergillosis (chronic progressive pulmonary aspergillosis and simple pulmonary 
aspergilloma) at Day 42 will be provided by treatment (Table 26).
The overall response rate for all aspergillosis (invasive aspergillosis and chronic pulmonary 
aspergillosis are pooled) at EOT will be provided by treatment.
Clinical, radiological and mycological response rates for invasive aspergillosis and for 
chronic pulmonary aspergillosis (chronic progressive pulmonary aspergillosis and simple 
pulmonary aspergilloma) at Day 42 and Day 84 will be provided by treatment.
The overall response for the subjects with fusariosis and zygomycosis will be listed for MK-
5592 treatment arm since the enrollment of these infections will be very limited.
As a sensitivity analysis, the overall response rates for invasive aspergillosis at Day 42 and 
for chronic pulmonary aspergillosis at Day 84 will be provided by treatment in the PP 
population. For the PP analysis, a subject with missing post-treatment response data or with 
‘unable to determine’ response will be excluded. In addition, the overall response rates will 
be provided in the ITT population and also the overall response rates by investigators/sub-
investigators will be provided in the FAS population.
Table 26 Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Methods
Analysis 
Population
Missing Data 
Approach
Primary
Overall response rates for invasive 
aspergillosis at Day 42 and for 
chronic pulmonary aspergillosis at 
Day 84
P
95% CI with Clopper-
Pearson Exact Method
FAS
CF†
S
Point Estimate
PP
CF†
S
Point Estimate
ITT
CF†
S
Point Estimate: 
Assessment
by investigators/sub-
investigators
FAS
CF†
Secondary
Overall response rates for invasive 
aspergillosis at Day 84 and for 
chronic pulmonary aspergillosis at 
Day 42
P
Point Estimate
FAS
CF†
Overall response
rate for  all 
aspergillosis 
at 
EOT 
(invasive 
aspergillosis and chronic pulmonary 
aspergillosis are pooled)
P
Point Estimate
FAS
CF†
Clinical 
response 
rates, 
radiological response
rates and 
myological 
response
rates 
for 
invasive 
aspergillosis 
and 
for 
chronic pulmonary aspergillosis at 
Day 42 and Day 84
P
Point Estimate
FAS
CF†
†CF: Carried-forward method
 
 
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8.2.5.1.3
 
 
8.2.5.1.4 Accounting for Missing Data
For the primary analyses in FAS and ITT (overall response rates for invasive aspergillosis at 
Day 42 and for chronic pulmonary aspergillosis at Day 84), missing data will be imputed by 
a carried-forward method. Baseline values will not be carried forward and if there is no data 
after treatment, the missing data will be considered as failure.  Data with ‘unable to 
determine’ will be considered as failure as well. For the overall response rates for invasive 
aspergillosis at Day 84 and for chronic pulmonary aspergillosis at Day 42, and also clinical, 
radiological and mycological response rates at Day 42 and Day 84 for both aspergillosis, the 
missing data will be imputed likewise.
For the analyses in PP population, a subject with missing post-treatment response data or 
with ‘unable to determine’ response will be excluded.
8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 27) but tier 1 events are 
not defined in this protocol. The tiers differ with respect to the analyses that will be 
performed.  Membership in Tier 2 requires that at least 4 patients in any treatment group 
exhibit the event; all other adverse experiences and predefined limits of change will belong to 
Tier 3. In addition, the broad clinical and laboratory AE categories consisting of the 
percentage of patients with any AE, a drug related AE, a serious AE, an AE which is both 
drug-related and serious, and who discontinued due to an AE will be considered Tier 2 
endpoints.
Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will  include zero when both treatment groups 
have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences.  Because many 95% confidence intervals may be provided without 
adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse experiences and predefined limits of 
change.
 
 
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Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters will be considered Tier 3 safety parameters.  Summary statistics for baseline, on-
treatment, and change from baseline values will be provided by treatment group in table 
format.
Table 27 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Not defined in this protocol
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs(incidence ≥4 of 
patients in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of 
patients in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
8.2.5.3
Summary of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of patients screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
 
Multiplicity
8.2.6
No multiplicity adjustment is necessary since no hypothesis is tested in this study.
Sample Size and Power Calculations
8.2.7
This study initially planned to enroll a total of 90 subjects, but due to the modification in 
protocol such as inclusion and exclusion criteria, an additional 90 subjects will be enrolled as 
 
 
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cohort 2
 
.  The cohort 2 will enroll subjects as initially planned for this 
protocol as follows:
The target number of subjects for the safety analyses will be 90 subjects (MK-5592 treatment 
arm: 60 subjects, Voriconazole treatment arm: 30 subjects) in this study.  From past 
experiences of the sponsor as well as information of competitors a total number of 90 
subjects were set as a target number with consideration of recruitment feasibility.  
A total of 90 subjects include subjects with invasive aspergillosis and chronic pulmonary 
aspergillosis (chronic progressive pulmonary aspergillosis
and simple pulmonary 
aspergilloma). In order to obtain MK-5592 data as much as possible with a limitation of the 
sample size, the allocation ratio was set 2 to 1. 15 subjects with invasive aspergillosis as a 
target number will be enrolled.  Fusariosis and zygomycosis are very rare deep-seated fungal 
infections and it is reported that Voriconazole is not effective for treatment of zygomycosis, 
so subjects with those infections will not be randomized and will be enrolled in the MK-5592 
treatment arm without a target number of enrollment.  
According to clinical database of Posaconazole Oral Suspension, which is approved and 
available in the markets of Europe and the United States, as well as clinical studies of MK-
5592 in the new formulations up to date, the incident rates of frequently observed adverse 
experiences (pyrexia, diarrhea, nausea, headache, vomiting and cough) are expected to be 
approximately 10% - 20%.  Assuming that incident rates of the MK-5592 arm and 
Voriconazole arm are comparable, the half-width of the 95% confidence interval for the 
difference of the incidence rates will be 14.6% - 17.9% with 60 subjects of the MK-5922 arm 
and 30 subjects of the Voriconazole arm (Table 28).  If a particular adverse experience is not
observed in any of the 60 patients in the MK-5592 treatment arm, the true incidence rate for 
the particular adverse experience is less than 2.6% with 80% confidence. For efficacy 
assessment, assuming that response rate of 60% (80%), the lower limits of confidence 
interval for MK-5922 arm will be 46.5% (67.7%) with the sample size of 60.
Table 28 95% Confidence Interval for Difference of the Incidence Rates for Adverse Events
95% Confidence Interval
Incident Rates
for both arms (difference of 0%)
Lower Bound
Upper Bound
A half-width of the 
95% CI
10%
-12.5
16.8
14.6%
15%
-15.9
16.4
16.1%
20%
-16.3
19.5
17.9%
Incidence Rates for the MK-5592 and Voriconazole treatment arm are assumed to be equal.
(MK-5592: 60 subjects, Voriconazole: 30 subjects)
95% confidence interval was calculated with the Miettinen and Nurminen method.
 
 
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Subgroup Analyses and Effect of Baseline Factors
8.2.8
To determine whether the treatment effect is consistent across various subgroups, the 
treatment effect for the primary endpoint will be estimated by the disease category in the 
following factors:

Sex (female, male)

Age (<65 vs. ≥65 years)

Weight (<60, ≥60 kg)

Fungal species

Rout of administration (oral, IV, switch)

Diagnosis (proven, probable)
Interim Analysis
8.2.9
Formal interim analyses are not planned in this study. Safety and PK data will be reviewed 
by the sponsor on an ongoing basis.  No alpha adjustment is needed since no hypothesis is 
tested in this study.
Compliance (Medication Adherence)
8.2.10
In this study, as part of the routine recording of the amount of study treatment taken by each 
patient, the volume of injection and the number of tablets remaining in study packaging will 
be counted, reviewed, and recorded at regular intervals.  These results will be used to 
calculate patient compliance.
8.2.10.1 IV Route
Drug accountability data for MK-5592 and Voriconazole will be collected during the study. 
Compliance with protocol-directed MK-5592 and Voriconazole will be measured by patients: 
(1) receiving unscheduled study agent infusions, (2) missing an infusion, (3) receiving 
incorrect study agent dose, and (4) receiving an infusion at rate greater than a rate specified
in the protocol. Numbers and percentages of patients with any deviation in these measures 
will be reported by treatment for the FAS and ASaT population.
Compliance will be assessed using the off-drug therapy records.  On each day, each patient 
should take a certain infusion dosage.  The compliance rate for each patient will be computed 
as follows:
Therapy
on 
be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 

x 100.
Study period is defined as the number of days that the patient has been in the active treatment 
phase of the trial.
 
 
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8.2.10.2 Oral Therapy
A day within the study will be considered an “On-Therapy” day if the patient takes the 
required number of tablets. For a patient who is followed for the entire study period, the 
“Number of Days Should be on Therapy” is the total number of days from randomization to 
the last scheduled day for treatment administration for that patient.  For a patient who
discontinued from the study permanently, the “Number of Days Should be on Therapy” is the 
total number of days from randomization to the earlier/later date of the last dose of study 
medication.
For each patient, percent compliance will then be calculated using the following formula:
Therapy
on 
be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 

x 100.
Summary statistics will be provided on percent compliance by treatment group for the FAS 
and ASaT.
Extent of Exposure
8.2.11
The extent to exposure to study treatment will be evaluated by summary statistics (N, mean 
median, standard deviation) and frequencies for the “Number of Days on Therapy” by 
treatment group.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product
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 29.
Table 29 Product Descriptions
Product Name & Potency
Dosage Form
MK-5592 18 mg/mL, 300 mg/vial
IV solution for injection
MK-5592, 100 mg
Tablet
Voriconazole, 200 mg/vial
Lyophilized Powder 
Voriconazole, 50 mg
Tablet
 
 
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9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
MK-5592 IV solution will be supplied as kits containing one vial.  MK-5592 tablets will be 
supplied as bottles containing 30 tablets. No kitting is required.  Voriconazole Lyophilized 
Powder will be supplied as kits containing ten vials.  Voriconazole tablets will be supplied as 
kits containing 50 tablets in PTP sheets.  All of clinical supplies will be supplied as open 
label.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
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 
 
 
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employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
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.
 
 
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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.
10.2 Compliance With Financial Disclosure Requirements
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.
10.3 Compliance With Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
 
 
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The sponsor 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 discarding 
trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
 
 
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In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [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.
10.4 Compliance With Trial Registration and Results Posting Requirements
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.
10.5 Quality Management System
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.
 
 
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10.6 Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided by the Sponsor.
10.7 Publications
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. 
 
 
 
 
 
  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 
 
 
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paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
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. S. Fujiuchi, Deep-seated mycoses, Hokkaido-Iho, 01-Feb-2006
2. Development committee
of guideline for deep-seated mycoses, Guideline for 
management of deep-seated mycoses 2007 (in Japanese). 
3. K. Kamei, Imported mycoses in Japan and their problems. Medical Mycology Journal 
53：103-108, 2012 (in Japanese).
4. T. Tagono, K. Shibuya, H. Kume et al, Estimated numbers of visceral mycoses in case of 
leukemia and MDS in Japan : Analysis of the data from the annual of the pathological 
autopsy cases and vital statics in Japan．Medical Mycology Journal 53：53-58, 2012 (in 
Japanese). 
5. van Burik JA, Hare RS, Solomon HF, Corrado ML, Kontoyiannis DP. Posaconazole is 
effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases.  Clin 
Infect Dis. 2006 Apr 1;42(7):e61-5. 
6. Greenberg RN, Mullane K, van Burik JA, Raad I, Abzug MJ, Anstead G, et al.
Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006 
Jan;50(1):126-33.
7. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, et al. 
Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl 
J Med. 2002 Aug 8;347(6):408-15.
 
 
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8. Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal 
infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis. 2004 
Sep 1;39(5):743-6. Epub 2004 Aug 13.
9. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving 
voriconazole prophylaxis. Clin infect Dis 39,584-590, 2004.
10. Munayyer HK, Mann PA, Chau AS, Yarosh-Tomaine T, Greene JR, Hare RS, et al.
Posaconazole is a potent inhibitor of sterol 14α-demethylation in yeasts and molds. 
Antimicrob Agents Chemother. 2004;48:3690-6.
11. Heimark L, Shipkova P, Greene J, Munayyer H, Yarosh-Tomaine T, DiDomenico B, et 
al. Mechanism of azole antifungal activity as determined by liquid chromatographic/mass 
spectrometric monitoring of ergosterol biosynthesis. J Mass Spectrom. 2002;37:265-9.
12. Chau AS, Chen G, McNicholas PM, Mann PA. Molecular basis for enhanced activity of 
posaconazole against Absidia corymbifera and Rhizopus oryzae. Antimicrob Agents 
Chemother. 2006;50:3917-9
13. T. Mori, Y. Yahata, Y. Chikune, Zygomycosis．Medical Mycology Journal 52：283-
289, 2011
14. Ben De Pauw, Thomas J. Walsh, J. Peter Donnelly, David A. Stevens, John E. Edwards, 
et.al, 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. Clin Infec Disease 2008; 46:1813-21
15. Brahm H. Segal, Raoul Herbrecht, David A. Stevens,Luis Ostrosky-Zeichner, Jack Sobel. 
et al., Defining Responses to Therapy and Study Outcomes in Clinical Trials of Invasive 
Fungal Diseases: Mycoses Study Group and European Organization for Research and 
Treatment of Cancer Consensus Criteria. Clin Infect Dis 2008; 47:674–83
16. K. Cadranel, B. Philippe, C. Hennequin, A. Bergeron, E. Bergot, et. al. Voriconazole for 
chronic pulmonary aspergillosis: a prospective multicenter trial. Eur J Clin Microbiol 
Infect Dis. 2012; 31: 3231-39
17. S. Kohno, K. Izumikawa, K. Ogawa, A. Kurashima, N. Okimoto, et al., Intravenous 
micafungin versus voriconazole for chronic pulmonary aspergillosis: A multicenter trial 
in Japan. Journal of Infection. 2010; 62: 410-418
18. Clinical evaluation committee of antifungal agents. Guideline for clinical evaluation 
committee of antifungal agents in Japanese society of chemotherapy. Japanese Journal of 
Chemotherapy. 2012; 60: 347-353
 
 
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12.0 APPENDICES
12.1 Merck Code of Conduct for Clinical Trials
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
i.
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. 
ii.
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.
iii.
Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
1.
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. 
2.
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.
3.
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.  
4.
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

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.

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.

Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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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
 
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12.3 Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
 
 
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12.5 Clinical Study Conduct System
Clinical study conduct system is shown in attachment 1 and 2.
 
 
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13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
13.2 Investigator
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                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
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