Clinical trial NCT04218851
Conditions: Invasive Aspergillosis
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-07-02; Completion date: 2023-12-18
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the safety, efficacy, and pharmacokinetics of posaconazole (POS) intravenous (IV) and oral formulations in pediatric participants 2 to \<18 years of age with invasive aspergillosis (IA).

Detailed description:

Arms: arm 1: On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.
Interventions: intervention 1: Posaconazole IV intervention 2: Posaconazole PFS intervention 3: Posaconazole tablet
Intervention descriptions: intervention 1: Posaconazole (POS) 6 mg/kg body weight by IV infusion intervention 2: Dosing based on weight-band taken orally intervention 3: POS tablet 300 mg taken orally

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04218851 
Document Date: 
02-SEP-2022
A Phase 2, Open-Label, Non-Comparative Clinical Trial to Study the 
Safety and Efficacy of Posaconazole (POS, MK-5592) in Pediatric 
Participants Aged 2 to Less Than 18 Years With Invasive 
Aspergillosis


PRODUCT: MK-5592  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2, Open-Label, Non-Comparative Clinical Trial to Study the Safety 
and Efficacy of Posaconazole (POS, MK-5592) in Pediatric Participants Aged 2 to Less Than 
18 Years With Invasive Aspergillosis
Protocol Number: 104-04
Compound Number: MK-5592
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
51,316; 75,061; 125,097
EudraCT
2019-002267-10
Approval Date: 02 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
02-SEP-2022
To revise exclusion criteria to include the specific K values used in the 
modified Schwartz formula for males of different ages.
Amendment 03
19-JUL-2022
To 1) align dosing of the powder for suspension formulation with the dosing 
algorithm given in the approved product labeling for pediatric use, 2) update the 
definitions of possible, probable, or proven IA to align with the 2020 
EORTC/MSG criteria, and 3) update the prohibited and allowed medications 
lists to align with approved product labeling.
Amendment 02
15-DEC-2020
To provide details for IV dosing requirements; to clarify procedures (ie, ECG 
and diagnostic imaging) in the Schedule of Activities; to clarify maximum 
blood volume and method for calculating creatinine clearance; to remove 
pregnancy exclusion to avoid potential confusion with the pregnancy criteria in 
the list of inclusions; and to update informed consent text to align with current 
informed consent/assent procedures.
Amendment 01
21-APR-2020
To remove the device-related adverse event reporting language and the Future 
Biomedical Research (FBR) substudy from the protocol.
Original Protocol
17-JUL-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
To revise exclusion criteria to include the specific K values used in the modified Schwartz formula for males of different ages.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria
Exclusion criterion 13 was revised to 
show the proportionality constant (K) 
separately for pre-and post-adolescent 
male children and to change the lower 
bound of the age range for male and 
female children from 1 year to 2 years.
To revise exclusion criteria to include the specific K 
values used in the modified Schwartz formula for 
males of different ages.
1.1 Synopsis
1.2 Schema
4.3.1 Starting Dose for This 
Study
6.1 Study Intervention(s) 
Administered
Added Table 1 to outline weight-band 
dosing in Sec. 4.3.1 and added reference 
to Table 1 in other sections outlined here.
To align the dosing of the PFS formulation with 
approved product labeling for the PFS when used in the 
pediatric population and achieve a similar target 
exposure for all participants.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities
3 Hypotheses, objectives, 
and endpoints
4.1 Overall Design
4.2.1.1 Efficacy Endpoints
5.1 Inclusion Criteria
8.1.4 Medical History
8.1.5.1 Prior 
Medications8.2.2 
Diagnostic Imaging
8.2.3 Mycology Testing
8.2.4 IFI Assessment
8.2.7 Aspergillus
Galactomannan EIA and 
PCR
9.5.1 Efficacy Analysis 
Population
10.9 Appendix 9
•
Updated definitions used for IA 
disease classification and included 
possible in addition to proven and 
probable IA.
•
Added statement to say that medical 
history should include any history of 
graft vs host disease.
•
Clarified text about the recording of 
chemotherapeutic agents for active 
treatment of malignancy, as well as T-
cell and B-cell immunosuppressive 
therapies.
•
Text added to ensure that recording of 
imaging includes sufficient details to 
reflect use of the EORTC/MSG 2020 
criteria to support the classification of 
IA.
•
Secondary objectives were revised to 
add 'possible' to IA.
•
Added note in SoA for optional PCR 
testing in the Mycology testing row.
Updated to reflect the 2020 EORTC/MSG criteria’s 
classification of possible, probable, or proven IA. 
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Section # and Name
Description of Change 
Brief Rationale 
6.5 Concomitant Therapy
6.5.1 Medications Allowed 
with Caution and Clinical 
Monitoring
Updated Table 4 Prohibited Medications 
During Study Treatment:
•
Relocated the following prohibited 
medications to medications allowed 
with caution: anthracycline, trisenox, 
cyclophosphamide, vinca alkaloids, 
and sirolimus.
•
Added venetoclax to the prohibited
medication list.
Updated Table 5 list of medications 
allowed with caution and monitoring to 
add anthracycline, trisenox, 
cyclophosphamide, vinca alkaloids, and 
sirolimus.
Updated Table 5 Additional Medications 
Allowed During the Study That Require 
Monitoring and/or Dose Adjustment to 
add antineoplastics, chemotherapy agents, 
and tyrosine kinase inhibitors.
To align with allowable/prohibited medications as 
noted in approved product labeling with the inclusion 
of cautionary language.
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Section # and Name
Description of Change 
Brief Rationale 
2.1 Study Rationale
2.2.1 Pharmaceutical and 
Therapeutic Background
2.3 Benefit/Risk 
Assessment
4.2 Scientific Rationale for 
Study Design
4.2.2 Rationale for the Use 
of Comparator/Placebo
4.3.3 Rationale for Dose 
Interval and Study Design
Updated text to reflect data from 
completed studies and current product 
labeling:

Added clinical study data and 
approval regarding POS IV and tablet 
for the primary treatment of IA.

Added clinical study data and 
approval regarding POS IV, PFS, and 
tablet for use in pediatric patients 2 to 
<18 years of age in the salvage 
treatment and the prophylaxis of 
invasive fungal infections.

Updated text to reflect new pediatric 
and adult efficacy and safety 
information for IV, tablet, and PFS 
formulations.
Updated background/rationale to reflect additional 
study data/status and new health authority approvals 
for pediatric and adult patients.
1.1 Synopsis
4.1 Overall Design
Updated wording for evaluable 
participants for the efficacy evaluation in 
each age cohort.
Clarified that the FAS population includes study 
participants with possible, probable, or proven IA and 
who have at least 1 postrandomization assessment. The 
inclusion of possible, probable, or proven IA as the 
population to be analyzed in the efficacy analyses 
reflects the use of a similar population used in the 
primary efficacy analyses of the adult study (P069) of 
posaconazole in the treatment of invasive aspergillosis. 
Data from that study were used to support the 
registration of posaconazole IV and oral for the 
treatment of invasive aspergillosis in adults.
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Section # and Name
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria
•
Updated Table 2 Prohibited 
Medications Before Start of Study 
Treatment.
•
Removed Gilbert’s disease.
•
Added hereditary fructose intolerance.
•
Removed use of CPAP/BPAP as an 
exclusion criterion.
•
To align the allowed and prohibited medications 
with the most recent approved product labeling.
•
Current approved product labeling allows 
posaconazole to be given to patients with Gilbert’s 
disease.
•
Approved product labeling recommends against the 
use of posaconazole PFS in patients with hereditary 
fructose intolerance due to the presence of sucrose 
and sorbitol in the suspending vehicle that is 
admixed with the PFS powder.
•
Allowance of CPAP/BPAP reflects the potential 
use of these modalities in patients with pulmonary 
aspergillosis and respiratory insufficiency.
2.2.3 Ongoing Clinical 
Studies
Updated to reflect that there are currently 
only 2 ongoing studies for posaconazole, 
this study (P104) and a Phase 2 study 
(P127).
Updated to reflect the current status of ongoing clinical 
studies.
4.2.1.2 Safety Endpoints
Clarified that the primary study endpoint 
is the safety of POS in the pediatric 
population as assessed by the evaluation 
of treatment-related AEs. Other 
assessments may include all AEs, ECGs, 
and laboratory tests.
Clarified the wording in this section to align with the 
wording in the SAP related to the primary study 
endpoint.
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Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria
Modified Inclusion Criterion 7 to require
that participants must weigh at least 10 kg 
to be included in the study.
The restriction to be placed on inclusion of participants 
who weigh at least 10 kg reflects the approved labeled 
dosing table for the PFS that requires children 2 to <18
years of age to weigh at least 10 kg to receive PFS 
dosing.
7.1 Discontinuation of 
Study Intervention
Updated text to allow study intervention 
to be interrupted for up to 3 days with 
repeat monitoring of liver function 
testing. Study intervention may be 
resumed if repeated liver function testing 
parameters decreases to lower values.
Transient interruption of study medication is 
considered as appropriate clinical management of the 
study participants if the liver function testing parameter 
abnormalities are transient, and if the abnormalities are 
judged unrelated to study drug.
9.1 Statistical Analysis Plan
Updated to reflect amendment changes.
Updated for clarity.
1.1 Synopsis
3 Hypotheses, Objectives, 
and Endpoints
9.4.1.2 Pharmacokinetic 
Endpoints
9.6.2 Pharmacokinetic 
Analysis
Updated sections to explain that modeling 
analysis will be based on actual dose 
administered, and that certain PK 
parameters will be reported in a separate 
report.
The updated text provides additional details that the 
modeling analyses will be based on the dose of IV and 
oral formulations given.
9.6.3 Safety Analysis
Updated text to specify that safety 
summaries will be presented in aggregate.
The updated text clarified the data presentation format 
for the summary of safety analyses.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.1 Global Clinical 
Response
9.9.1 Efficacy Analysis
•
Global clinical response definition 
expanded in text.
•
Updated text to outline the global 
clinical response seen in adolescents 
and adults.
•
Updated Observed Global Clinical 
Response Table 9 to remove first 2 
rows.
•
To more clearly define global clinical response.
•
To align with observed data in trials/literature as it 
relates to expected clinical response.
•
Based upon data from the adult study (P069), the 
observed global clinical response rates in 
participants with invasive aspergillosis after 12 
weeks of therapy are expected to be in the range of 
40%, thus rates higher than 60% have been 
removed from Table 9.
8.9.1 Screening
•
Clarified text to say that informed 
consent/assent must be obtained 
before any study-specific procedures 
are performed other than those 
procedures conducted for the purpose 
of routine clinical care.
•
Added imaging and mycology testing 
to the list of local laboratory tests.
•
The text related to informed consent was modified 
to clarify the timeframe in which study-specific 
procedures may be obtained relative to the signing 
of the informed consent/assent.
•
There was a clarification as to the source of 
imaging and mycology testing to indicate that local 
testing results would be used. These tests will be 
conducted to support the disease diagnosis and 
classification of possible, probable, or proven 
invasive aspergillosis.
8.9.2.3 End of Treatment 
(EOT) Visits
Clarified that participants who withdraw 
consent for participation or who are 
withdrawn from the study for any reason 
should complete both the EOT Visit and 
the final mortality assessment at Day 114.
Updated for clarity.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
8.1.1 Informed 
Consent/Assent
8.1.1.1 General Informed 
Consent/Assent
8.9.1 Screening
Modified to ensure that assent is used in 
all places where ICF is discussed.
To align with global consent/assent requirements for 
adolescent and pediatric populations.
Title Page
10.1.1 Code of Conduct for 
Trials
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
4.4 Beginning and End of 
Study Definition
Added study start definition for European 
Economic Area countries.
To align with the EU CTR.
8.4 Adverse Events (AEs), 
Serious Adverse Events 
(SAEs), and Other 
Reportable Safety Events
10.3.1 Definitions of 
Medication Error, Misuse, 
and Abuse
Added section 10.3.1 to define medication 
error, misuse and abuse and indicate that 
AEs associated with the above should be 
reported.
To align with the EU CTR.
10.7 Appendix 7
Remove Czech Republic country-specific 
language.
The Czech Republic is no longer being considered for 
participation in the study.
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Section # and Name
Description of Change 
Brief Rationale 
Throughout Document
Minor administrative, formatting, 
grammatical, and typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of the 
intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................20
1.1
Synopsis.................................................................................................................20
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities (SoA)................................................................................25
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................34
2.2.1
Pharmaceutical and Therapeutic Background .............................................34
2.2.2
Preclinical and Clinical Studies ...................................................................34
2.2.3
Ongoing Clinical Studies.............................................................................35
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................35
4
STUDY DESIGN............................................................................................................37
4.1
Overall Design......................................................................................................37
4.2
Scientific Rationale for Study Design.................................................................38
4.2.1
Rationale for Endpoints ...............................................................................38
4.2.1.1
Efficacy Endpoints.............................................................................38
4.2.1.2
Safety Endpoints................................................................................39
4.2.1.3
Pharmacokinetic Endpoints ...............................................................39
4.2.1.4
Additional Endpoints .........................................................................39
4.2.2
Rationale for the Use of Comparator/Placebo .............................................39
4.3
Justification for Dose...........................................................................................39
4.3.1
Starting Dose for This Study........................................................................39
4.3.2
Maximum Dose/Exposure for This Study ...................................................40
4.3.3
Rationale for Dose Interval and Study Design ............................................40
4.4
Beginning and End of Study Definition .............................................................41
4.4.1
Clinical Criteria for Early Study Termination .............................................41
5
STUDY POPULATION ................................................................................................41
5.1
Inclusion Criteria.................................................................................................41
5.2
Exclusion Criteria................................................................................................44
5.3
Lifestyle Considerations......................................................................................47
5.4
Screen Failures.....................................................................................................47
5.5
Participant Replacement Strategy......................................................................47
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6
STUDY INTERVENTION............................................................................................48
6.1
Study Intervention(s) Administered...................................................................48
6.2
Preparation/Handling/Storage/Accountability .................................................50
6.2.1
Dose Preparation..........................................................................................50
6.2.2
Handling, Storage, and Accountability........................................................50
6.3
Measures to Minimize Bias: Randomization and Blinding..............................51
6.3.1
Intervention Assignment..............................................................................51
6.3.2
Stratification.................................................................................................51
6.3.3
Blinding........................................................................................................51
6.4
Study Intervention Compliance..........................................................................51
6.5
Concomitant Therapy..........................................................................................51
6.5.1
Medications Allowed With Caution and Clinical Monitoring.....................53
6.5.2
Rescue Medications and Supportive Care ...................................................56
6.6
Dose Modification (Escalation/Titration/Other)...............................................56
6.7
Intervention After the End of the Study............................................................56
6.8
Clinical Supplies Disclosure................................................................................57
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................57
7.1
Discontinuation of Study Intervention...............................................................57
7.2
Participant Withdrawal From the Study...........................................................58
7.3
Lost to Follow-up .................................................................................................58
8
STUDY ASSESSMENTS AND PROCEDURES........................................................59
8.1
Administrative and General Procedures ...........................................................59
8.1.1
Informed Consent/Assent.............................................................................59
8.1.1.1
General Informed Consent/Assent.....................................................60
8.1.2
Inclusion/Exclusion Criteria ........................................................................60
8.1.3
Participant Identification Card.....................................................................60
8.1.4
Medical History ...........................................................................................61
8.1.5
Prior and Concomitant Medications Review...............................................61
8.1.5.1
Prior Medications...............................................................................61
8.1.5.2
Concomitant Medications..................................................................61
8.1.6
Assignment of Screening Number...............................................................61
8.1.7
Assignment of Treatment/Randomization Number.....................................62
8.1.8
Study Intervention Administration ..............................................................62
8.1.9
Discontinuation and Withdrawal .................................................................62
8.1.10
Participant Blinding/Unblinding..................................................................63
8.1.11
Calibration of Equipment.............................................................................63
8.2
Efficacy/Immunogenicity Assessments ..............................................................63
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8.2.1
Global Clinical Response.............................................................................63
8.2.2
Diagnostic Imaging......................................................................................64
8.2.3
Mycology Testing........................................................................................65
8.2.4
IFI Assessment.............................................................................................65
8.2.5
Relapse Assessment.....................................................................................65
8.2.6
Mortality Assessment...................................................................................65
8.2.7
Aspergillus Galactomannan EIA and PCR ..................................................65
8.3
Safety Assessments...............................................................................................66
8.3.1
Physical Examinations.................................................................................66
8.3.2
Vital Signs....................................................................................................67
8.3.3
Electrocardiograms ......................................................................................67
8.3.4
Clinical Safety Laboratory Assessments .....................................................67
8.3.5
Assessment of Palatability and Acceptability..............................................68
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................68
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................69
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......71
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...71
8.4.4
Regulatory Reporting Requirements for SAE .............................................71
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................71
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................72
8.4.7
Events of Clinical Interest (ECIs)................................................................72
8.5
Treatment of Overdose........................................................................................72
8.6
Pharmacokinetics.................................................................................................72
8.6.1
Blood Collection for Plasma MK-5592 .......................................................73
8.7
Pharmacodynamics..............................................................................................73
8.8
Future Biomedical Research Sample Collection...............................................73
8.9
Visit Requirements...............................................................................................73
8.9.1
Screening......................................................................................................73
8.9.2
Treatment Period Visits ...............................................................................73
8.9.2.1
Day 1 Visit.........................................................................................73
8.9.2.2
Treatment Period................................................................................74
8.9.2.3
End of Treatment (EOT) Visits..........................................................74
8.9.3
Post-Treatment Visits...................................................................................74
9
STATISTICAL ANALYSIS PLAN .............................................................................74
9.1
Statistical Analysis Plan Summary.....................................................................74
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9.2
Responsibility for Analyses/In-House Blinding ................................................76
9.3
Hypotheses/Estimation ........................................................................................76
9.4
Analysis Endpoints...............................................................................................76
9.4.1
Efficacy/Pharmacokinetic Endpoints...........................................................76
9.4.1.1
Efficacy Endpoints.............................................................................76
9.4.1.2
Pharmacokinetic Endpoints ...............................................................76
9.4.1.3
Tertiary/Exploratory Endpoints .........................................................77
9.4.2
Safety Endpoints..........................................................................................77
9.4.3
Additional Endpoints ...................................................................................77
9.4.4
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints......77
9.5
Analysis Populations............................................................................................77
9.5.1
Efficacy Analysis Populations.....................................................................77
9.5.2
Pharmacokinetic Analysis Population .........................................................78
9.5.3
Safety Analysis Populations ........................................................................78
9.6
Statistical Methods...............................................................................................78
9.6.1
Efficacy Analysis.........................................................................................78
9.6.2
Pharmacokinetic Analysis............................................................................78
9.6.3
Safety Analysis ............................................................................................78
9.6.4
Other Analyses.............................................................................................79
9.7
Interim Analyses ..................................................................................................80
9.8
Multiplicity ...........................................................................................................80
9.9
Sample Size and Power Calculations .................................................................80
9.9.1
Efficacy Analysis.........................................................................................80
9.9.2
Safety Analysis ............................................................................................80
9.10
Subgroup Analyses...............................................................................................81
9.11
Compliance (Medication Adherence).................................................................81
9.12
Extent of Exposure...............................................................................................82
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................83
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........83
10.1.1
Code of Conduct for Clinical Trials.............................................................83
10.1.2
Financial Disclosure.....................................................................................85
10.1.3
Data Protection.............................................................................................85
10.1.3.1
Confidentiality of Data ......................................................................86
10.1.3.2
Confidentiality of Participant Records...............................................86
10.1.3.3
Confidentiality of IRB/IEC Information............................................86
10.1.4
Committees Structure...................................................................................86
10.1.4.1
Executive Oversight Committee........................................................86
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10.1.4.2
External Data Monitoring Committee ...............................................87
10.1.5
Publication Policy........................................................................................87
10.1.6
Compliance with Study Registration and Results Posting Requirements ...87
10.1.7
Compliance with Law, Audit, and Debarment ............................................88
10.1.8
Data Quality Assurance ...............................................................................88
10.1.9
Source Documents .......................................................................................89
10.1.10
Study and Site Closure.................................................................................90
10.2
Appendix 2: Clinical Laboratory Tests..............................................................91
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................93
10.3.1
Definitions of Medication Error, Misuse, and Abuse:.................................93
10.3.2
Definition of AE ..........................................................................................93
10.3.3
Definition of SAE ........................................................................................94
10.3.4
Additional Events Reported.........................................................................95
10.3.5
Recording AE and SAE ...............................................................................96
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................99
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................101
10.5
Appendix 5: Contraceptive Guidance..............................................................102
10.5.1
Definitions..................................................................................................102
10.5.2
Contraception Requirements......................................................................103
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................104
10.7
Appendix 7: Country-specific Requirements..................................................105
10.8
Appendix 8: Abbreviations ...............................................................................106
10.9
Appendix 9: Criteria for Diagnosis of Invasive Aspergillosis........................108
11
REFERENCES.............................................................................................................113
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LIST OF TABLES
Table 1
Dosing of the PFS......................................................................................40
Table 2
Prohibited Medications Before Start of Study Treatment..........................45
Table 3
Study Treatments .......................................................................................49
Table 4
Prohibited Medications During Study Treatment......................................52
Table 5
Additional Medications Allowed During the Study That Require 
Monitoring and/or Dose Adjustment .........................................................54
Table 6
Global Clinical Response using 2008 EORTC/MSG Definitions.............64
Table 7
Reporting Time Periods and Time Frames for Adverse Events and
Other Reportable Safety Events.................................................................70
Table 8
Analysis Strategy for Safety Parameters....................................................79
Table 9
Summary of Potential Observed Global Clinical Response Rates and 
95% Confidence Intervals..........................................................................80
Table 10
Estimate of Incidence of a Specific AE and Upper Limit of 95% CI 
Based on a Hypothetical Number of Participants with that Specific AE ..81
Table 11
Protocol-Required Safety and Other Laboratory Assessments..................91
Table 12
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit 
and by Sample Types.................................................................................92
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LIST OF FIGURES
Figure 1
Trial Design ...............................................................................................24
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2, Open-Label, Non-Comparative Clinical Trial to Study the Safety 
and Efficacy of Posaconazole (POS, MK-5592) in Pediatric Participants Aged 2 to Less Than 
18 Years With Invasive Aspergillosis
Short Title: Posaconazole (MK-5592) IV and oral in children with invasive aspergillosis
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for this trial. The following objectives and endpoints will be 
evaluated in male and female pediatric participants aged 2 to <18 years with invasive 
aspergillosis (IA):
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety of POS 
(IV and oral formulations overall)
- Treatment-related AEs
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the efficacy of POS 
(IV and oral formulations overall) in 
participants with possible, probable, or 
proven IA
- Global clinical response (partial or 
complete response)
- Objective: To evaluate relapse in 
participants with possible, probable, or 
proven IA who have completed treatment 
with POS (IV and oral formulations overall) 
and achieved favorable global clinical 
response (complete or partial) 
- Relapse of IA, defined as the 
re-emergence of clinical, radiographic, or 
other relevant abnormalities indicating IA 
- Objective: To characterize the PK of POS 
overall and by formulation
- Key PK parameters, consisting of Cavg, 
Cmin, Cmax, AUC, and Tmax, using sparse 
plasma concentration sampling (steady state 
trough and peak)
- Analysis of exposure-response (efficacy 
and safety) relationships
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- Objective: To summarize the palatability 
and acceptability of POS powder for 
suspension (PFS) formulation
- Participants’ categorical perception of the 
taste of the PFS formulation
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Invasive aspergillosis
Population
Male and female participants aged ≥2 to <18 years with 
invasive aspergillosis
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent/assent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 30 participants will be enrolled in the trial to achieve at least 15 participants
in the Full Analysis Set (FAS) population (defined in Section 9.5.1) as characterized below.
Participants will be enrolled into the following age cohorts, which will enroll simultaneously:
•
Age Cohort 1 (aged 2 to <12 years): approximately 20 participants enrolled to achieve at 
least 10 in the FAS population who transition to oral therapy (PFS or tablet) for at least 7 
days after the end of IV treatment with POS.
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•
Age Cohort 2 (aged 12 years to <18 years): approximately 10 participants enrolled to 
achieve at least 5 in the FAS population who transition to oral therapy (PFS or tablet) for 
at least 7 days after the end of IV treatment with POS.
Intervention Groups and Duration:
Intervention 
Groups
Treatment 
Name
Drug
Dose Strength
Dose 
Frequency
Route 
of 
Admin-
istration
Regimen/ 
Treatment 
Periodb
Use
Posaconazole
Posaconazole
IV a
18 mg/mL
QD, except 
BID on 
Day 1
IV 
infusion
Day 1: BID 
6 mg/kg
Day 2 through 
end of IV 
dosing:
QD 6 mg/kg
Test Product
Posaconazole
If weight 
≤40 kg: 
Posaconazole 
PFS 
30 mg/mL
QD
Oral 
Days 8 – 84:
weight-band 
dosing, see 
Table 1.
Posaconazole
If weight 
>40 kg: 
Posaconazole
Tablet
100 mg
QD
Oral
Days 8 – 84:
300 mg
Abbreviations: BID = twice daily; IV = intravenous; PFS = powder for delayed-release oral 
suspension; QD = once daily.
a: There is a maximum dose of 300 mg per administration; on Day 1 only, dosing frequency is 
BID, with up to 300 mg IV in each dose.
b: The posaconazole IV formulation is to be administered for a minimum of 7 days; oral 
formulations (PFS or tablet) may be administered beginning on Day 8, as clinically 
indicated.
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: MK-5592; Noxafil; SCH 56592.
Total 
Number
There will be a single intervention arm.
Duration of 
Participation
Each participant will participate in the trial for up to approximately 
18 weeks (128 days) from the time the participant or legally acceptable 
representative provides documented informed consent/assent through the 
final contact. After a screening phase of up to 2 weeks (14 days), each 
participant will be followed for the trial duration of approximately 
114 days. All participants are to be followed for the entire trial period 
regardless of the duration of study therapy, unless consent/assent has been 
withdrawn. Participants are to receive assigned study treatment for 6 to 12 
weeks (42 to 84 days); actual treatment duration for each participant will be 
based on the investigator’s clinical judgment.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Other Oversight Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The trial design is depicted in Figure 1.
Figure 1
Trial Design
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1.3
Schedule of Activities (SoA)
  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
Administrative Procedures
Assign 
screening 
number 
X
Obtain informed 
consent/assent
X
Issue participant 
identification
card
X
X
See Section 8.1.3
Review inclus./
exclus. criteria
X
X
Medical history
X
Prior/concom.
medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing Procedures
Stratification 
and treatment 
allocation no. 
assigned by IRT
X
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  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
POS 
(MK-5592) 
administration
X
X
X
X
X
X
X
X
X
Daily from Day 
1 through 
Week 12. IV 
dose on Day 1 
BID; subsequent 
doses QD.
Collect unused 
medications
X
X
X
X
X
X
X
For participants 
receiving oral 
formulations 
only.
Dosing 
compliance 
assessment
X
X
X
X
X
X
X
Safety and Tolerability Procedures
Vital signs 
(heart rate, 
blood pressure, 
respiratory rate, 
temperature)
X
X
X
X
X
X
X
X
X
X
X
X
X
While on IV 
treatment, vital 
signs to be 
collected daily. 
While on oral 
treatment, vital 
signs to be 
collected at each 
visit.
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  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
Urine or serum 
pregnancy test 
(Females of 
childbearing 
potential only)
X
X
X
X
X
X
X
X
If pregnancy test 
perform at 
Screening and 
Day 1 visit 
occurs >24 hours
later, pregnancy 
test to be 
repeated at 
Day 1 visit. 
Full physical 
examination
X
Directed 
physical 
examination
X
X
X
X
X
X
X
X
X
X
X
Body weight 
(kg) 
X
X
X
X
X
X
X
After Day 1, 
weight to be 
measured when 
oral treatment is 
initiated (within 
3 days before
initiating oral 
treatment).
Height
X
AE/SAE 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
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  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
12-lead ECG
X
X
X
X
X
X
X
Day 1: predose. 
While on POS 
IV, ECG to be 
obtained after 
completion of 
infusion. While 
on oral POS, 
ECG can be 
performed 
without regard to 
timing of study 
treatment. See 
Section 10.7, 
Appendix 7 for
country-specific 
ECG 
requirements.
Hematology and 
serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
At Day 1, repeat 
hematology and 
chemistry only if 
>2 days since 
screening 
laboratory 
assessments.
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  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
PFS:
Assessment of 
palatability and 
acceptability
X
X
X
X
X
X
X
For participants 
receiving PFS 
formulation, to 
be performed
only on first and 
last days of PFS 
treatment.
Efficacy Procedures
Assess global 
clinical 
response
X
X
X
Diagnostic 
imaging
Xc
Xd
Xd
Xd
Xd
Xd
Xd
Xc
Xd
Xd
X
c Required for 
all sites of 
infection only at 
screening and 
EOT.
d. At other visits, 
if clinical 
condition
changes, 
additional 
imaging can be 
performed at the 
clinician’s 
discretion.
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  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
IFI assessment 
X
X
X
X
X
X
X
X
X
X
X
MSG/EORTC 
criteria; details in 
Appendix 9.
Assessment of 
relapse
X
X
Relapse to be 
assessed only in 
participants who 
have achieved a 
favorable clinical 
response and 
have completed 
study treatment.
Mortality 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
Mortality to be 
assessed through 
Day 114 visit for 
all participants.
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  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
Sample for 
Aspergillus
galactomannan 
EIA
X
X
X
X
X
X
X
X
X
X
X
X
X
If collected 
within 7 days of 
Day 1, can be 
used for 
screening 
purposes. Collect 
samples as 
clinically 
indicated.
Mycology 
testing (direct 
and indirect 
test)
X
X
X
X
X
X
X
X
X
X
Required at 
Screening, Wk 6 
& 12, and EOT 
visits, unless 
clinically 
inappropriate. 
Additional 
optional testing,
including 
Aspergillus PCR,
will be 
performed as 
clinically 
indicated. See 
Appendix 9.
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  Study Period Screening
Treatment
Follow-Up
Unsch Notes
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOTa
10
11
12
Unsch
a. Participants 
who discontinue 
study therapy 
before Wk 12
should have an 
EOT Visit 
within 3 days 
after EOT. 
Scheduled 
Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Days 7-
9) 
Wk 2 
(Days
12-18)
Wk 4 
(Days
25-33)
Wk 6 
(Days
39-47)
Wk 9
(Days
60-68)
Wk 12
(Days
81-89)
EOT 
14 (+2) 
days 
after last 
dose
28 (+2) 
days 
after last 
dose
Day 114 
(+7 days) Unschb
b. Procedures at 
unscheduled 
visits to be 
performed as 
clinically 
appropriate.
PK/Biomarkers
Plasma PK 
assessment
X
X
X
X
X
X
X
X
X
Abbreviations: AE = adverse event; ECG = electrocardiogram; BAL = broncho-alveolar lavage; EIA = enzyme immunoassay; EOT = end of treatment; IA = invasive aspergillosis; 
IFI = invasive fungal infection; IRT = interactive response technology; IV = intravenous; PFS = powder for oral suspension; PK = pharmacokinetics; POS = posaconazole 
(MK-5592); SAE = serious adverse event; Wk = week.
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2
INTRODUCTION
2.1
Study Rationale
As the number of immunocompromised patients, both adult and pediatric, continues to 
increase, IFIs, including IA, play a significant role in the morbidity and mortality seen in this 
population. There continues to be a need for the development of effective treatment options,
particularly in the pediatric population for whom there are limited clinical study data 
detailing the treatment of IA. Recent advances in the adult population include the approval of 
POS in the US, European Union, and other countries for the primary treatment of IA [E.U. 
Summary of Product Characteristics 2022] [U.S. Prescribing Information 2022]. These
approvals were based upon the completion of a prospective, randomized, double-blind study 
that showed the safety and efficacy of POS IV and tablet for the treatment of IA in 
adolescents and adults [Maertens, J. A., et al 2021].
Invasive aspergillosis occurs in pediatric (and adult) populations that are 
immunocompromised due to various pathologic and other factors, eg, malignancy, solid 
organ transplant or HSCT, primary immunodeficiency. The incidence rates of IA in 
high -risk patients vary by disease type and, in some instances, by geography and the use of 
prophylactic agents.
In children, IA is associated with significant increases in hospital length of stay and high 
overall in hospital mortality rates. Analyses of data from several major US hospitals showed 
an overall incidence of IA among hospitalized immunocompromised children of 437/100,000 
(0.4%) [Pana, Z. D., et al 2017], and mortality rates in children with IA between 18% and 
37% [Burgos, A., et al 2008].
Despite this unmet medical need, IA infections in immunocompromised pediatric patients 
have been understudied. To date, pediatric IA treatment options have been extrapolated from 
IA adult studies and treatment options [Burgos, A., et al 2008]. Current guidelines [Patterson, 
T. F., et al 2016] for the management of IA in adult patients recommend voriconazole (VOR)
for the primary treatment of invasive pulmonary aspergillosis, with posaconazole,
isavuconazole, or lipid formulations of amphotericin B as alternative primary 
therapies[Douglas, A. P., et al 2021]. However, guidelines are limited given the paucity of 
prospective study data in the pediatric population.
A small number of studies have provided data regarding recent treatment choices for 
pediatric patients diagnosed with IA. A 2017 trial of VOR in pediatric participants with IA 
demonstrated that safety and efficacy outcomes were consistent with previous findings in 
adult patients [Martin, J. M., et al 2017]. In this 2017 trial, 31 children (14 with proven or 
probable infection) were enrolled and treated for IA for 6 to 12 weeks. After 6 to 12 weeks of 
VOR therapy, the global clinical response was 64%. AEs were common, with 30/31 (97%) 
participants reporting one or more AEs, and 16/31 (52%) of the AEs were considered related 
to study therapy. In this trial, an association between hepatic AEs and higher VOR exposures 
was noted, although due to the small sample size, data interpretation was limited. Overall, 
48% of participants treated with VOR discontinued therapy early. These results indicate the 
need to identify alternate therapies for IA that are more efficacious and/or better tolerated.
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POS is a highly active triazole with potential advantages in terms of tolerability and drug 
interactions. POS (IV, PFS, and tablet formulations) has been recently approved for use in 
children 2 to <18 years of age for the salvage treatment and the prophylaxis of IFIs. This 
approval was based on data from a prospective PK and safety study that evaluated POS IV 
and PFS in children 2 to 17 years of age who were at high risk of an invasive fungal infection
[Groll, A. H., et al 2020].
The use of newer formulations of POS (PFS, tablet, and IV) provides higher POS 
concentrations in pediatric patients than the oral suspension formulation and supports the use 
of the IV formulation in pediatric patients who are unable to tolerate oral dosing. As the 
newer IV, tablet, and PFS formulations of POS achieve higher POS exposures, the newer 
formulations have the potential for improved clinical effectiveness.
As immunocompromised pediatric patients are at risk for IA, it is appropriate to study the 
efficacy and safety of POS IV and oral formulations (PFS and tablets) for the primary 
treatment of IA in children. This trial evaluates safety, efficacy, and PK of POS IV and oral 
formulations (PFS and tablets) in pediatric participants 2 to <18 years of age with IA. 
2.2
Background
Refer to the IB and approved product labeling for detailed background information on 
posaconazole (MK-5592, POS).
2.2.1
Pharmaceutical and Therapeutic Background
POS is a broad-spectrum triazole antifungal compound approved for the prophylaxis and 
salvage treatment of IFIs in pediatric patients 2 to <18 years of age. POS is also approved for 
the primary treatment of IA as well as prophylaxis and salvage treatment of IFIs in 
adolescents and adults. The approved labeling of indications and patient populations vary by 
country. Currently approved POS formulations include an IV solution and 3 oral 
formulations (a pre-mixed liquid suspension, a powder for suspension to be mixed in a 
suspending vehicle, and a delayed-release tablet). The powder for suspension and the
delayed-release gastric tablet formulations overcome limitations in the oral bioavailability of 
the oral suspension, allowing for once-daily dosing and, as such, are preferred oral 
formulations. The oral PFS formulation consists of the same delayed-release compound as 
the tablet in a formulation that allows for more flexible weight-based dosing. A Phase 1B 
trial [MK-5592-097 (P097)] has provided PK and safety data for use of the IV and PFS 
formulations, when given prophylactically to children at risk of IFI, that supported the 
approval of these formulations in patients 2 through 17 years of age.
2.2.2
Preclinical and Clinical Studies
Refer to the IB and approved POS labeling for detailed information on prior preclinical and 
clinical studies conducted with POS.
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2.2.3
Ongoing Clinical Studies
There is 1 study ongoing, in addition to the current study, that is evaluating the use of POS in 
the pediatric population. In addition to this protocol, there is also another ongoing Phase 2 
clinical study of POS evaluation in the treatment of invasive fungal infections in pediatric 
patients 0 to 2 years of age (P127).
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
POS has been shown to be of benefit in the treatment of IA and other IFIs in controlled as 
well as uncontrolled studies and in salvage therapy studies using the IV, tablet, and oral 
suspension formulation in adults, and the IV and PFS formulation in pediatric participants
[Walsh, T. J., et al 2007] [Lehrnbecher, T., et al 2010] [Maertens, J. A., et al 2021] [Groll, A. 
H., et al 2020]. In addition, literature reports of POS IV and tablet have indicated the benefit 
of the POS when used to treat mold infections, including IA, in high-risk patients [Conant, 
M. M., et al 2015] [Jeong, W., et al 2016]. The most common toxicities that have been 
reported with POS include gastrointestinal events (diarrhea, nausea, and vomiting), fever, 
headache, and cough. The following risks have been identified in patients treated with POS 
per product labeling: hypersensitivity, hepatic toxicity, QTc prolongation, and drug 
interactions. Refer to current POS (NOXAFILTM) product labeling for additional 
information. The safety and efficacy of POS in children <2 years of age has not been 
established. Current product labeling indicates approval in children 2 years of age and older 
and adults.
Additional details regarding specific benefits and risks for participants participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for this trial. The following objectives and endpoints will be 
evaluated in male and female pediatric participants aged 2 to <18 years with invasive 
aspergillosis (IA): time points at which each of the endpoints will be evaluated are presented 
in Section 9.1.
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Objectives
Endpoints
Primary
•
Objective: To evaluate the safety of POS 
(IV and oral formulations overall)
•
Treatment-related AEs
Secondary
•
Objective: To evaluate the efficacy of 
POS (IV and oral formulations overall) in 
participants with possible, probable, or 
proven IA
•
Global clinical response (partial or 
complete response)
•
Objective: To evaluate relapse in 
participants with possible, probable, or
proven IA who have completed treatment 
with POS (IV and oral formulations 
overall) and achieved favorable global 
clinical response (complete or partial) 
•
Relapse of IA, defined as the 
re-emergence of clinical, radiographic, 
or other relevant abnormalities 
indicating IA 
•
Objective: To characterize the PK of 
POS overall and by formulation
•
Key PK parameters, consisting of 
Cavg, Cmin, Cmax, AUC, and Tmax, 
using sparse plasma concentration 
sampling (steady-state trough and 
peak)
•
Analysis of exposure-response 
(efficacy and safety) relationships
•
Objective: To summarize the palatability 
and acceptability of POS powder for 
suspension (PFS) formulation
•
Participants’ categorical perception of 
the taste of the PFS formulation
Tertiary/Exploratory
•
Objective: To evaluate all-cause 
mortality in participants treated with POS 
(IV and oral formulations overall)
•
Deaths
The timing of all assessments, including those not directly related to endpoints, is described 
elsewhere in the protocol (Sections 1.3, 8.2, 8.3, 8.4, 8.6, 9.1 and 9.4).
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4
STUDY DESIGN
4.1
Overall Design
This is a nonrandomized, open-label, noncomparative, Phase 2, multi-site trial of POS IV and 
oral formulations in pediatric participants aged 2 to <18 years with IA, as defined by 2020 
European Organization for Research and Treatment of Cancer/Mycoses Study Group 
(EORTC/MSG) consensus definitions [Donnelly, J. P., et al 2020]. Individuals who meet the 
criteria for possible, probable, or proven IA will be enrolled.
After a screening period of up to 14 days, participants will be allocated to receive open-label 
POS study treatment. All participants will initiate treatment with the POS IV formulation. 
After a minimum of 7 days on POS IV, and when the participant is considered clinically 
stable and able to take oral study treatment, per investigator judgment, participants may 
transition to oral study treatment with either the POS tablet formulation or the POS PFS 
formulation, based on their weight. The initial transition to POS oral formulation (either PFS 
or tablet) should occur no later than the Week 9 visit and must occur under medical 
supervision at the study site. After transitioning to one of the oral POS formulations, 
additional transitions between oral and IV formulations are permitted as clinically indicated.
The planned total duration of study treatment across all formulations is 6 to 12 weeks (42 to 
84 days); the actual treatment duration for each participant will be based on the investigator’s
clinical judgment. Participants should complete all study visits regardless of when they 
complete study treatment. Doses and additional details of study treatment are provided in 
Section 6.1.
Safety, efficacy, and PK assessments will be conducted throughout the treatment period, and 
safety and efficacy assessments at the follow-up visits, 14 (+2) and 28 (+2) days after the last 
dose of study treatment and at Day 114 (+7 days), as specified in Section 1.3. All participants 
will be followed for survival through Day 114. The trial’s objectives are stated in Section 3 
and include safety (primary objective) as well as efficacy, PK, and palatability and 
acceptability (secondary objectives).
Participants will participate in the trial for up to approximately 128 days: up to 14 days of 
screening, up to 84 days of treatment, and approximately 30 days of follow-up after the 
84-day planned treatment period.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
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Approximately 30 participants will be enrolled to achieve at least 15 participants as 
characterized below in the FAS population (Section 9.5.1). Participants will be enrolled into 
the following age cohorts, which will enroll simultaneously:
•
Age Cohort 1 (2 years to <12 years of age): approximately 20 participants enrolled to 
achieve at least 10 in the FAS population who transition to oral therapy (PFS or tablet) 
for at least 7 days after the end of IV treatment with POS.
•
Age Cohort 2 (12 years to <18 years of age): approximately 10 participants enrolled to 
achieve at least 5 in the FAS population who transition to oral therapy (PFS or tablet) for 
at least 7 days after the end of IV treatment with POS.
For ongoing safety evaluations and to ensure safe study conduct, an independent, external 
DMC will be established. Specific details regarding the DMC will be described in the DMC 
charter.
4.2
Scientific Rationale for Study Design
As immunocompromised pediatric patients (aged <18 years of age) are at high risk for IA, 
newer treatments are needed for pediatric patient populations. POS IV and tablet 
formulations have been studied in adolescents and adults for the primary treatment of IA and 
have demonstrated efficacy and safety for this indication. Thus, it is reasonable to further
study the safety and efficacy of POS IV, tablet, and PFS in the primary treatment of IA in the 
pediatric population (see Section 2.2.3).
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Efficacy is not a primary endpoint in this study. The efficacy endpoint (secondary) is the 
proportion of participants with a diagnosis of possible, probable, or proven IA and a 
favorable global clinical response. This endpoint will be assessed by the investigator using 
the published definitions for defining responses to therapy and study outcomes in clinical 
trials of invasive fungal diseases [Segal, B. H., et al 2008] and as presented in Section 8.2.1. 
The assessment of the efficacy endpoint in pediatric participants with a classification of 
possible, probable, or proven IA is similar to the efficacy population analyzed in the adult 
study (MK-5592-069 P069) of IA. Additional efficacy endpoints are:
•
An assessment of relapse of IA in participants with possible, probable, or proven IA who 
have achieved a favorable global clinical response after completion of study treatment 
(secondary endpoint, Section 9.4.1.1).
•
An evaluation of all-cause mortality at Study Day 42 (exploratory endpoint, 
Section 9.4.1.3). All-cause mortality at Study Day 42 as an efficacy endpoint has been 
considered an accepted endpoint for recent clinical studies of IA in adults and 
adolescents[Martin, J. M., et al 2017]. All-cause mortality will also be evaluated at Study 
Day 114.
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4.2.1.2
Safety Endpoints
The safety of POS in this pediatric population will be primarily assessed by the evaluation of 
treatment-related AEs. Other assessments may include evaluation of all AEs (regardless of 
causality), as well as laboratory and ECG safety parameters.
4.2.1.3
Pharmacokinetic Endpoints
Key PK parameters will be calculated from sparse plasma concentration data based on 
previously developed population PK models for each formulation in pediatric participants.
Exposure/response assessments will also be conducted, including an exploration of the 
relationship between PK parameters and measures of efficacy and safety.
4.2.1.4
Additional Endpoints
Palatability and acceptability parameters for the POS PFS formulation will be assessed in all 
participants who receive this formulation (refer to Section 8.3.5 for further details of the 
palatability assessment).
4.2.2
Rationale for the Use of Comparator/Placebo
This study is designed to obtain efficacy and safety information regarding the use of POS IV 
and oral formulations as primary treatment of IA in children ≥2 and <18 years of age. To 
obtain as much experience as possible with POS treatment in this trial, given the limited 
participant population, no comparator will be assessed. POS has previously been 
demonstrated to be efficacious in the primary treatment of IA in a double-blind comparative 
study of POS IV and tablet compared with VOR IV and oral formulations when given to 
adults and adolescents [Maertens, J. A., et al 2021].
Given the high rate of mortality of IA among untreated patients, the use of a placebo 
treatment arm has not been considered.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
All randomized participants will begin study dosing with the IV formulation of POS. The 
dose of 6 mg/kg/day for the IV formulation was chosen for this study based on the results of 
the Phase 1B PK and safety study of POS in children and adolescents (P097) as well as the 
approved dosing of POS IV for children 2 years of age and older. Participants will receive 
POS IV at a dose of 6 mg/kg/day BID on Day 1 and QD thereafter.
After at least 7 days and when clinically appropriate, participants can be switched to an oral 
formulation. Participants weighing ≤40 kg will transition to the PFS formulation. The dosing 
for the PFS formulation, shown in Table 1, reflects the approved pediatric weight-based 
dosing of this formulation and reflects the approved labeled dosing of this formulation. 
Weight-band dosing is expected to provide POS exposures similar to that previously 
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specified in the protocol before implementation of this amendment. Participants weighing 
>40 kg will transition to the tablet at a dose of 300 mg. The choice of 40 kg as the weight to 
transition to a 300-mg tablet dose aligns with the pediatric dosing of the tablet in approved 
product labeling for POS tablet. The dosing of the tablet also reflects the approved dosing of 
POS tablet as shown in product labelling for the treatment of IA.
Table 1
Dosing of the PFS
Weight (kg)
PFS Dose (volume)
10-<12 kg
90 mg (3 mL)
12-<17 kg
120 mg (4 mL)
17-<21 kg
150 mg (5 mL)
21-<26 kg
180 mg (6 mL)
26-<36 kg
210 mg (7 mL)
36-40 kg
240 mg (8 mL)
PFS= powder for delayed release oral suspension
4.3.2
Maximum Dose/Exposure for This Study
For a given participant, the maximum planned dose of POS is 300 mg per administration 
(administered BID on Day 1 and QD on subsequent days for a maximum of 84 days). 
Participants who weigh >40 kg will receive the maximum planned dose of 300 mg. The 
maximum total daily dosing established for this study reflects the approved dose for POS 
solid oral tablet and POS IV solution formulations, which is 300 mg BID on Day 1 followed 
by 300 mg QD.
4.3.3
Rationale for Dose Interval and Study Design
In this study, all participants will initiate treatment with IV POS and may transition to oral 
POS after a minimum of 7 days on IV study treatment and as clinically indicated. 
Participants who weigh >40 kg will transition to the tablet as the oral formulation;
participants who weigh ≤40 kg and are able to transition to an oral formulation will transition 
to PFS. Both IV and oral treatments have been used to treat IA and other IFIs in controlled 
studies of IA as well as in uncontrolled studies and in salvage therapy studies [Walsh, T. J., 
et al 2007] [Lehrnbecher, T., et al 2010] [Conant, M. M., et al 2015] [Jeong, W., et al 2016]. 
Consistent with the POS (NOXAFIL) label, POS is administered twice on the first day of 
study treatment and then QD for the duration of treatment.
The planned duration of study treatment is 6 to 12 weeks (42 to 84 days); this aligns with 
current recommendations for the treatment of IA, which call for a minimum duration of 
treatment of 6 to 12 weeks [Patterson, T. F., et al 2016].
In this study, participants with possible IA will begin study treatment before their diagnosis 
of IA is confirmed. Early initiation of antifungal treatment while the definitive diagnostic 
evaluation is in progress is recommended by current guidelines [Patterson, T. F., et al 2016].
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent, or is lost to follow-up 
(ie, the participant is unable to be contacted by the investigator).
For the purposes of analysis and reporting, the overall study ends when the Sponsor receives 
the last laboratory result or at the time of final contact with the last participant, whichever 
comes last. If the study includes countries in the EEA, the local start of the study in the EEA 
is defined as First Site Ready in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study 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 study population 
as a whole is unacceptable.  In addition, further recruitment in the study or at (a) particular 
study 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.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1), our studies include people 
of varying age, race, ethnicity, and sex. The collection and use of these demographic data are 
to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Male/female participants with a diagnosis of possible, probable, or proven IA aged 2 to <18 
years will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has a diagnosis of possible, probable, or proven IA per 2020 European Organization for 
Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) disease 
definitions (Appendix 9).
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2. If enrolled with a possible or probable IA diagnosis, has one or more of the following 
risks as per 2020 EORTC/MSG disease definitions (Appendix 9).
o
Recent history of neutropenia (<0.5 × 109 neutrophils/L [<500 neutrophils/mm3]) 
(within 30 days before screening).
o
Receipt of an allogeneic HSCT.
o
Receipt of a solid organ transplant.
o
Hematologic malignancy currently under treatment or has been treated in the recent 
past.
o
Treatment with other recognized T-cell immunosuppressants, such as calcineurin 
inhibitors, TNF-α blockers, specific monoclonal antibodies (such as alemtuzumab), or 
nucleoside analogues during the past 90 days.
o
Prolonged use corticosteroids for ≥3 weeks in the past 60 days (average minimum 
dose of ≥0.3 mg/kg/day of prednisone equivalent).
o
Congenital or inherited severe immunodeficiency (including, but not limited to 
chronic granulomatous disease, STAT 3 deficiency, CARD9 deficiency, STAT-1 gain 
of function, or severe combined immunodeficiency).
o
Treatment with recognized B-cell immunosuppressants, such as Bruton’s tyrosine 
kinase inhibitors, eg, ibrutinib.
o
Acute graft-versus-host disease grade III or IV involving the gut, lungs, or liver that is 
refractory to first-line treatment with steroids.
3. If enrolled with a possible or probable IA diagnosis, meets mycologic and clinical criteria 
as per 2020 EORTC/MSG disease definitions (Appendix 9).
o
Possible IA includes participants with clinical criteria, with the anticipation that 
further diagnostic workup is in progress as clinically feasible and may result in 
updated classification of the invasive fungal infection as per the 2020 EORTC/MSG 
disease definitions (Appendix 9).
o
Probable IA includes participants with clinical criteria, along with mycological 
criteria including serum, plasma, CSF, or BAL fluid Aspergillus galactomannan 
antigen, or Aspergillus PCR test positive in plasma, serum, whole blood, or BAL 
fluid, or evidence of Aspergillus by histology or microscopy, or positive culture of a 
specimen taken by nonsterile sampling of an infected site as per 2020 EORTC/MSG 
disease definitions (Appendix 9).
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4. If enrolled with a proven IA diagnosis, has demonstrated fungal elements (by cytology, 
microscopy, or histopathology, including Aspergillus nucleic acid probe where available) 
or positive culture for Aspergillus of a tissue specimen obtained from an otherwise sterile 
site as per 2020 EORTC/MSG disease definitions (Appendix 9).
5. Has a central line (eg, central venous catheter, peripherally inserted central catheter) in 
place or planned to be in place before beginning IV study treatment.
6. Has clinical symptoms consistent with an acute episode of IA, defined as duration of 
clinical syndrome of <30 days.
Demographics
7. Is male or female, and ≥2 years of age and <18 years of age at the time of first dose of 
study treatment and weighs at least 10 kg. Participants may be of any race/ethnicity.
Male Participants
Contraceptive use by males should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 30 days after the last dose of study treatment:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause Appendix 5) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a female of childbearing potential who is 
not currently pregnant. Note: Males with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration.
Female Participants
Contraceptive use by females should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
-
Is not a female of childbearing potential
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OR
-
Is a female of childbearing potential and using a contraceptive method that is highly 
effective (with a failure rate of <1% per year), with low user dependency, or be 
abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis), as described in Appendix 5 during the 
intervention period and for at least 30 days after the last dose of study intervention. 
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
-
A female of childbearing potential must have a negative highly sensitive pregnancy 
test (urine or serum as required by local regulations) within 24 hours before the first 
dose of study intervention.
• Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
• The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a female with an early 
undetected pregnancy.
Informed Consent/Assent
10. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study.
See Section 10.7, Appendix 7 for country-specific inclusion criteria requirements.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has chronic (≥30 days’ duration) IA, relapsed/recurrent IA, or refractory IA that has not 
responded to prior antifungal treatment.
2. Has cystic fibrosis, pulmonary sarcoidosis, aspergilloma, or allergic bronchopulmonary 
aspergillosis.
3. Has known hypersensitivity or other serious adverse reaction to any azole antifungal 
therapy, or to any other ingredient of the study treatment used.
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4. Has any known history of torsade de pointes, unstable cardiac arrhythmia or 
proarrhythmic conditions, a history of recent myocardial infarction, congenital or 
acquired QT prolongation, or cardiomyopathy in the context of cardiac failure within 
90 days of time of first dose of study treatment.
5. Has known hereditary fructose intolerance.
6. Has known galactose intolerance, Lapp lactase deficiency, or glucose-galactose 
malabsorption.
7. Is on artificial ventilation at the time of first dose of study treatment.
8. Has any condition that, in the opinion of the investigator, may interfere with optimal 
participation in the study.
Prior/Concomitant Therapy
9. Has received any treatment specifically listed in Table 2 within the specified timeframes 
before the start of study treatment.
Table 2
Prohibited Medications Before Start of Study Treatment
Prohibited Medications Before Start of Study 
Treatment
Prohibited Time Period Before Day 1 
of Study Treatmenta
Any investigational drug (new chemical or 
biological entities): may be permitted with the 
approval of the Sponsor’s Clinical Director
Only permitted with approval of the 
Sponsor’s Clinical Director prior to start 
of study therapy
Systemic antifungal treatment (oral, intravenous,
or inhaled) when used to treat current fungal 
infection episode
Prohibited if duration of treatment for 
current fungal infection is ≥96 hours 
before Day 1
Azole antifungal prophylaxis with mold activity 
(ie, itraconazole, voriconazole, isavuconazole)
Prohibited unless approval provided by 
the study Sponsor’s Clinical Director 
prior to study randomization. Without 
Sponsor approval, prohibited if duration 
of mold-active azole prophylaxis therapy 
exceeds 13 days prior to study 
randomization
Astemizole
Prohibited if taken within 24 hours before
Day 1
Cisapride, ebastine, halofantrine, pimozide, 
quinidine, and terfenadine
Prohibited if taken within 24 hours before
Day 1
Ergot alkaloids (ergotamine, dihydroergotamine, 
or other members of this class)
Prohibited if taken within 24 hours before
Day 1
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Prohibited Medications Before Start of Study 
Treatment
Prohibited Time Period Before Day 1 
of Study Treatmenta
Disopyramide
Prohibited if taken within 24 hours before
Day 1
Bepridil
Prohibited if taken within 24 hours before
Day 1
Ibutilide
Prohibited if taken within 24 hours before
Day 1
Haloperidol
Prohibited if taken within 24 hours before
Day 1
HMG-CoA reductase inhibitors metabolized via 
CYP3A4 (eg, simvastatin, lovastatin, and 
atorvastatin)
Prohibited if taken within 24 hours before
Day 1
Atazanavir, efavirenz, fosamprenavir, or 
ritonavir
Prohibited if taken within 24 hours before
Day 1
Venetoclax
Prohibited if taken within 24 hours of 
Day 1
Abbreviations: CYP = cytochrome P450; HMG-CoA=beta-hydroxy-beta-methylglutaryl-CoA.
a These waiting times should be observed immediately before start of study treatment and during study 
treatment in participants receiving a prohibited treatment as prior treatment.
Prior/Concurrent Clinical Study Experience
10. Has enrolled previously in the current study and been discontinued.
Diagnostic Assessments
11. Has QTc prolongation (based on either Fridericia or Bazett’s correction) at screening 
>500 msec.
12. Has significant liver dysfunction (defined as total bilirubin >1.5 × ULN AND AST or 
ALT >3 × ULN with normal alkaline phosphatase) at screening.
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13. Has calculated creatinine clearance <20 mL/min/1.73 m2 (modified Schwartz formula) at 
screening. Creatinine clearance will be calculated using the following equation:
Modified Schwartz formula
Creatinine clearance = K × (height in cm)
(creatinine in mg/dL)
K (proportionality constant):
Male child (≥2 year to <13 years): K=0.55
Male child (≥13 year to <18 years): K=0.70
Female child (≥2 year to <18 years): K=0.55
Other Exclusions
14. Is not expected, in the opinion of the investigator, to survive for at least 1 month after the 
initiation of study treatment.
15. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
See Section 10.7, Appendix 7 for country-specific exclusion criteria requirements.
5.3
Lifestyle Considerations
There are no diet or activity restrictions for this study.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently entered into the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
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6
STUDY INTERVENTION
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The interventions to be used in this study are outlined in Table 3. For dosing of the PFS see 
Table 1.
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Table 3
Study Treatments
Arm Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment Period
Use
IMP or
NIMP/AxMP
Sourcing
Posaconazole Experi-
mental
IV
Drug
Vial
18 mg/mL
6 mg/kg 
Doses are not to 
exceed 300 mg 
per administration
IV Infusion Day 1: BID
Day 2 through end 
of IV dosing: QD
Test 
Product
IMP
Centrally 
sourced with 
the ability to 
source locally 
if required
Posaconazole Experi-
mental
Powder for 
suspension 
(PFS)
Drug
Powder for 
Suspension
30 mg/mL
Dosing based on 
weight-band.
To be 
administered to 
participants 
≤40 kg
Oral
Days 8 – 84: QD
Test 
Product
IMP
Centrally 
sourced with 
the ability to 
source locally 
if required
Posaconazole Experi-
mental
Tablet
Drug
Tablet
100 mg
300 mg
To be 
administered to 
participants 
>40 kg
Oral
Days 8 – 84: QD
Test 
Product
IMP
Centrally 
sourced with 
the ability to 
source locally 
if required
Abbreviations: AxMP Auxiliary Medical Product, EEA=European Economic Area, IMP= Investigational medical product, NIMP=non-investigational medical product, QD= 
Once daily
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in Table 3 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
The rationale for the selection of doses to be used in this study is provided in Section 4.3, 
Justification for Dose.
The participant’s body weight at Day 1 will be used to calculate the dose of POS IV study 
treatment. The participant’s body weight as measured within 3 days before the first day of 
oral POS treatment will be used to calculate all subsequent doses of oral POS: any participant 
whose weight is ≤40 kg will transition to the PFS formulation; any participant whose weight 
is >40 kg will transition to the tablet formulation and will receive 300 mg as 3 × 100-mg 
tablets. For any subsequent switch from oral to IV formulation, the IV dose will be calculated
based on the participant’s weight before the initial switch to an oral formulation.
Instructions for preparation of the IV infusion and the PFS oral solution are found in the 
Pharmacy Manual. Instructions for administration of PFS will be provided to caregivers 
separately.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
All participants will receive POS as study treatment throughout the study, with the initial 
formulation for all participants being the IV formulation. Allocation numbers will be 
assigned by an IRT system.
6.3.2
Stratification
Treatment randomization/allocation will be stratified according to the following factors:
Participant’s age at the time of first dose of study treatment:
1. Age Cohort 1: 2 years to <12 years of age.
2. Age Cohort 2: 12 years to <18 years of age.
6.3.3
Blinding
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the treatment administered.
6.4
Study Intervention Compliance
The volume of injection and the number of tablets/sachets remaining in study packaging will 
be counted, reviewed, and recorded at regular intervals to monitor treatment compliance.
The shifting of the timing of a dose (within the window provided in Section 8.1.8 to 
accommodate a participant’s schedule) is not considered an interruption.
Interruptions from the protocol-specified treatment plan for ≥7 days require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication. If there is a clinical 
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indication for any medications or vaccinations specifically prohibited, discontinuation from 
study intervention may be required. The investigator should discuss any questions regarding 
this with the Sponsor Clinical Director. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the participant’s primary physician. However, 
the decision to continue the participant on study intervention requires the mutual agreement 
of the investigator, the Sponsor, and the participant.
Medications prohibited during study treatment are presented in Table 4.
Table 4
Prohibited Medications During Study Treatment
Prohibited Medications During Study Treatment
Time Perioda
Any investigational drug (new chemical or biological entities): 
Investigational use of approved products or chemotherapy 
regimens may be permitted with the approval of the Sponsor’s 
Clinical Director before use.
Prohibited during study treatment
Systemic antifungals other than echinocandins (oral, intravenous,
or inhaled) as outlined below
Prohibited during study treatment
Echinocandin antifungals (caspofungin, anidulafungin, 
micafungin)
Prohibited during study treatment except 
when given for the treatment of invasive 
candidiasis for a maximum duration of 14 
days
Astemizole
Prohibited during study treatment
Cisapride, ebastine, halofantrine, pimozide, quinidine, and 
terfenadine
Prohibited during study treatment
Ergot alkaloids (ergotamine, dihydroergotamine, or other 
members of this class)
Prohibited during study treatment
Disopyramide
Prohibited during study treatment
Bepridil
Prohibited during study treatment
Ibutilide
Prohibited during study treatment
Haloperidol
Prohibited during study treatment
Barbiturates, carbamazepine, cimetidine, isoniazid, phenytoin, 
rifabutin, rifampin, and St. John’s Wort (Hypericum perforatum)
Prohibited during study treatment
HMG-CoA reductase inhibitors metabolized via CYP3A4 (eg, 
simvastatin, lovastatin, and atorvastatin)
Prohibited during study treatment
Atazanavir, efavirenz, fosamprenavir, or ritonavir
Prohibited during study treatment
Venetoclax
Prohibited during study treatment
Abbreviations: CYP = cytochrome P450; HMG-CoA=beta-hydroxy-beta-methylglutaryl-CoA.
a Medications prohibited during study treatment should not be given during study treatment and for 7 days 
following the cessation of study treatment. Any deviations to this time period must be discussed with the study 
team/clinical monitor before initiating any concomitant therapies listed above.
All medications not listed in Table 4 are permitted in the study. Specific medications that are 
allowed with caution and/or monitoring are presented in Section 6.5.1.
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The following topical nonabsorbable antifungals may be used for the treatment of 
oropharyngeal candidiasis, vaginal candidiasis, or cutaneous fungal infection: oral 
amphotericin B, miconazole (oral or topical), nystatin (oral or topical), and clotrimazole (oral 
or topical). All other antifungal therapies must be approved by the Sponsor before use.
6.5.1
Medications Allowed With Caution and Clinical Monitoring
Clinical and/or QTc monitoring is recommended when the study treatment is coadministered 
with one of the following drugs that have reported a potential risk of torsades de pointes:

Antiarrhythmics (amiodarone, dofetilide, procainamide, sotalol)

Chlorpromazine

Clarithromycin

Domperidone

Droperidol

Levomethadyl

Mesoridazine

Methadone

Erythromycin

Sparfloxacin

Thioridazine
Medications that are allowed with caution and/or monitoring are presented in Table 5. These 
drugs are permitted, although their efficacy and safety should be clinically monitored and/or 
serum levels followed with appropriate dosage adjustments as necessary at the initiation of 
study treatment, periodically during treatment, and after discontinuation of study treatment.
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Table 5
Additional Medications Allowed During the Study That Require Monitoring
and/or Dose Adjustment
Medication Class
Medication Namea
Recommendation
Anticoagulants
Coumadin-type
Coumadin-type anticoagulants are permitted, although 
their efficacy and safety should be clinically monitored 
and/or serum levels followed with appropriate dosage 
adjustments as necessary at the initiation of study
treatment, periodically during treatment, and after 
discontinuation of study treatment.
Antiretroviral Therapy
Multiple
As HIV protease inhibitors and NNRTIs are CYP3A4 
substrates, it is expected that POS will increase plasma 
levels of these antiretroviral agents. Participants should be 
carefully monitored for any occurrence of toxicity during 
the coadministration of POS and these agents.
NOTE: Coadministration of POS with atazanavir, 
efavirenz, fosamprenavir, or ritonavir is not permitted 
during the treatment phase of the study.
Benzodiazepines
Alprazolam
Midazolam
Triazolam
POS 200 mg orally once daily increased the AUC of 
midazolam by 83% following IV administration. Due to 
the inhibition of intestinal CYP3A4 by POS, an even 
greater effect of POS on the AUC of midazolam is 
expected following oral administration. Dose adjustments 
should be considered for all benzodiazepines that are 
metabolized through CYP3A4. POS interferes with the 
hepatic clearance of triazolam and midazolam, and thus, 
may enhance the sedative effects of these agents. 
Therefore, these agents should not be used unless 
monitoring is provided for excessive sedation
Calcium Channel 
Blockers
Diltiazem
Nifedipine
Nisoldipine
Verapamil
For calcium channel blockers metabolized through 
CYP3A4 (eg, diltiazem, nifedipine, nisoldipine, 
verapamil), frequent monitoring for AEs and toxicity 
related to calcium channel blockers is recommended 
during coadministration with POS. Dose adjustment of 
calcium channel blockers may be required.
Cardiac Glycosides
Digoxin
Administration of other azoles has been associated with 
increases in digoxin levels. Digoxin levels should be 
monitored when initiating or discontinuing POS treatment.
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Medication Class
Medication Namea
Recommendation
Antineoplastic/
Immunosuppressive
Cyclophosphamide
Periodic blood work should be obtained to monitor 
complete blood count as well as the function of other 
organs (such as kidneys and liver). Toxicity monitoring to 
include monitoring for potential myelosuppression, bone 
marrow failure, urinary tract and renal toxicity, 
cardiotoxicity including myocarditis, congestive heart 
failure, and arrhythmia, and pulmonary toxicity. Close 
monitoring for potential toxicity should occur during 
coadministration.
Antineoplastic
Trisenox
Prior to initiating therapy with Trisenox, a 12-lead ECG 
should be performed, and serum electrolytes (potassium, 
calcium, and magnesium) and creatinine should be 
assessed. Pre-existing electrolyte abnormalities should be 
corrected and, if possible, drugs that are known to prolong 
the QT interval should be discontinued. If it is not possible 
to discontinue the interacting drug, perform cardiac 
monitoring frequently. Monitor ECG weekly, and more 
frequently for clinically unstable patients.
Chemotherapeutic 
Agents
Anthracycline-
based 
chemotherapeutics
During coadministration, close monitoring for potential 
cardiotoxicity and hepatotoxicity should occur.
Chemotherapeutic 
Agents
Vinca alkaloids (eg, 
vincristine and 
vinblastine)
Concomitant administration of azole antifungals, including 
POS, may increase the plasma concentrations of vinca 
alkaloids, which may lead to neurotoxicity and other 
serious adverse reactions. Reserve azole antifungals, 
including POS, for patients receiving a vinca alkaloid,
including vincristine, who have no alternative antifungal 
treatment options.
Immunosuppressive 
Sirolimus
Concomitant administration of POS with sirolimus 
increases the sirolimus blood concentrations by 
approximately 9-fold and can result in sirolimus toxicity. 
Monitoring of sirolimus blood levels should be performed 
on initiation, during coadministration, and on 
discontinuation of POS treatment, with adjustment of 
sirolimus doses as necessary.
Immunosuppressive
Cyclosporine
In heart transplant, patients on stable doses of 
cyclosporine, POS 200 mg QD increased cyclosporine 
concentrations requiring dose reductions of up to 29%. 
Cases of elevated cyclosporine concentrations resulting in 
SAEs, including nephrotoxicity were reported in clinical 
efficacy studies. Monitoring of cyclosporine blood levels 
should be performed on initiation, during 
coadministration, and on discontinuation of POS 
treatment, with adjustment of cyclosporine doses as 
necessary.
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Medication Class
Medication Namea
Recommendation
Immunosuppressive
Tacrolimus
POS increased Cmax and AUC of tacrolimus (0.05 mg/kg 
body weight single-dose) by 121% and 358%, 
respectively. Clinically significant interactions resulting in 
hospitalization and/or POS discontinuation were reported 
in clinical efficacy studies. When initiating POS treatment 
in participants already receiving tacrolimus, the dose of 
tacrolimus dose should be reduced (eg, to about one-third 
of the current dose). Thereafter, blood levels of tacrolimus 
should be monitored carefully during coadministration, 
and on discontinuation of POS, and the dose of tacrolimus 
should be adjusted as necessary.
Oral Hypoglycemic 
Agents/Sulfonylureas
Glipizide
Glucose concentrations decreased in some healthy 
participants when glipizide was coadministered with POS. 
Monitoring of glucose concentrations is recommended in 
diabetic participants.
Tyrosine kinase 
inhibitors
Ibrutinib
During coadministration with POS, dose adjustment of 
ibrutinib per product label should occur. Interruption of 
ibrutinib dose/dose modification for Grade 3 or greater 
hematologic toxicity is recommended.
Xanthine Derivatives
Theophylline
Theophylline is permitted, although its efficacy and safety 
should be clinically monitored and/or serum levels 
followed with appropriate dosage adjustments as necessary 
at the initiation of study treatment, periodically during 
treatment, and after discontinuation of study treatment.
Abbreviations: AUC=area under the concentration-time curve; Cmax=observed maximal concentration; 
CYP=cytochrome P450; ECG=electrocardiogram; HIV=human immunodeficiency virus; IV=intravenous; 
NNRTI=non-nucleoside reverse transcriptase inhibitor; POS=posaconazole; QD=once daily; SAE=serious 
adverse event.
a Not all medications from a specific medication class are necessarily listed here.
6.5.2
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modifications are planned in this study. 
6.7
Intervention After the End of the Study
There is no study-specified treatment following the end of the study. Following the 
completion of study treatment, study participants may continue to receive additional non-
study antifungal treatment for the episode of IA or as secondary antifungal prophylaxis as 
clinically indicated.
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6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.9.2.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and Section
8.9.2.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.
•
The participant has a confirmed positive pregnancy test.
•
Serious adverse experience related to study therapy or the occurrence of an adverse 
experience (clinical or laboratory) that, in the judgment of the investigator, warrants 
withdrawal of study therapy.
•
If the QTc interval is >500 msec (based on either Fridericia or Bazett’s correction), study 
therapy may be interrupted for up to 3 days with concomitant monitoring and correction 
of electrolytes. Study therapy may be resumed if QTc interval decreases to <500 msec.
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•
If during study treatment the participant has AST or ALT ≥3 × ULN and bilirubin ≥2 ×
ULN and alkaline phosphatase <2 × ULN, then study therapy may be interrupted for up 
to 3 days with repeat monitoring of liver function testing. Study therapy may be resumed 
if repeated liver function testing parameters no longer meet the criteria outlined above
and the change is unrelated to study intervention based on the opinion of the investigator. 
Study therapy should be permanently discontinued if liver function testing continues to 
exceed the specified parameters with repeat testing regardless of relationship to study 
medication.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
See Section 10.7, Appendix 7 for country-specific discontinuation of study intervention 
requirements.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 8.1.9 – Withdrawal/Discontinuation. Participants with possible 
IA for whom proven or probable IA cannot be confirmed will not be withdrawn from the 
study. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
●
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, phone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note:  A participant is not considered lost to follow-up until the last scheduled visit for 
the individual participant.  The missing data for the participant will be managed via the 
pre-specified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
●
Study procedures and their timing are summarized in the SoA.
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
●
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before documented ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
●
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), and thus local 
regulations may require that additional informed consent, and assent if applicable, be 
obtained from the participant. In these cases, such evaluations/testing will be performed 
in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the trial, 
including any extra assessments that may be required, will not exceed 78.6 mL Table 12.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each potential 
participant or their legally acceptable representative prior to participating in this clinical 
study. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented consent is in place.
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8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent form. The form must include the trial protocol number, 
trial protocol title, dated signature, and agreement of the participant (or his/her legally 
acceptable representative) and of the person conducting the consent/assent discussion. 
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent/assent form or addendum to the original consent form 
that captures the participant’s or participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent/assent.
Specifics about the study and the study population are to be included in the study informed 
consent/assent form.
Informed consent/assent will adhere to IRB/IEC requirements, applicable laws and 
regulations, and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain study site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides documented informed consent/assent. At the 
time of treatment allocation/randomization, site personnel will add the 
treatment/randomization number to the Participant Identification Card.
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8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history should include details regarding underlying conditions that may qualify the 
participant for possible, probable, or proven IA according to 2020 EORTC/MSG criteria
(Appendix 9). The medical history should include details regarding any ongoing or prior 
cancer diagnoses, immunosuppressive conditions (including HIV), transplant procedures
(HSCT or solid organ), and any history of graft-versus-host disease (acute or chronic). The 
history should also include details regarding recent or ongoing bacterial infectious episodes 
and any prior histories of invasive fungal infection, as well as details regarding the current 
episode of IA. Any history of hepatitis should also be recorded.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement and prohibited medications, for the 14 days before
initiation of POS treatment. Chemotherapeutic agents used for any chemotherapy regimen for 
active treatment of malignancy, as well as T-cell and B-cell immunosuppressive therapies 
and antifungal treatment within 30 days before the first dose of study treatment, are to be 
recorded.
•
Record prior medication (prescription or over the counter) taken within 14 days before 
starting the trial, including protocol-specified prohibited medications, as outlined in 
Section 5.2 (Table 2).
•
The identity of the therapy, the dates started and stopped (or notation of “continuing” if 
that is the case), and the reason for use must be recorded for all medications.
•
Participants receiving other systemic antifungal agents (IV, oral or nasal/inhaled) as
prophylactic therapy must discontinue these treatments before study treatment
administration. No other systemic antifungal agent may be administered during the study 
treatment phase (ie, POS IV solution/PFS/tablet) without Sponsor approval.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant
during the study. The identity of the therapy, the dates started and stopped (or notation of 
continuing if that is the case), and the reason for use must be recorded. The use of any 
concomitant medication must relate to an AE or the participant’s medical history.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment allocation.  Each 
participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
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Specific details on the screening visit requirements are provided in Section 8.9.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
IV infusions should be administered via a central line at approximately the same time each 
day. On the first 24 hours of IV dosing, there is a loading period during which 2 doses are 
given, separated by 12 hours. Subsequently, a single dose is given once daily. For the third 
dose, the dose should be timed to be given approximately 24 hours after the initial loading 
dose (ie, approximately 12 hours after the second loading dose). All subsequent IV doses 
should be administered approximately 24 hours apart. If for any reason the timing of the 
medication needs to be adjusted after the first dose, the dose time may be adjusted by ±3 
hours.
Doses of POS PFS and tablets will be administered every 24 hours during the oral treatment 
period, without regard to timing of food intake. If for any reason, the timing of the 
medication needs to be adjusted after the first dose, the dose time may be adjusted by ± 3 
hours. Participants who vomit within 30 minutes of POS PFS or tablet administration should 
be given a replacement dose as soon as the participant is able to take the new dose. Repeated 
episodes of vomiting should be recorded on the AE electronic case report form (eCRF) and 
the Study Medication eCRF.
If the dosing of study treatment 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 participant's eCRF and source documentation.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the EOT Visit should be performed (at the time of withdrawal).  Any adverse 
events which are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4.
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In addition, participants and caregivers/legally acceptable representatives should be informed 
that the site will attempt to contact them at Day 114 for a mortality assessment.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Global Clinical Response
The investigator will assess global clinical response at the Week 6 and Week 12 visits; in the 
event of early therapy discontinuation, global clinical response will be assessed at the EOT 
Visit. All data related to the evaluation of global clinical response will be collected, including 
clinical signs and symptoms, imaging, serologic testing, and fungal culture and histology. A 
global clinical response will be assessed by the investigator as favorable (positive) if the 
participant is alive and has a complete or partial response, using the definitions of responses 
to therapy and study outcomes in clinical trials of invasive fungal diseases at the time points 
of interest [Segal, B. H., et al 2008] (Table 6).
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Table 6
Global Clinical Response using 2008 EORTC/MSG Definitions
Outcome, Response
Definition
Success
Complete response
Survival within the prespecified period of observation, resolution 
of all attributable symptoms and signs of disease, resolution of 
radiological lesion(s), and documented clearance of infected sites 
that are accessible to repeated sampling.
Partial response
Survival within the prespecified period of observation, 
improvement in attributable symptoms and signs of disease, 
improvement of radiological lesion(s)a, and evidence of clearance 
of infected sites that are accessible to repeated sampling.
In the case of radiological stabilizationb, resolution of all 
attributable symptoms and signs of fungal disease; or where 
biopsy of an infected site shows no evidence of hyphae; or where 
culture is negative.
Failure
Stable response
Survival within the prespecified period of observation and minor 
or no improvement in fungal disease; or persistent isolation of 
Aspergillus spp or histological present in infected sites.
Progression of fungal disease
Worsening of clinical symptoms and signs of disease plus new 
sites of disease or radiological worsening; or persistent isolation 
of Aspergillus spp from infected sites.
Death
Death during the prespecified period of evaluation, regardless of 
attribution.
a Improvement of radiological lesions is defined as at least 25% reduction in diameter of radiological lesion.
b Radiological stabilization is defined as 0%-25% reduction in the diameter of the lesion.
8.2.2
Diagnostic Imaging
High-resolution CT scan is required for all participants with pulmonary sites of infection, as 
chest X-ray is deemed insufficient for assessment of pulmonary IA. 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. All imaging will be performed locally, and 
evaluation of infection will be recorded on the eCRF. Recording of imaging should include 
sufficient details to reflect use of the 2020 EORTC/MSG criteria to support the classification 
of IA.
At screening and end of treatment, diagnostic imaging is required for all sites of infection. 
Imaging can be conducted at other times if the clinical infectious condition changes relative 
to the previous assessment and repeat imaging is judged warranted by the clinician. If 
diagnostic imaging is conducted before Screening and within 7 days of Day 1, the results 
may be used for screening purposes.
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8.2.3
Mycology Testing
Mycology testing includes both histology samples and standard fungal cultures from all sites 
of suspected Aspergillus infection, as clinically appropriate. Mycology testing also includes 
galactomannan testing of plasma, serum, BAL, and CSF, as well as Aspergillus PCR testing 
of whole blood, serum, plasma, and BAL. Unless clinically inappropriate or not warranted 
due to the participant’s health, condition or disease progression/regression, mycology testing 
may occur at the following visits: Screening, Week 6, Week 12, and EOT. Additional 
mycology testing will be performed as clinically indicated and should correlate with potential 
disease regression/progression. All fungal culture results (positive or negative) as well as all 
galactomannan and Aspergillus PCR test results (positive or negative) are to be recorded on 
the eCRF.
8.2.4
IFI Assessment
IFI assessment will be performed at every visit and should include all clinical signs and 
symptoms that may be related to fungal or bacterial infections. Any clinical sign or symptom 
that is possibly, probably, or definitely related to a fungal infection should be identified. All 
participants will be evaluated for the presence of IA based on 2020 EORTC/MSG definitions 
at all visits (Appendix 9).
8.2.5
Relapse Assessment
Relapse of IA infection will be evaluated only in participants who have achieved favorable 
clinical response. Relapse will be assessed by the investigator through 28 days following 
completion of study treatment in those participants who have achieved a favorable clinical 
response.
8.2.6
Mortality Assessment
For each participant, including those who withdraw from the study, a survival assessment (ie, 
whether the participant is alive or has died) will be performed through Day 114. In the event 
of death, the cause and date of death will be recorded. This assessment can occur by review 
of medical records or by telephone contact with the participant or a family member/legally 
acceptable representative.
8.2.7
Aspergillus Galactomannan EIA and PCR
Samples (ie, serum, BAL, plasma, or CSF) may be collected for Aspergillus galactomannan 
enzyme immunoassay (EIA) at Screening and subsequent visits to support the IA diagnosis.
Samples (plasma, serum, whole blood, and BAL) may also be collected for Aspergillus PCR 
testing. The quantitative value and time of collection of the galactomannan sample should be 
documented for all galactomannan tests performed on participants. The results of all 
galactomannan samples taken during the period from screening to the follow-up visit should 
be provided. The results (positive or negative) of all samples taken for Aspergillus PCR 
testing should be provided.
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If samples for Aspergillus galactomannan EIA were collected before screening and within 
7 days of Day 1, results may be used for screening purposes. Galactomannan EIA serological 
test results may not be used to confirm a probable diagnosis of IA if participants have taken 
piperacillin/tazobactam within 72 hours of serum sampling. Indirect testing criteria that are 
supportive of a diagnosis of probable IA include:
Galactomannan detected in plasma, serum, BAL, or CSF:
•
Single serum or plasma ≥1.0
•
BAL fluid ≥1.0
•
Single serum or plasma ≥0.7 with BAL fluid ≥0.8
•
CSF ≥1.0
Aspergillus PCR testing, any 1 of the following:
•
Plasma, serum, or whole blood 2 or more consecutive PCR tests positive
•
BAL fluid 2 or more duplicate PCR tests positive
•
At least 1 PCR test positive in plasma, serum, or whole blood and 1 PCR test positive 
in BAL fluid
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. The complete 
physical examination includes the following assessments: general appearance, head, eyes,
ears/nose/throat, neck, lymph nodes, skin, lungs, heart, abdomen, musculoskeletal, and 
neurologic evaluations. Breast, rectal, and genitourinary/pelvic exams should be performed 
when clinically indicated.
Height and weight will also be measured and recorded. Height measurements should be taken 
without shoes and be recorded to the nearest cm. Body weight at baseline will be used to 
calculate the participant’s dose for the IV treatment phase of the study. The participant’s 
weight measured within 3 days before the first dose of oral treatment should be used to 
calculate all subsequent doses of the PFS oral formulation, as well doses of the IV 
formulation if the participant subsequently switches from an oral to the IV formulation. Body 
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weight should be obtained without shoes. At each required visit, it is preferred that the 
weight be measured on the same scale for the same individual. Measurements should be 
recorded to the nearest 0.1 kg.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard at any other 
visit when clinically indicated.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
•
Vital signs will include heart rate, blood pressure, respiratory rate, and body temperature.
8.3.3
Electrocardiograms
•
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
Any clinically significant abnormality on study treatment must be followed until 
stabilization or return to baseline. Refer to Section 7.1 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.
•
For small participants whose size does not allow for a standard 12-lead ECG, a modified 
12-lead ECG may be obtained.
Note: When the collection of vital signs, ECGs, and PK samples coincide, the blood samples 
for PK determination should be collected first (so that the PK samples are collected on time), 
followed by the vital signs, and then the ECG. It is preferred that the ECG be performed at 
the same time each day (eg, morning) to reduce diurnal variation.
8.3.4
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
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•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with local or central laboratory requirement, as applicable, and 
the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Assessment of Palatability and Acceptability
Palatability and acceptability will be assessed using the Palatability Acceptance Assessment. 
Palatability is measured using a 5-point facial hedonic scale depicting various degrees of 
tolerance. Participants will also be asked to report any problems experienced while taking the 
medication. All participants will rate the palatability and acceptability of the PFS formulation 
on the first and last days of the PFS treatment phase.
The Palatability Acceptance Assessment should be implemented with the following 
recommendations:
•
Ages 2 through 4 years: Completion by observer (parent/caregiver or health care 
provider).
•
Ages 5 through 13 years: Combined completion: the child participant should
complete the faces question and the observer should complete the remaining 
questions.
•
Ages 14 through 17 years: Completion directly by the child participant when 
possible.
Observer assessments should be based on what the parent/legally acceptable representative/
caregiver/health care provider has observed directly during and after medication 
administration, including the participant’s facial expressions, behavior, and what the 
participant says. Only individuals who have directly observed the participant taking the study 
treatment should complete the assessment.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an AE and/or SAE was associated with a medication error, 
misuse, or abuse. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention allocation through 14 days following cessation of treatment, all 
AEs, SAEs, and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and other events not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
allocated participants for outcome. Further information on follow-up procedures is given in 
Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
1. 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: This section reflects the handling of nonserious ECI. ECI events meeting SAE 
criteria are to be reported in the same manner as SAE. 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 study site guidance for assessment and follow-up of these 
criteria can be found in the Investigator Study File Binder (or equivalent).
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the protocol-specified dose as provided in 
Section 6.1.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor’s Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
Blood samples for the determination of POS plasma concentrations are to be collected 
predose, as near the dose as possible, at Day 1 and at the Week 1, 2, 4, 6, 9, and 12 Visits. 
For participants on the IV formulation, additional samples are to be collected within 
15 minutes after the end of infusion at Weeks 1, 2, 4, 6, 9, and 12. The Week 1 postdose PK 
sample is to be collected after a minimum of 7 days’ treatment with POS IV. For participants 
on oral tablet or PFS formulations who are hospitalized, an additional sample is to be 
collected between 3 and 6 hours postdose at Weeks 2, 4, 6, 9, and 12. The actual time of 
blood sample collection should be documented in the participant’s eCRF.
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If a participant discontinues study treatment early, a plasma sample for drug concentration 
should be obtained between 8 and 24 hours after the last dose of study treatment. However, if 
this recommended timing is not feasible, a blood sample should be taken and the date and 
time of the previous POS dose, as well as the date and time of the blood sample, should be 
noted in the participant’s eCRF.
8.6.1
Blood Collection for Plasma MK-5592
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Future biomedical research will not be conducted in this study.
8.9
Visit Requirements
Visit requirements are outlined in Section 1.3 (Schedule of Activities).  Specific procedure-
related details are provided above in Section 8.
8.9.1
Screening
All screening procedures outlined in the SoA must be performed within 14 days before 
enrollment into the study. Informed consent/assent must be obtained from the participant or 
legally acceptable representative of each participant before any study-specific procedures are 
performed other than those procedures conducted for the purpose of routine clinical care. 
Assent will be obtained from minors according to institutional practices. Before treatment 
assignment, potential participants must be evaluated to determine whether they fulfill the 
entry requirements as set forth in Sections 5.1 and 5.2. Local laboratory tests (pregnancy, 
hematology/chemistry, imaging, and mycology testing) will be used to evaluate eligibility 
criteria. Only potential participants with clinically acceptable results from all screening 
criteria are to be enrolled in the study.
8.9.2
Treatment Period Visits
8.9.2.1
Day 1 Visit
Day 1 procedures/assessments listed in the SoA must be performed before initiation of study 
therapy. Only hematology/chemistry and/or pregnancy tests are to be repeated if it has been 
more than 2 days or 1 day, respectively, since screening labs were performed. After 
confirming that all study inclusion/exclusion criteria are met, participant will be assigned a
study allocation number by an IRT and POS treatment will be administered.
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8.9.2.2
Treatment Period
All participants will initiate treatment with IV POS and may transition to oral POS after a 
minimum of 7 days on IV study treatment, as clinically indicated. Dosing selection and 
preparation are described in Section 4.3 and Section 6.2, respectively. Study visits in the 
treatment period will occur at Day 3 and Weeks 1, 2, 4, 6, 9 and 12. At these scheduled 
visits, procedures/assessments are to be performed according to the SoA.
8.9.2.3
End of Treatment (EOT) Visits
Participants who discontinue study therapy before 12 weeks should have an EOT Visit within 
3 days after the EOT. If the EOT Visit falls within the window for a regular scheduled visit,
the EOT Visit should occur instead of the scheduled visit and participants should complete 
all follow-up visits at 14 and 28 days after the last dose.
Every effort should be made, for participants who withdraw consent for participation or who 
are withdrawn from the study for any reason, to complete the EOT Visit as well as the final 
mortality assessment at Day 114.
8.9.3
Post-Treatment Visits
Participants will be required to return to the clinic approximately 14 days after the last dose 
of study treatment for the post-treatment visit. If the post-treatment visit occurs less than 
14 days after the last dose of study treatment, a subsequent follow-up phone call should be 
made at 14 days after the last dose to determine if any AEs have occurred since the post-
treatment clinic visit.
Participants will also be required to return to the clinic approximately 28 days after the last 
dose of study treatment for the post-treatment visit.
In addition, mortality data will be collected at Day 114 for all participants regardless of 
whether the participant discontinues study therapy early. If the Day 114 visit occurs after the 
28-day follow-up visit, the mortality follow-up can be conducted by phone call.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in a supplemental 
SAP and referenced in the Clinical Study Report for the study. Post hoc exploratory analyses
will be clearly identified in the Clinical Study Report.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
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Study Design Overview
A Phase 2, Open-Label, Non-Comparative Clinical Trial to Study the 
Safety and Efficacy of Posaconazole (POS, MK-5592) in Pediatric 
Participants Aged 2 to Less Than 18 Years With Invasive Aspergillosis
Treatment Assignment
Pediatric participants aged 2 to <18 years with IA will be allocated to 
receive POS (Day 1-7 IV formulation, Day 8-84 either IV, PFS or oral 
formulation). Participants will be enrolled into 2 age cohorts: Age Cohort 
1 (2 to <12 years) or Age Cohort 2 (12 to <18 years).
Analysis Populations
Safety: All Participants as Treated (APaT).
Efficacy:

Full Analysis Set (FAS) and

Responder Population.
Pharmacokinetics: All treated participants who receive at least 7 days of 
POS IV solution and have postdose PK sampling while on POS IV therapy
(PK Analysis Population).
Analysis populations are also defined in Section 9.5.
Primary Endpoint(s)
The primary safety endpoint is the proportion of participants in the APaT
population who experience 1 or more treatment-related AEs during POS 
study treatment (IV or oral) plus 14 days of follow-up.
There are no primary efficacy or pharmacokinetic endpoints.
Secondary Endpoints
•
Proportion of participants in the FAS population with a favorable global 
clinical response (partial or complete response) at the Week 6 (Day 42) 
Visit, at the Week 12 (Day 84) Visit, and at the EOT Visit (if different).
•
Proportion of participants in the Responder Population who have a 
relapse of IA at any point after achieving favorable global clinical 
response through 28 days post-treatment.
•
Cmin, Cmax, and Tmax, based upon sparse PK sampling (peak and 
trough concentration).
•
Analysis of exposure-response (efficacy and safety) relationships.
•
Participants’ categorical perception of palatability and acceptability of 
the PFS formulation.
Statistical Methods for 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Efficacy endpoints– overall proportion of participants in the FAS 
population with a favorable global clinical response at the Week 6, the
Week 12, and the EOT Visits – will be estimated and the corresponding 
95% confidence interval (CI) provided using the Clopper-Pearson 
method.
In addition, the overall proportion of participants in the Responder 
Population who had a relapse of IA through 28 days post-treatment will 
be provided along with other descriptive statistics.
A population PK analysis will be conducted as described in a separate 
Modeling Analysis Plan based on population PK models developed from 
prior pediatric and adult PK data for each formulation. Model-predicted 
individual concentration-time profiles will be used to derive Cmax, 
Cmin, Cavg, AUC, and Tmax. PK parameters for POS (Cmax, Cmin, 
Cavg, AUC, and Tmax) derived from the population PK analysis will be 
listed and summarized by formulation using descriptive statistics and to 
be summarized in a separate report.
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Statistical Methods for 
Safety Analyses
The APaT population will be used for safety analyses. The percentage of 
participants who experience drug-related AEs during the treatment period 
plus the first 14 days of follow-up will be provided along with the 
corresponding 95% CI using the Clopper-Pearson method.
Interim Analyses
There is no prespecified interim analysis planned for this open-label trial. 
However, interim reviews of safety and efficacy data will be conducted by 
the external DMC in accordance with its charter.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
The sample size was chosen based on clinical, not statistical,
considerations. 
9.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a nonrandomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. There are no hypotheses in this study.
9.4
Analysis Endpoints
Efficacy, pharmacokinetic and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy/Pharmacokinetic Endpoints
9.4.1.1
Efficacy Endpoints
There are no primary efficacy endpoints in this study. Efficacy endpoints include:
•
Proportions of participants in the FAS population who have a favorable global clinical 
response (partial or complete response), as assessed by the investigator using the 
definitions in Section 8.2.1 (Table 6), at the Week 6 Visit, Week 12 Visit, and EOT Visit.
•
Proportion of participants in the Responder Population who have a relapse of IA at any 
point after achieving favorable global clinical response through 28 days post-treatment. 
Relapse is defined as the re-emergence of clinical, radiographic, or other relevant 
abnormalities indicating IA.
9.4.1.2
Pharmacokinetic Endpoints
Observed peak and trough plasma concentrations will be measured directly from sparse 
sampling of plasma concentrations. Secondary PK parameters Cavg, Cmin, Cmax, AUC, and 
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Tmax will be estimated by population PK analysis and reported separately. An analysis of 
exposure-response (efficacy and safety) relationship will be conducted as part of the 
population PK analysis.
9.4.1.3
Tertiary/Exploratory Endpoints
The tertiary/exploratory endpoint is the proportion of participants in the APaT population 
who die at any point from the first dose of study treatment through Study Day 42 and through 
Study Day 114.
9.4.2
Safety Endpoints
The primary safety endpoint is the proportion of participants in the APaT population who 
experience 1 or more treatment-related AEs during POS study treatment phase (IV or oral) 
plus 14 days of follow-up.
9.4.3
Additional Endpoints
An additional secondary endpoint is participants’ categorical perception of the palatability 
and acceptability of the PFS formulation (Section 8.3.5).
9.4.4
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Based on the plasma concentration data obtained within this study, a separate population PK 
analysis will be performed. The prospective details of this analysis will be specified in a 
separate Modeling Analysis Plan.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The FAS population will serve as the primary population for the analysis of global clinical 
response data in this study. The efficacy analysis population to be studied (possible, 
probable, or proven IA) is similar to the population used for the primary efficacy analyses 
conducted in the adult study (P069) of invasive aspergillosis. The FAS population consists of 
all allocated participants who:

have possible, probable, or proven IA (based on modified 2020 EORTC/MSG 
definitions) as classified by the investigator,

receive at least 1 dose of study treatment,

have at least 1 post-allocation observation for the analysis endpoint subsequent to at 
least 1 dose of study treatment, and

have baseline data for those analyses that require baseline data.
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The Responder Population will serve as the population for the analysis of relapse.
•
The Responder Population consists of participants from the FAS population who have 
achieved a favorable global clinical response at the end of study treatment.
9.5.2
Pharmacokinetic Analysis Population
The primary PK population for this study will be all treated participants who receive at least 
7 days of POS IV solution treatment and have postdose POS PK sampling while on POS IV 
therapy.
9.5.3
Safety Analysis Populations
The APaT population will be used for the analysis of safety data and all-cause mortality in 
this study. This population consists of all enrolled participants who received at least 1 dose of 
study treatment, regardless of their IA classification.
9.6
Statistical Methods
9.6.1
Efficacy Analysis
The secondary efficacy endpoint, overall proportions of participants with a favorable global 
clinical response at Week 6, Week 12, and the EOT Visit, will be estimated and the 
corresponding 95% CI will be provided using the Clopper-Pearson method [Clopper, C. J. 
and Pearson, E. S. 1934]. A favorable global clinical response is defined in Section 8.2.1.
In addition, among those who had a favorable global clinical response, the overall proportion 
of participants who had a relapse of IA through 28 days post-treatment will be provided 
along with other descriptive statistics.
9.6.2
Pharmacokinetic Analysis
A population PK analysis will be conducted as described in a separate Modeling Analysis 
Plan based on population PK models developed from prior pediatric and adult PK data. The 
modeling analysis will be based on actual dose administered, which will account for 
differences in dosing regimen. Model-predicted individual concentration-time profiles will be 
used to determine Cmax, Cmin, Cavg, AUC, and Tmax. PK parameters for POS derived 
from the population PK analysis will be reported in a separate modeling and simulation 
report. Exposure/response assessments, including an exploration of the relationship between 
PK/PD indices with efficacy and safety time points, as available data allow, will be 
conducted as part of the population PK analysis and will also be reported separately.
9.6.3
Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory parameters. The primary safety analysis will summarize the safety data 
for participants during the treatment period (IV and oral treatment phases) plus 14 days of 
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follow-up. Additional safety summaries will be presented in aggregate and by age cohort. No 
further summary breakdowns by formulations will be performed due to small sample sizes 
and potential of switching participants back and forth among formulations.
In this descriptive study, the primary safety endpoint of the proportion of participants with 
drug-related AEs will be provided along with the corresponding 95% CI. The 95% CIs for 
the safety parameters will be estimated using the Clopper-Pearson method, which is a 
conservative exact method of providing CIs in this single-arm study.
All other safety parameters will be summarized using descriptive statistics. These include the 
proportion of participants with the following safety parameters: (1) at least 1 AE; (2) an 
SAE; (3) a serious and drug-related AE; (4) an AE leading to discontinuation; (5) specific 
AEs by System Organ Class; and (6) predefined limits of change in specific laboratory 
parameters. In addition, vital signs, 12-lead ECGs, and standard laboratory safety tests at 
time points specified in the SoA will be summarized as change from baseline.
The analysis strategy for the safety parameters is summarized in Table 8.
Table 8
Analysis Strategy for Safety Parameters
Safety Endpoint 
95% CI
Descriptive Statistics
Any AE
X
Any SAE
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
Discontinuation due to AE
X
Specific AEs, SOCs or PDLCs
X
Change from Baseline Results (laboratory, 
ECGs, vital signs)
X
Abbreviations: AE=adverse event; CI=confidence interval; ECG = electrocardiogram; PDLC=Predefined Limit of
Change; SAE=serious adverse event; SOC=System Organ Class; X=results will be provided.
Missing values will be handled using the Data-As-Observed approach; that is, any missing 
values will be excluded from the analysis.
9.6.4
Other Analyses
Palatability and acceptability of the POS PFS formulation, measured using a 5-point facial 
hedonic scale depicting various degrees of tolerance, will be summarized. The proportion of 
participants responding in each category to each of the questions on the first and on the last 
days of the PFS treatment phase will be tabulated.
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9.7
Interim Analyses
There is no prespecified interim analysis planned for this open-label trial. However, interim 
reviews of safety and efficacy data will be conducted by the external DMC in accordance 
with its charter.
9.8
Multiplicity
No multiplicity adjustments are planned for this study.
9.9
Sample Size and Power Calculations
9.9.1
Efficacy Analysis
The sample size was chosen based on clinical considerations, not statistical ones. However, 
of interest is the precision of the estimates of efficacy. The width of the 95% CI for the 
global clinical response rate will depend on the size of the population and the number of 
participants who achieve a favorable clinical response. In a study completed in 2019 (P069)
in 575 adults and adolescents to study efficacy and safety of POS versus VOR for the 
treatment of invasive aspergillosis, the favorable global clinical response rates at Week 6 and 
Week 12 for the participants on POS were 45% and 42%, respectively [Maertens, J. A., et al 
2021].
Table 9 summarizes the observed global clinical response rate and the corresponding 95% CI
for a variety of observed response rates for a population of 15 participants (the overall 
evaluable population).
Table 9
Summary of Potential Observed Global Clinical Response Rates and 
95% Confidence Intervals
Number of 
Participants in 
Population
Number Achieving 
Clinical Response
Observed Global 
Clinical Response
95% Confidence 
Intervala
15
9
60.0%
[32.3, 83.7]
6
40.0%
[16.3, 67.7]
3
20.0%
[4.3, 48.1]
a Confidence intervals are based on the Clopper-Pearson method [Clopper, C. J. and Pearson, E. S. 1934].
9.9.2
Safety Analysis
The primary safety analysis will summarize the safety data for participants during the 
treatment period (IV and oral treatment phases) plus 14 days of follow-up.
The APaT population is expected to include approximately 30 participants. The estimate of 
and the upper bound of the 95% CI for the underlying percentage of participants with a 
specific AE, given various hypothetical observed number of participants with that specific 
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AE within the study, are provided in Table 10. These calculations are based on the exact 
binomial method proposed by Clopper and Pearson.
Table 10
Estimate of Incidence of a Specific AE and Upper Limit of 95% CI Based on a 
Hypothetical Number of Participants with that Specific AE
N
Hypothetical Number of 
Participants with AE
Estimate of 
Incidence
95% CI Upper 
Limita
30
0
0.0%
9.5%
2
6.7%
22.1%
5
16.7%
34.7%
10
33.3%
52.8%
15
50.0%
68.7%
Abbreviations: AE=adverse event; CI = confidence interval.
a Based on the 2-sided exact 95% confidence interval (CI) on a binomial proportion [Clopper, C. J. and Pearson, E. S. 
1934].
9.10
Subgroup Analyses
No subgroup analyses are planned in this study.
9.11
Compliance (Medication Adherence)
The date and time of administration of each dose of POS, whether IV or oral (tablet or PFS) 
formulation, will be collected via eCRF to assess compliance for each participant. For the IV 
formulation, length of infusion will also be recorded.
For each participant who completes or who discontinues from the study or discontinues from 
study treatment, percent compliance will be calculated using the following formula:
The numerator, ie, ‘Number of Days on Therapy’, is defined as the total number of days on 
which a participant receives actual treatment (ie, at least 1 infusion, sachet [containing PFS]
or tablet of POS). The denominator, ie, ‘Number of Days Should be on Therapy’, is defined 
as the total number of days from the date of the first dose through the date of the last dose of 
study treatment.
Summary statistics such as mean and range of percent compliance for POS study treatment 
(IV, tablet, and PFS formulations) will be provided by age cohort and overall for the APaT
population.
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9.12
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics (N, mean, 
median, standard deviation) and frequency for the “Number of Days on Therapy” by age 
cohort and overall.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD 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 that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
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 IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study 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.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant 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 participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. 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.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the external DMC regarding the study.
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10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants and recommend to the
EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team, meeting 
facilitation, the study governance structure, and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
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By signing this protocol, the investigator acknowledges that the statutory obligations under
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study 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 or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants; documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 11 will be performed by the local or central laboratory, as 
applicable.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Sections 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 11
Protocol-Required Safety and Other Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count 
White blood cell (WBC) count 
with Differential
Absolute neutrophil count (ANC)
Hemoglobin
Hematocrit
Chemistry
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
aminotransferase
(AST)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above 
the upper limit 
of normal)
Albumin
Bicarbonate
Chloride
Magnesium
Creatinine
Sodium
Alanine 
aminotransferase
(ALT)
Glucose
(fasting or 
non-fasting)
Calcium
Alkaline 
phosphatase
Other Tests
• Urine or Serum β human chorionic gonadotropin (β-hCG) pregnancy 
test (as needed for females of childbearing potential)
• Samples for Aspergillus galactomannan enzyme immunoassay (EIA)
Investigators must document their review of each laboratory safety report.
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Table 12
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types
Study Period
Screening
Treatment
Follow-Up
Unsch
Maximum 
Total 
estimated 
volume per 
participant
(mL)
Visit 
Number/Title
1 
Screening
2 
Baseline
3
4
5
6
7
8
9
EOT
10
11
Unsch
Scheduled Day/ 
Week and 
Window
Days 
-14 to -1
Day 1
Day 3 
(±1 day)
Wk 1 
(Day
7-9) 
Wk 2 
(Day 
12-18)
Wk 4 
(Day 
25-33)
Wk 6 
(Day 
39-47)
Wk 9 
(Day 
60-68)
Wk 12
(Day 
81-89)
EOTa
14 (+2) 
days after 
last dose
28 (+2) 
days 
after last 
dose
Unschb
Approximate Blood Volume
Urine or Serum 
Pregnancy Testc
1
1
-
-
-
1
-
1
1
1
1
1
-
8
Hematology and 
Serum 
Chemistrye
4
4
4
4
4
4
4
4
4
4
4
4
4
52
Serum or plasma 
for Aspergillus
Galactomannan 
EIA
1
1
1
1
1
1
1
1
1
1
1
1
1
13
Plasma 
Pharmacokinetic 
Assessmentd
-
0.35
-
0.7
0.7
0.7
0.7
0.7
0.7
0.35
-
-
0.7
5.6
eCRF=electronic case report form; EIA=enzyme immunoassay; EOT=End of treatment; IV=intravenous; PK=pharmacokinetics; POS=Posaconazole; Unsch.=unscheduled; 
WK=Week
a. Participants who discontinue study therapy before 12 weeks should have an EOT Visit within 3 days after the EOT. If the EOT Visit falls within the window for a regularly 
scheduled visit, the EOT Visit should occur instead of that regularly scheduled visit.
b. Blood sample collection at unscheduled visits should only be performed as clinically appropriate.
c. Blood volume applies to serum pregnancy test
d. Samples to be collected predose at Day 1 and Weeks 1, 2, 4, 6, 9, & 12. The Week 1 postdose PK sample is to be collected after a minimum of 7 days’ treatment with POS IV. 
For participants on IV formulation, additional samples to be collected within 15 minutes after the end of infusion at Weeks 1, 2, 4, 6, 9, & 12; for participants on either oral 
formulation who are hospitalized, additional samples to be collected between 3 and 6 hours postdose. If participant discontinues study treatment early, a PK sample is to be 
collected ≥8 and ≤24 hours after the last dose of study treatment, irrespective of formulation; however, if this timing is not feasible, a blood sample should be taken and the date 
and time of the previous POS dose, as well as the date and time of the blood sample, should be noted in the participant’s eCRF (additional details in Section 8.6).
e. If weight is <12 kg, the blood volume for each visit should be reduced in accordance with local guidelines for blood sample volumes to be collected from pediatric 
participants.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse:
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
- Grade 1: Mild; asymptomatic or mild 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 of hospitalization indicated; disabling; limiting self-
care ADL.
- Grade 4: Life threatening consequences; urgent intervention indicated.
- Grade 5: Death related to AE.
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Assessment of causality
●
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 product and the adverse event 
based upon the available information
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor's 
product caused the adverse event:
-
Exposure:  Is there evidence that the participant 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 studies 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
-
Dechallenge: Was the Sponsor's product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge. 
◦
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor's product; (3) the study is a single-dose drug study); or (4) Sponsor's 
product(s) is/are only used one time.)
-
Rechallenge:  Was the participant 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.
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(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study); or (3) Sponsor's 
product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS 
SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, 
OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL 
POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL 
DIRECTOR, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
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:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product.  (Also entered 
for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
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●
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each adverse event causality to the combination regimen or 
to a single agent of the combination.  In general, causality attribution should be assigned 
to the combination regimen (ie, to all agents in the regimen). However, causality 
attribution may be assigned to a single agent if in the investigator’s opinion, there is 
sufficient data to support full attribution of the adverse event to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
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•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Females of Childbearing Potential
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Females in the following categories are not considered females of childbearing potential:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in females not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
• Progestogen-only subdermal contraceptive implantb,c
• IUSc,d
• IUD
• Bilateral tubal occlusion
• Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the female of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. A spermatogenesis cycle is approximately 90 
days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Contraceptive use by males or females should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those 
which inhibit ovulation.
Male condoms must be used in addition to hormonal contraception.
IUS is a progestin-releasing IUD.
Note: The following are not acceptable methods of contraception:
-Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-Male condom with cap, diaphragm, or sponge with spermicide.
-Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable
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10.7
Appendix 7: Country-specific Requirements
South Korea:
•
Section 5.1, Inclusion Criterion 3: CSF galactomannan testing may be performed at 
the investigator’s discretion; however, in this case, there should be other supporting 
criteria to establish IA diagnosis and classification (Appendix 9).
•
Section 5.2, Exclusion Criterion 13: In South Korea, an individual who has calculated 
creatinine clearance < 50 mL/min/1.73 m2 (modified Schwartz formula) at screening 
will be excluded from participation.
Italy:
•
Section 1.3, Schedule of Activities: In Italy, ECGs are to be performed at each 
treatment visit (Screening, Day 1, Day 3, Week 1, Week 2, Week 4, Week 6, Week 9, 
Week 12, EOT, and Unscheduled). Investigators have the flexibility, based on their 
judgment, to perform ECGs more frequently if warranted.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living 
AE
adverse event 
ALT
alanine aminotransferase
APaT
all participants as treated (population)
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BID
twice daily
CAC
Clinical Adjudication Committee
Cavg
average plasma concentration
CI
confidence interval
Cmax
observed maximal concentration 
Cmin
observed minimal concentration
CNS
central nervous system 
CRF
Case Report Form 
CRU
clinical research unit
CSF
cerebral spinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale 
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
EEA
European Economic Area
EIA
enzyme immunoassay 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EOT
end of treatment
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration 
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
HRT
hormone replacement therapy
HSCT
hematopoietic stem cell transplant
IA
invasive aspergillosis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFI
invasive fungal infection
IND
Investigational New Drug 
IRB
Institutional Review Board 
IRT
Interactive Response Technology
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Abbreviation
Expanded Term
ITZ
itraconazole
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MTD
maximum tolerated dose 
NDA
New Drug Application 
NNRTIs
non-nucleoside reverse transcriptase inhibitors
PCR
polymerase chain reaction
PFS
gastro-resistant powder and solvent for oral suspension (formulation of posaconazole)
PK
pharmacokinetic
POS
Posaconazole
QD
once daily
QP2
(Sponsor’s department of quantitative pharmacology and pharmacometrics)
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
Tmax
time to maximum concentration
TNF-α
tumor necrosis factor-alpha
ULN
upper limit of normal
VOR
voriconazole
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10.9
Appendix 9: Criteria for Diagnosis of Invasive Aspergillosis
To determine if a potential participant meets the 2020 EORTC/MSG consensus criteria 
[Donnelly, J. P., et al 2020] for possible, probable, or proven invasive aspergillosis, use the 
criteria below.
A potential participant can be diagnosed as 
having…
…if they have:
PROVEN Invasive Aspergillosis
One of the required criteria
PROBABLE Invasive Aspergillosis
One host factor AND
One clinical criterion AND
One mycological criterion
POSSIBLE Invasive Aspergillosis
One host factor AND
One clinical criterion
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Criteria for Proven Invasive Aspergillosis

Tissue nucleic acid diagnosis: Amplification of fungal DNA by PCR combined 
with DNA sequencing when molds are seen in formalin-fixed paraffin-embedded tissue
OR

Microscopic analysis of sterile material: Tissue histopathologic, cytopathologic, or 
direct microscopic examination of a needle aspiration or biopsy specimen showing 
hyphal forms with evidence of associated tissue damage (either microscopically or as 
an infiltrate or lesion by imaging)a
OR

Culture of sterile material: 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, excluding 
BAL, paranasal or mastoid sinus cavity, and urine.
a: 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 (eg, 
calcofluor or blankophor).
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Evidence for Probable and Possible Invasive Aspergillosis Host Factors

Recent history of neutropenia (<0.5 × 109 neutrophils/L [<500 neutrophils/mm3]) 
temporally related to the onset of fungal diseasea.

Hematologic malignancy, ie, active malignancy, in receipt of treatment for this 
malignancy, and those in remission in the recent past. These patients would comprise 
largely acute leukemias and lymphomas.

Receipt of solid organ transplant.

Receipt of an allogeneic HSCT.

Treatment with other recognized T-cell immune suppressants, such as calcineurin 
inhibitors, tumor necrosis factor-a blockers, lymphocyte specific monoclonal 
antibodies, immunosuppressive nucleoside analogues during the past 90 days.

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 in the past 60 days.

Treatment with recognized B-cell immunosuppressants, such as Bruton’s tyrosine 
kinase inhibitors, eg, ibrutinib.

Acute graft-versus-host disease grade III or IV involving the gut, lungs, or liver that is 
refractory to first-line treatment with steroids.

Inherited severe immunodeficiency (such as chronic granulomatous disease, severe
combined immunodeficiency, or STAT 3 deficiency).
a: Modified from the 2020 EORTC/MSG consensus criteria: any duration of neutropenia 
is acceptable for possible criteria in this study.
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Evidence for Probable and Possible Invasive Aspergillosis Clinical Criteriaa

Pulmonary aspergillosis b
o
The presence of 1 of the following 4 signs on CT:

Dense, well-circumscribed lesions(s) with or without a halo sign

Air-crescent sign

Cavity

Wedge-shaped and segmental or lobar consolidation

Tracheobronchitis
o
Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on 
bronchoscopic analysis

Sinonasal disease
o
Acute localized pain (including pain radiating to the eye)
o
Nasal ulcer with black eschar
o
Extension from the paranasal sinus across bony barriers, including into the orbit

CNS infection
o
At least 1 of the following 2 signs:

Focal lesions on imaging

Meningeal enhancement on MRI or CT
a: Must be consistent with the mycological findings, if any, and must be temporally related 
to current episode.
b: Every reasonable attempt should be made to exclude an alternative etiology.
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Evidence for Probable Invasive Aspergillosis
Mycological Criteria

Direct test
o
Pulmonary disease

Aspergillus, recovered by culture from sputum, BAL, bronchial brush, 
or aspirate

Microscopical detection of fungal elements in sputum, BAL, bronchial 
brush, or aspirate indicating a mold
o
Tracheobronchitis

Aspergillus recovered by culture of BAL or bronchial brush

Microscopic detection of fungal elements in BAL or bronchial brush 
indicating a mold
o
Sinonasal diseases

Mold recovered by culture of sinus aspirate samples

Microscopic detection of fungal elements in sinus aspirate samples 
indicating a mold

Indirect tests (detection of antigen or cell-wall constituents)
o
Galactomannan detected in plasma, serum, BAL, or CSF

Any one of the following:

Single serum or plasma ≥1.0

BAL fluid ≥1.0

Single serum or plasma ≥0.7 with BAL fluid ≥0.8

CSF ≥1.0
o
Aspergillus PCR

Any one of the following:

Plasma, serum, or whole blood 2 or more consecutive PCR tests 
positive

BAL fluid 2 or more duplicate PCR tests positive

At least 1 PCR test positive in plasma, serum, or whole blood and 
1 PCR test positive in BAL fluid
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11
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