A Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous (IV) and Powder for Oral Suspension Formulations of Posaconazole (POS) in Immunocompromised Pediatric Subjects With Neutropenia
Phase: PHASE1
Conditions: Neutropenia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02452034
Document Date: 
10-May-2017
A Study of the Safety, Tolerability, and Pharmacokinetics of 
Intravenous (IV) and Powder for Oral Suspension Formulations of 
Posaconazole (POS) in Immunocompromised Pediatric Subjects 
with Neutropenia

Product:  MK-5592 
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Protocol/Amendment No.: 097-02 
MK-5592-097-02 Final Protocol
10-May-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A..
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous (IV) and Powder 
for Oral Suspension Formulations of Posaconazole (POS) in Immunocompromised Pediatric 
Subjects with Neutropenia
IND NUMBER:  75,061
EudraCT NUMBER:  2014-002807-10
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
2.1
Trial Diagram........................................................................................................ 20
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
Primary Objective(s) & Hypothesis(es) .............................................................. 22
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 22
3.2
Exploratory Objectives: ....................................................................................... 22
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
4.1
Pharmaceutical and Therapeutic Background .................................................... 23
4.1.1
Rationale................................................................................................................ 24
4.2
Rationale for the Trial and Selected Subject Population .................................... 24
4.2.1
Rationale for Dose Selection/Regimen............................................................... 25
4.2.2
4.2.2.1
Starting Dose for This Trial ......................................................................... 28
4.2.2.2
Maximum Dose/Exposure for This Trial..................................................... 29
4.2.2.3
Rationale for Dose Interval and Trial Design .............................................. 30
Rationale for Pharmacokinetic Targets............................................................... 30
4.2.3
Rationale for Endpoints ...................................................................................... 31
4.2.4
4.2.4.1
Efficacy Endpoints....................................................................................... 31
4.2.4.2
Safety Endpoints .......................................................................................... 31
4.2.4.3
Pharmacokinetic Endpoints ......................................................................... 32
4.2.4.4
Additional Endpoints ................................................................................... 32
4.2.4.5
Planned Exploratory Biomarker Research................................................... 32
4.2.4.6
Future Biomedical Research........................................................................ 32
5.0
METHODOLOGY ................................................................................................... 33
Entry Criteria........................................................................................................ 33
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 33
5.1.1
 
 
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Subject Inclusion Criteria.................................................................................... 33
5.1.2
Subject Exclusion Criteria .................................................................................. 34
5.1.3
Trial Treatment(s) ................................................................................................ 35
5.2
Dose Selection/Modification .............................................................................. 38
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 38
5.2.1.2
Dose Escalation............................................................................................ 38
Timing of Dose Administration .......................................................................... 38
5.2.2
Trial Blinding/Masking....................................................................................... 38
5.2.3
Treatment Allocation............................................................................................ 38
5.3
Stratification.......................................................................................................... 39
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 39
5.5
Medications Prohibited Prior to Study Drug Administration and During the 
5.5.1
Study Treatment Phase ....................................................................................... 39
Medications Allowed During the Study ............................................................. 40
5.5.2
Medications Allowed With Caution and Clinical Monitoring............................ 41
5.5.3
Rescue Medications & Supportive Care............................................................. 43
5.6
Diet/Activity/Other Considerations..................................................................... 43
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 43
5.8
Subject Replacement Strategy............................................................................. 44
5.9
Beginning and End of the Trial ........................................................................... 45
5.10
Clinical Criteria for Early Trial Termination ................................................... 45
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 46
PART 1: (Visits 1-14) SCREENING, BASELINE & POS IV SOLUTION 
6.1
VISITS ................................................................................................................... 46
PART 2: (VISITS 15-28) ORAL (PFS) TREATMENT AND FOLLOW-
6.2
UP VISITS............................................................................................................. 48
7.0
TRIAL PROCEDURES ........................................................................................... 50
Trial Procedures ................................................................................................... 50
7.1
Administrative Procedures.................................................................................. 50
7.1.1
7.1.1.1
Informed Consent......................................................................................... 50
7.1.1.1.1
General Informed Consent.................................................................... 50
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 51
 
 
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7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 51
7.1.1.3
Subject Identification Card .......................................................................... 51
7.1.1.4
Medical History ........................................................................................... 51
7.1.1.5
Prior and Concomitant Medications Review ............................................... 52
7.1.1.5.1
Prior Medications.................................................................................. 52
7.1.1.5.2
Concomitant Medications..................................................................... 52
7.1.1.6
Assignment of Screening Number............................................................... 52
7.1.1.7
Assignment of Randomization Number....................................................... 53
7.1.1.8
Trial Compliance (Medication).................................................................... 53
Clinical Procedures/Assessments........................................................................ 53
7.1.2
7.1.2.1
Physical Examination................................................................................... 53
7.1.2.2
Body Weight (kg) ........................................................................................ 53
7.1.2.3
Height (cm) .................................................................................................. 53
7.1.2.4
Vital Signs.................................................................................................... 54
7.1.2.5
Electrocardiogram........................................................................................ 54
7.1.2.6
Chest Radiograph......................................................................................... 55
7.1.2.7
IV Study Drug Administration/Infusion Site Examination ......................... 55
7.1.2.8
Oral Study Drug Administration (PFS) ....................................................... 55
7.1.2.8.1
Outpatient Administration of Oral Study Medication (PFS) ................ 56
7.1.2.9
Assessment of Palatability (Taste)............................................................... 57
7.1.2.10 Adverse Event Monitoring........................................................................... 57
7.1.2.11 Survival Assessment .................................................................................... 57
Laboratory Procedures/Assessments .................................................................. 57
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis & 
Other ............................................................................................................ 57
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 59
7.1.3.2.1
Blood Collection for Plasma Posaconazole Levels of MK-5592 ......... 59
7.1.3.3
Future Biomedical Research........................................................................ 59
Other Procedures................................................................................................. 60
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 60
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 60
7.1.4.2
Blinding/Unblinding .................................................................................... 60
 
 
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7.1.4.3
Calibration of Critical Equipment................................................................ 60
Visit Requirements.............................................................................................. 61
7.1.5
7.1.5.1
Screening...................................................................................................... 61
7.1.5.2
Baseline Visit............................................................................................... 62
7.1.5.3
Treatment Day(s) ......................................................................................... 62
7.1.5.3.1
POS IV Treatment Days ....................................................................... 63
7.1.5.3.2
POS PFS Treatment Days..................................................................... 64
7.1.5.4
Post-Trial/14 Day Follow-up....................................................................... 65
7.1.5.5
Survival Assessment .................................................................................... 65
7.1.5.6
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 66
Assessing and Recording Adverse Events .......................................................... 66
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 67
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 67
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 68
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 68
7.2.3.2
Events of Clinical Interest............................................................................ 69
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 69
Evaluating Adverse Events ................................................................................. 70
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 73
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 73
7.3
Data Monitoring Committee ............................................................................... 73
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 73
Statistical Analysis Plan Summary ..................................................................... 73
8.1
Pharmacokinetic Analyses .................................................................................. 74
8.1.1
Safety Analyses................................................................................................... 74
8.1.2
Efficacy Analyses ............................................................................................... 74
8.1.3
Power and Sample Size....................................................................................... 74
8.1.4
Statistical Analysis Plan ....................................................................................... 75
8.2
Pharmacokinetic Analysis Plan........................................................................... 75
8.2.1
Safety Analyses................................................................................................... 75
8.2.2
Efficacy Analyses ............................................................................................... 76
8.2.3
 
 
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Other Analyses.................................................................................................... 76
8.2.4
Power and Sample Size....................................................................................... 76
8.2.5
Interim Analysis.................................................................................................. 76
8.2.6
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 77
Investigational Product ........................................................................................ 77
9.1
Packaging and Labeling Information ................................................................. 77
9.2
Clinical Supplies Disclosure................................................................................. 77
9.3
Storage and Handling Requirements.................................................................. 77
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 78
9.5
Standard Policies................................................................................................... 78
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 78
Confidentiality....................................................................................................... 78
10.1
Confidentiality of Data ....................................................................................... 78
10.1.1
Confidentiality of Subject Records ..................................................................... 78
10.1.2
Confidentiality of Investigator Information........................................................ 79
10.1.3
Confidentiality of IRB/IEC Information............................................................. 79
10.1.4
Compliance with Financial Disclosure Requirements....................................... 79
10.2
Compliance with Law, Audit and Debarment ................................................... 80
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 82
10.4
Quality Management System............................................................................... 82
10.5
Data Management................................................................................................. 82
10.6
Publications ........................................................................................................... 82
10.7
11.0
LIST OF REFERENCES......................................................................................... 84
12.0
APPENDICES........................................................................................................... 85
Merck Code of Conduct for Clinical Trials........................................................ 85
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 87
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 93
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 102
List of Abbreviations .......................................................................................... 103
12.5
 
 
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13.0
SIGNATURES......................................................................................................... 106
Sponsor's Representative ................................................................................... 106
13.1
Investigator.......................................................................................................... 106
13.2
 
 
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LIST OF TABLES
Table 1
Number of Subjects per Cavg Range by Age group and Formulation for PK 
Evaluable Subjects in Dose Cohort #1 (3.5 mg/kg/d) and Dose Cohort #2 
(4.5 mg/kg/d) of MK-5592-097.............................................................................. 27
Table 2
Summary of Posaconazole Plasma Steady State Pharmacokinetic 
Parameters for Dose Cohort #1 (3.5 mg/kg/d) and Dose Cohort #2 (4.5 
mg/kg/d) by Age Group and Dose Formulation in PK Evaluable Subjects 
from MK-5592-097 ................................................................................................ 28
Table 3
Posaconazole Exposures at Steady State During Treatment with 
Posaconazole Oral Suspension from Pivotal Trials Supporting Safety and 
Efficacy in Adult Patients....................................................................................... 30
Table 4
Clinical Response Rates by Cavg Quartile Analyses from Pivotal Trials of 
POS Oral Suspension Supporting Safety and Efficacy in Adult Patients .............. 31
Table 5
Trial Treatment ....................................................................................................... 37
Table 6
Prohibited Medications Prior to Study Drug Administration and During the 
Study Treatment Phase........................................................................................... 40
Table 7
Medications Allowed During the Study that Require Monitoring ......................... 41
Table 8
Laboratory Tests ..................................................................................................... 58
Table 9
Evaluating Adverse Events..................................................................................... 71
Table 10 Product Descriptions .............................................................................................. 77
 
 
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LIST OF FIGURES
          
Figure 1
Study Trial Design .............................................................................................. 21
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number(s)
Section Title(s)
Description of Change(s)
Rationale
1.0;
2.1;
2.2;
4.2.1; 
4.2.2;
4.2.2.1;
4.2.2.2;
5.2;
8.1.4;
8.2.5
Trial Summary;
Trial Design;
Trial Diagram;
Rationale for the Trial and 
Selected Subject Population;
Rationale 
for 
Dose 
Selection/Regimen;
Starting Dose for This Trial;
Maximum Dose/Exposure for 
This Trial;
Trial Treatments;
Power and Sample Size;
Power and Sample Size
Addition of a third dose cohort 
(6 mg/kg) based on review of 
the PK data from Dose Cohort 
#1 (3.5
mg/kg) and Dose 
Cohort #2 (4.5 mg/kg) which 
have completed enrollment.
Based on interim analysis of 
the 
first 
2 
enrolled 
dose 
cohorts, the 4.5 mg/kg dose 
cohort (currently the highest 
dose cohort in the protocol) 
achieved 
exposures 
(as 
measured 
by 
mean 
Cavg
concentrations) 
that 
were 
significantly lower than the 
exposure seen in adult studies 
of the POS IV and tablet 
formulations. Therefore, in an 
effort to achieve systemic POS 
exposure more closely aligned 
with the exposure profile in 
adults,
a third dose cohort 
(6 mg/kg, Dose Cohort #3) is 
being added to the study.
 
 
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1.0;
2.1;
8.2.5
Trial Summary;
Trial Design;
Power and Sample Size
Addition of 36 subjects to the 
study to be enrolled in the 
newly added third dose cohort 
(6 mg/kg).
The 
number 
of 
subjects 
enrolled in this cohort is being 
increased from a minimum of 
24 subjects, as was enrolled in 
the initial two dose cohorts, to a 
minimum of 36 in order to 
generate a more robust safety 
database at the likely dose that 
will achieve sufficient PK 
exposures.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number(s)
Section Title (s)
Description of Change (s)
Rationale
Note: a few grammar edits were included throughout the protocol to enhance readability.
4.2.2.2
Maximum 
Dose/Exposure 
for This Trial
Additional 
description 
of 
300 mg/day as maximum 
dose.
Clarification of reasoning of the maximum dose 
choice.
5.1.2
Subject Inclusion Criteria
The 
following 
text 
was 
deleted 
from 
inclusion 
criterion 
#5: 
“Sexually 
active 
females
of 
childbearing potential must 
have 
a 
negative 
urine 
pregnancy test which must 
be followed up with a 
confirmed negative serum 
pregnancy 
test 
(β-HCG) 
within 48 hours following 
the screening visit.”
A serum pregnancy test is no longer required at 
Screening.
Pregnancy is listed as an exclusion 
criterion, and details of serum and urine test 
requirements are now clarified in Section 6.1, Trial 
Flow Chart Part 1, footnote e, and in Section 7.1.3, 
Laboratory Procedures/Assessments.
 
 
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6.1 (Part 1)
Trial Flow Chart Part 1: 
(Visits 1-14)
Footnote e, addition of the 
following language: If a 
serum pregnancy test is 
performed at screening and 
the baseline visit occurs 
more than 2 days after 
screening, 
the 
serum 
pregnancy test should be 
repeated at the baseline visit. 
If the baseline visit occurs 2 
days 
or 
less 
from 
the 
screening 
visit, 
serum 
pregnancy test is sufficient 
and a pregnancy test does 
not need to be repeated at 
the baseline visit. A urine 
pregnancy 
test 
may 
be 
substituted 
for 
a 
serum 
pregnancy 
test 
at 
the 
screening visit; however, if a 
urine pregnancy test is used 
for screening, it must be 
followed 
up 
with 
a 
confirmed negative serum 
pregnancy test within 48 
hours.
To 
provide 
clarification 
of 
pregnancy 
testing 
requirements at screening and baseline visits. And to
clarify that negative serum pregnancy test results are 
required before treatment.
6.1 (Part 1)
Trial Flow Chart Part 1: 
(Visits 1-14)
Addition of total protein to 
footnote f to align with 
Laboratory Tests in Table 8. 
In Section 7.1.3.1.
Correction of a typographical error; total protein was 
inadvertently left out of footnote f in the prior protocol 
version.
 
 
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6.2 (Part 2)
Trial Flow Chart Part 2: 
(Visits 15-28)
Addition of a check mark in 
the 
prior/concomitant 
medications 
row 
in 
the 
column for the Follow-up 14 
Days after End of Therapy 
(Visit 27).
Correction of a typographical error. The collection of 
concomitant medications is a required part of the 
safety follow-up per Section 7.1.1.5.2 of the protocol 
and the Data Entry Guidelines.
6.2 (Part 2)
Trial Flow Chart Part 2: 
(Visits 15-28)
Addition of total protein to 
footnote h
to align with 
Laboratory Tests in Table 6.
Correction of a typographical error, total protein was 
inadvertently left out of footnote f in the prior protocol 
version.
7.1.2.7
IV 
Study
Drug 
Administration/ 
Infusion 
Site Examination
Clarification of IV dosing: 
loading dose (BID) versus 
subsequent 
dosing 
(once 
daily dosing).
IV drug administration needed to be described with 
additional details.
7.1.3.1
Laboratory
Safety 
Evaluations, Table 8
Deletion 
of 
Urinalysis 
column 
and 
addition 
of 
pregnancy 
test 
footnote. 
Footnote added to 
state 
when urine pregnancy test 
may be used, and the need 
for 
a 
follow-up 
serum 
pregnancy test.
Clarification that urine pregnancy tests could be 
substituted for serum pregnancy tests at screening.
7.1.3.1
Laboratory
Safety 
Evaluations, Table 8
Addition 
of 
magnesium 
testing as part of chemistry 
testing.
Correction of a typographical error. Magnesium 
testing is included in the chemistry testing in Sections 
6.1 and 6.2 on the Trial Flow Chart (in footnotes f and 
h, respectively), but was inadvertently excluded from 
Table 8.
 
 
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7.1.5.1
Visit 
Requirements/Screening 
Electrocardiogram
Addition of the following 
text for clarification:
A single ECG or telemetry 
may be used to evaluate QTc 
for 
eligibility 
at 
the 
screening visit, however two 
12 lead ECGs performed 5 
minutes apart must be done 
at the Baseline Visit to 
confirm QTc criteria for 
study eligibility before study 
drug dosing occurs.
To provide clarification of the ECG testing 
requirements at the baseline and screening visits.
7.1.5.2
Baseline Visit
Addition of the following 
text for clarification:
Two 
12 lead 
ECGs 
performed 5 minutes apart 
must be done at the Baseline 
Visit to confirm QTc criteria 
for study eligibility before 
study drug dosing occurs.
Additional ECG information, including number and 
criteria.
7.1.5.2
Baseline Visit
Explanation 
of 
repeat 
pregnancy test.
Rationale for repeated pregnancy tests needed to be 
included in repeated laboratory tests.
 
 
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8.2.6
Interim Analysis
Description 
of 
interim 
analysis that was performed 
on first 2 dose cohorts, and 
statement that no formal 
interim analysis is planned 
for the third dose cohort.
The interim analysis was the basis for the addition of 
the 6 mg/kg dose cohort.
9.2
Packaging and Labeling
Text 
revised 
for 
clarification. The text in 
Section 9.2 in the first 
amendment states that on 
Day 1 subjects will be 
dispensed two vials for their 
dose of POS IV solution. 
The new text is as follows:
On Day 1 of POS IV 
solution, subjects will be 
dispensed 2 vials which are 
to be taken as 2 separate 
doses to be administered 12 
hours apart (BID). This will 
be followed by 1 vial daily 
on days 2-10, or until IV 
treatment is completed.
The text is being updated in order to clarify that on 
Day 1 subjects will receive 2 vials meant to be taken 
as 2 separate doses 12 hours apart and they are not to 
be taken together as one dose. Additional text added 
for clarification.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Safety, tolerability, & PK of IV & oral POS in immunocompromised 
children.
Trial Phase
1B
Clinical Indication
Prophylaxis of invasive fungal infections in immunocompromised 
pediatric subjects with neutropenia or expected neutropenia.
Trial Type
Interventional
Type of control
No treatment control
Route of administration
IV and oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Two treatment groups by age (which will enroll simultaneously): 
Age Group 1 (Young Children): 2 to < 7 years of age, and
Age Group 2 (Adolescents/Older Children): 7 to 17 years of age
Three dosing cohorts within each Age Group (which will enroll 
sequentially):

3.5 mg/kg/day (a minimum of 24 subjects across both age groups)

4.5 mg/kg/day (a minimum of 24 subjects across both age groups)

6 mg/kg/day (a minimum of 36 subjects across both age groups)
The maximum dose is 300 mg in all dose cohorts. Subjects that would 
receive >300 mg based on weight based dosing will receive 300 mg.
Note that earlier versions of the protocol (MK-5592-097-00 and 
01), included the first dose cohorts (3.5 and 4.5 mg/kg daily). These 
dose cohorts have completed enrollment. The third dose cohort (6 
mg/kg daily) is a new addition with this version of the protocol
(MK-5592-097-02).
Number of trial subjects
Approximately 84 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 
32 months from the time the first subject signs the informed consent 
until the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial for approximately 120 days, 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of 7 days, each 
subject will receive study drug for a maximum of 28 days.  The last 
study visit will be 14 days +/- 2 days after administration of the last 
dose of study drug. A survival assessment will be also performed 
anytime between Days 90 to 110.
Randomization Ratio
Non-randomized
A list of abbreviations used in this document can be found in Appendix 12.5.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a nonrandomized, multicenter, open-label, sequential dose-escalation study of the 
safety, tolerability, and PK of 2 posaconazole (POS, MK-5592) formulations in pediatric 
subjects: (1) an intravenous (IV), sulfobutylether-beta-cyclodextrin-containing (SBEβCD) 
formulation which is currently approved in adults (hereafter referred to as “POS IV 
solution”) and (2) powder for oral suspension prepared as a single-use powder for 
reconstitution (which has the same components contained within the adult-approved POS 
oral tablet; hereafter referred to as “POS PFS”). In this study, these 2 formulations will be 
administered to immunocompromised children and adolescents ages 2 years to 17 years with 
neutropenia or expected neutropenia (absolute neutrophil count <500/mm3). The study will
be conducted in conformance with Good Clinical Practices.
All subjects will be administered POS IV solution for a minimum of 10 days. Those subjects 
who are still neutropenic will then switch to oral treatment with the POS PFS for a minimum 
of 10 days; however, subjects may continue on POS IV solution beyond Day 10, if a subject 
cannot tolerate or refuses to take oral medication. Transition to POS PFS, rather than 
remaining on POS IV solution, is preferred.
Those subjects who complete at least 10 days of POS IV solution and are both willing and 
able to tolerate oral treatment will start on oral treatment the next day and will be 
administered POS PFS for a minimum of 10 days. Those subjects who continue on POS IV 
solution beyond Day 10 may transition to POS PFS at any time through Day 18 that they are 
able to tolerate oral medication, or they may complete study treatment with POS IV solution 
only. POS PFS may also be continued beyond 10 days of treatment if the subject remains 
neutropenic. However, the maximum total duration of POS, administered as either IV 
solution or POS PFS, is 28 days.
There will be two age groups in this study. Both age groups will enroll simultaneously. The 
original protocol, MK-5592-097-00, outlined the study of two dose cohorts, 3.5 mg/kg and 
4.5 mg/kg. At the time of this amendment, these dose cohorts, 3.5 mg/kg and 4.5 mg/kg, 
have completed enrollment. This protocol amendment, MK-5592-097-02, adds a third dose 
cohort, 6 mg/kg, based on the observed PK in Dose Cohort 1 and 2. See the Study Rationale 
in Section 4.2.2. Dose cohorts will enroll sequentially. Each POS formulation (IV and POS 
PFS) will be assessed separately within each dose cohort. If a dose cohort within a specific 
age group has an acceptable safety profile and does not achieve the target exposure for both
formulations, dosing will be escalated to the next dose cohort within that same age group.
The two age groups (Young Children [ages 2 - < 7 years; Age Group 1]; Adolescents/Older 
children [7 to 17 years; Age Group 2]) will enroll simultaneously:
 
 
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•
Age Group 1: Young Children (minimum of 36* subjects, age 2 to <7 years)
•
Dose Cohort #1: A minimum of 12 subjects will receive POS IV solution at 
3.5 mg/kg (maximum 300 mg/dose, 3.5 mg/kg IV BID on Day 1, then 
3.5 mg/kg IV once daily on Days 2-10). Thereafter, subjects will either 
proceed to POS PFS at 3.5 mg/kg (maximum 300 mg/dose) once daily or 
continue on POS IV solution, if they are unwilling or unable to tolerate POS 
PFS.
•
Dose Cohort #2: A minimum of 12 subjects will receive POS IV solution at
4.5 mg/kg (maximum 300 mg/dose, 4.5 mg/kg IV BID on Day 1, then 
4.5 mg/kg IV once daily on Days 2-10). Thereafter, subjects will either 
proceed to POS PFS at 4.5 mg/kg (maximum 300 mg/dose) once daily or 
continue on POS IV solution, if they are unwilling or unable to tolerate POS 
PFS.
•
Dose Cohort #3: A minimum of 12 subjects will receive POS IV solution at
6 mg/kg (maximum 300 mg/dose, 6 mg/kg IV BID on Day 1, then 6 mg/kg IV
once daily on Days 2-10), Thereafter, subjects will either proceed to POS PFS 
at 6 mg/kg (maximum 300 mg/dose) once daily or continue on POS IV 
solution, if they are unwilling or unable to tolerate POS PFS. 

Age Group 2: Adolescents/Older Children) (minimum of 36* subjects, age 7 
to 17 years)
•
Dose Cohort #1: A minimum of 12 subjects will receive POS IV solution at 
3.5 mg/kg (maximum 300 mg/dose, 3.5 mg/kg IV BID on Day 1, then 
3.5 mg/kg IV once daily on Days 2-10). Thereafter, subjects will either 
proceed to POS PFS at 3.5 mg/kg (maximum 300 mg/dose) once daily or 
continue on POS IV solution, if they are unwilling or unable to tolerate POS 
PFS.
•
Dose Cohort #2: A minimum of 12 subjects will receive POS IV solution at 
4.5 mg/kg (maximum 300 mg/dose, 4.5 mg/kg IV BID on Day 1, then 
4.5 mg/kg IV once daily on Days 2-10). Thereafter, subjects will either 
proceed to POS PFS at 4.5 mg/kg (maximum 300 mg/dose) once daily or 
continue on POS IV solution if they are unwilling or unable to tolerate POS 
PFS.
•
Dose Cohort #3: A minimum of 12 subjects will receive POS IV solution at
6 mg/kg (maximum 300 mg/dose, 6 mg/kg IV BID on Day 1, then 6 mg/kg IV
once daily on Days 2-10). Thereafter, subjects will either proceed to POS PFS 
at 6 mg/kg (maximum 300 mg/dose) once daily or continue on POS IV 
solution if they are unwilling or unable to tolerate POS PFS. 
*NOTE: In addition to the minimum of 72 subjects required to complete each of the 3 dose 
cohorts in the 2 age groups, for Dose Cohort #3, an additional 12 subjects will be enrolled 
 
 
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without regard to age group in Dose Cohort #3. Therefore, in total, a minimum of 84 subjects 
will be enrolled for the entire study.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted in Figure 1 below.
 
 
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Figure 1
Study Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To evaluate the pharmacokinetics (PK) of POS IV solution and POS PFS 
administered to immunocompromised pediatric subjects (ages 2 years to 17 years)
with neutropenia or expected neutropenia.
Estimation: The plasma pharmacokinetics profile [AUC, Cmax, Cmin, and Cavg] 
following administration of POS IV solution and POS PFS will be summarized by 
age group and dose cohort.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To evaluate the safety and tolerability of POS IV solution and POS PFS 
administered to immunocompromised pediatric subjects (ages 2 years to 17 years)
with neutropenia or expected neutropenia
Estimation:  Safety parameters will be summarized for each age group and dose 
cohort.
Exploratory Objectives:
3.3
1) Objective: To evaluate the palatability and acceptability of POS PFS
2) Objective: To evaluate the PK of sulfobutylether-beta-cyclodextrin (SBEβCD)
4.0 BACKGROUND & RATIONALE
Background
4.1
Posaconazole (POS) is a broad-spectrum triazole antifungal compound which exhibits potent
antifungal activity against a variety of yeasts and molds, including strains that are resistant to 
amphotericin B (AMB), fluconazole (FLZ), voriconazole (VOR), or itraconazole (ITZ).
POS has shown excellent in vitro activity when compared with ITZ, FLZ, VOR, and AMB 
against most of the more than 25,000 strains of yeasts and molds including FLZ-resistant 
(FLZ-R), VOR-resistant (VOR-R), ITZ-resistant (ITZ-R), and amphotericin B-resistant 
(AMB-R) strains. A global surveillance study focusing on Candida and Aspergillus isolates 
was conducted for an eight year period spanning 2001 to 2009: no major changes in 
susceptibility to POS were observed. Results in clinically relevant animal models of 
aspergillosis, candidiasis, and other serious fungal infections demonstrated the potential 
benefit of therapeutic and prophylactic administration of POS.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on POS.
 
 
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Pharmaceutical and Therapeutic Background
4.1.1
POS is a triazole antifungal compound for the treatment of serious fungal infections. POS, 
like other azoles, blocks the synthesis of ergosterol, a key component of the fungal 
membrane, through the inhibition of the enzyme lanosterol 14–demethylase (CYP51).
Several POS formulations have been developed for both oral and intravenous (IV) 
administration in adults. The current oral formulations for adults include the POS oral 
suspension (approved by the FDA in 2006) and the POS oral tablet (approved by the FDA in 
2013). POS oral suspension, an aqueous suspension containing 40 mg/mL of POS, was 
initially approved for use in adults for the prophylaxis and treatment of invasive fungal 
infections (IFI). The indications for POS oral suspension vary by country. POS oral 
suspension is commercially available in United States (US), the European Economic Area 
(EEA), Switzerland, and other regions of the world. 
The current IV formulation of POS, the POS IV solution, is an aqueous injectable 
cyclodextrin-based solution containing 18mg/ml of POS to be diluted with either 0.9% saline 
or 5 % dextrose solution prior to IV administration. It includes the solubilizer, 
sulfobutylether-beta-cyclodextrin (SBEβCD). POS IV solution has completed Phase III trials 
in adults. The IV formulation was granted approval for use in adults in the US in March 2014 
and was granted approval for use in adults by the Committee for Medicinal Products for 
Human Use (CHMP) of the European Medicines Agency (EMA) in September 2014.
The POS oral tablet, which contains 100 mg of POS per tablet interspersed with a 
pH-resistant polymer hypromellose acetate succinate (HPMCAS), has completed Phase III 
trials in adults and was granted approval for use in adults in the US in November 2013 and in 
the EU in April 2014. The current POS oral tablet is too large to be easily swallowed by 
young children. The Sponsor does not believe that a smaller strength tablet (e.g., 20 mg) will 
address the needs for the pediatric patient population for two key reasons: 1) a single-strength 
tablet that cannot be divided will not allow for weight-based dosing, which is the most 
appropriate means of dosing pediatric patients, and 2) such tablets would still need to be 
swallowed whole, which is a formidable task, particularly for younger children. However, an 
oral equivalent, such as a pediatric oral formulation containing POS (interspersed with 
HPMCAS polymer as a single-use powder for reconstitution (wherein the powder is mixed 
with liquid and then administered as an oral drink to the patient), could potentially fulfill the 
need. To this end, the Sponsor plans to utilize the same POS/HPMCAS intermediate 
developed for the POS tablet in a single-use powder for reconstitution (i.e., POS PFS) for use 
in pediatric patients. This represents a more age-appropriate and dose-flexible formulation 
platform to support pediatric clinical trials, while potentially offering similar benefits of 
improved absorption and PK as the POS tablet used in adults. 
The Sponsor has evaluated a prototype of the PFS formulation, a powder for oral suspension 
formulation, in an initial trial in adult healthy volunteers (PN106), comparing the PK of the 
POS oral powder formulation with the POS tablet. The trial completed in 4Q2012 and the 
Clinical Study Report (CSR) was finalized in June 2013. Final results demonstrate that this 
pediatric oral formulation has favorable pharmacokinetics (with plasma levels comparable to 
 
 
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those of the adult oral tablet), is well tolerated, and is not associated with major taste issues.
Pediatric dosing of the POS PFS was informed by results from this study based on the top 
potency of 300 mg.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Rationale for Current Trial
IFIs 
are 
a leading cause of infectious disease morbidity 
and mortality in 
immunocompromised patients. As in adults, the pediatric population at risk for developing 
IFI, primarily due to neutropenia and T-cell dysfunction, includes, but is not limited to 
allogeneic stem cell transplant (SCT) recipients, patients with acute leukemias, 
myelodysplasia, severe aplastic anemia, and advanced stage non-Hodgkin’s lymphoma. The 
incidence of IFI in pediatric patients with cancer ranges from 5% to 20%, but this incidence 
is higher in certain subgroups such as recipients of stem cell transplants (up to 16%), subjects 
with acute leukemia (10% to 20%), and subjects with acute myelogenous leukemia (9%) [1],
[2], [3], [4].
As a potent triazole antifungal agent with a wide spectrum of activity against both pathogenic 
yeasts and molds, POS may be useful in pediatric patients who are at risk for developing IFI. 
The decision to initiate prophylaxis for IFI is dependent on the underlying disease and the 
degree of immunosuppression of the patient. Currently, there is no standard of care for 
prophylaxis in this patient population. In the current Infectious Diseases Society of America 
(IDSA) Clinical Practice Guidelines for the Management of Candidiasis, POS is included in 
the list of agents recommended for prophylaxis of candidiasis in neutropenic patients;
however, there are no specific recommendations for pediatric patients. Furthermore, 
exposure to POS appears to be correlated with efficacy. Based on the available clinical 
efficacy data, the fact that candidiasis is the most common pediatric IFI and that the spectrum 
of activity of POS includes Aspergillus, the next most common pediatric IFI, the use of POS 
in the immunocompromised patient population is justified.
For pediatric patients, two new formulations of POS are under development: the POS IV
solution (same formulation as in adults) and the POS powder for oral suspension (PFS) 
formulation (containing similar components to those employed in the adult oral tablet). Both 
new formulations will potentially benefit the pediatric population. The POS IV solution may 
be used in hospitalized patients who are unable to tolerate oral intake or in whom there is 
concern for poor oral drug absorption. The POS PFS is anticipated to have a more favorable 
PK profile than the currently available POS oral suspension, based on data from adult studies 
evaluating the solid oral tablet. Given the potential benefit to pediatric patients, the new 
formulations merit study in this population. The study of both formulations is combined into 
one trial for two principal reasons. First, the transition of therapy from IV to oral 
administration when patients are able to tolerate oral therapy while still requiring antifungal 
prophylaxis reflects current clinical practice. Second, given the substantial challenges of 
enrolling trials in this pediatric patient population, evaluating both formulations in one study 
 
 
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may provide information beneficial to patients earlier than if the formulations were evaluated 
in 2 separate trials which would be competing for the same population.
The intention of this study is to collect pharmacokinetics (PK), safety, and tolerability 
information on POS administered as POS IV solution, followed by POS PFS to neutropenic 
pediatric subjects, or pediatric subjects who are expected to become neutropenic, and who 
are at risk of developing IFI. The subjects will range in age from 2 years to 17 years of age. 
This age range represents the pediatric population at risk of developing IFI for which data are 
lacking. The study design includes an assessment of safety for all treated subjects at each 
dose level for each age group employing rapid data collection and centralized analysis.
Rationale for Age Groups in this Study
As noted above, the intention of this study is to characterize the PK, safety, and tolerability
of the POS IV solution and the POS PFS in a prophylactic setting (namely, in neutropenic 
pediatric subjects who are at risk for developing IFI).
Presently there is no oral formulation of POS approved for pediatric patients <13 years of 
age. Therefore, the POS PFS (containing similar components to those employed in the adult 
oral tablet) is under investigation. 
The subjects in this study will range in age from 2 years to 17 years. The subject population 
will be divided into two age groups.
•
Young Children (Age Group 1) will be subjects 2 years to < 7 years,
•
Adolescents/Older Children (Age Group 2) will be subjects 7 years to 17 years.
Three dosage levels of POS are planned for each Age Group (3.5 mg/kg daily, Dose 
Cohort #1; 4.5 mg/kg daily, Dose Cohort #2; 6 mg/kg daily, Dose Cohort #3). Note that the 
original protocol, MK-5592-097-00, had Dose Cohorts #1 and #2, 3.5 and 4.5 mg/kg daily, 
respectively. The third dose cohort, 6 mg/kg daily, was added in amendment, 
MK-5592-097-02.
The study design includes an assessment for safety for all treated subjects at each dose level 
for each age group employing rapid data collection and centralized analysis.
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying Investigators Brochure (IB) and Informed Consent documents.
Rationale for Dose Selection/Regimen
4.2.2
Rationale for dose cohorts 1 and 2 included in original protocol version, MK-5592-097-00
The starting dose of 3.5 mg/kg/day for the POS IV solution and POS PFS formulation was 
projected via modeling and simulation to achieve the pharmacokinetic (PK) target of an 
average concentration (Cavg) of between 500 and 2500 ng/mL in approximately 90% of 
patients 2 to 17 years of age (see Section 4.2.3 for details regarding the PK target). In this 
 
 
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study, if at least 10 out of 12 PK-evaluable patients in a dose cohort achieve a Cavg in the 
specified range the PK exposure target will be considered to have been met.
Specifically, utilizing population PK models developed for the POS IV solution and the 
POS PFS formulation based on observed adult PK data, simulations were conducted to 
project the exposure in the pediatric population. The PK profile of the POS PFS formulation 
is expected to be comparable to the POS tablet, based on results of a biocomparison study 
conducted in adults. The PK concentration versus time profile in the pediatric population was 
projected by allometrically scaling model parameters by body weight, and simulating the 
resulting profiles, then calculating the distribution of projected Cavg values for each 
formulation for young children (2 to <7 years) and adolescents (7 to 17 years).
For the POS IV solution, a dose of 3.5 mg/kg/day was expected to result in 91% of young 
children (2 to <7 years) and 96% of adolescents/older children (7 to 17 years) with Cavg
values within the target range of 500 and 2500 ng/mL. For the POS PFS formulation, 85% of 
young children (2 to <7 years) and 90% of adolescents (7 to 17 years) were expected to 
achieve the PK target.
For the POS IV solution, a dose of 4.5 mg/kg/day was expected to result in 94% of young 
children (2 to <7 years) and 88% of adolescents/older children (7 to 17 years) with Cavg
values within the target range of 500 and 2500 ng/mL. For the POS PFS formulation, 90% of 
young children (2 to <7 years) and 86% of adolescents/older children (7 to 17 years) were 
expected to achieve the PK target.
Rationale for the addition of third dose cohort (6 mg/kg) in Amendment MK-5592-097-02
At the time of this amendment, MK-5592-097-02, the 3.5 mg/kg and 4.5 mg/kg dose cohorts 
have completed enrollment. Based on interim analysis, although the 4.5 mg/kg dose cohort 
achieved the primary PK target of ~90% of subjects having a steady state Cavg POS 
concentration between 500 and 2500 ng/mL for both the IV solution and oral PFS 
formulations in both age groups (see Table 1), the overall exposures (as measured by mean 
Cavg concentrations) were markedly lower than the exposure seen in adult studies of the POS 
tablet (see Table 2). Specifically in Age Group 1, mean Cavg values were approximately 
30-40% lower than what was seen in an adult study of the oral tablet (1080 ng/mL and 
976 ng/mL for the IV and PFS, respectively, compared with 1580 ng/mL for the tablet). 
Therefore, in an effort to achieve systemic POS exposure more closely aligned with the 
exposure profile in adults, a third dose cohort (6 mg/kg, up to a maximum of 300 mg) is 
being added to the study.
The selection of the 6 mg/kg/day for Dose Cohort #3 was supported by a modeling and 
simulation analysis, which predicted the geometric mean Cavg and the fraction of subjects
with Cavg falling within the target range of 500-2500 ng/mL at higher doses for each 
formulation and age group. Specifically, a population PK model was developed for the IV 
and PFS formulation based on observed pediatric PK data in Dose Cohorts 1 and 2 (3.5 and 
4.5 mg/kg, respectively) and simulations were conducted to project the exposure in the same 
pediatric age groups for each formulation at doses of 6 and 7.5 mg/kg.
 
 
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For the POS IV solution, a dose of 6 mg/kg/day is expected to result in 97% of subjects in 
Age Group 1 (2 to <7 years) and 87% of subjects in Age Group 2 (7 to 17 years) with Cavg
values within the target range of 500 and 2500 ng/mL Geometric mean Cavg values for IV are 
predicted to be 1343 ng/mL and 1651 ng/mL for Age Groups 1 and 2, respectively. For the 
POS PFS formulation, 83.5% of Age Group 1 (2 to <7 years) and 82% of Age Group 2 (7 to 
17 years) are expected to achieve the PK target. Geometric mean Cavg values for PFS are 
predicted to be 847 ng/mL and 1083 ng/mL for Age Group 1 and 2, respectively.
A dose of 7.5 mg/kg/day is predicted to result in less than 80% of Age Group 2 (7 to 
17 years) having Cavg values within the target range of 500 and 2500 ng/mL for either 
formulation. This is because a substantial fraction will have Cavg values above 2500 ng/mL 
indicating that this dose would result in too many subjects exceeding the PK target for this 
Age Group. Taken together, the simulations support that 6 mg/kg/day is the most appropriate 
dose to be used for both formulations across both age groups in Dose Cohort 3.
The primary PK driver for the addition of the third dose cohort (6 mg/kg, up to a maximum 
of 300 mg per administration) is the low Cavg values seen in Age Group 1 (2 years to <7 
years) (see Table 1). Age Group 2 (7 years to 17 years) will be included in Dose Cohort #3 in 
order to determine if it is possible to identify a single dose for both formulations that 
achieves adequate exposure across both Age Groups, since a single weight-based dose across 
all ages is preferable. Because the maximum dose is capped at the adult dose of 300 mg (BID 
Day 1 and once daily each successive day), the increase in exposure in Age Group 2 will be
limited because any subject 50 kg or heavier (most prevalent in the Adolescents/Older 
Children group) will receive a maximum dose of 300 mg/d.
Table 1
Number of Subjects per Cavg Range by Age group and Formulation for PK 
Evaluable Subjects in Dose Cohort #1 (3.5 mg/kg/d) and Dose Cohort #2 (4.5
mg/kg/d) of MK-5592-097
Dose
Age
Group
Dose
Type
N
<200
200 -
<500
500 -
<2500
2500 -
<3650
>3650
3.5 
mg/kg
1
(2 to <7 yrs 
old)
IV
11
0
2 (18%)
9 (82%)
0
0
PFS
5†
0
3 (60%)
2 (40%)
0
0
2
(7 to 17 yrs 
old)
IV
19†
0
0
18 (95%)
1 (5%)
0
PFS
10
0
1 (10%)
9 (90%)
0
0
4.5 
mg/kg
1
(2 to <7 yrs 
old)
IV
13
0
0
13 (100 %)
0
0
PFS
7†
0
1 (14%)
6 (86%)
0
0
2
(7 to 17 yrs 
old)
IV
14
0
0
13 (93%)
1 (7%)
0
PFS
8†
0
0
8 (100%)
0
0
†Due to subjects being at steady state, the predose value was assumed to be equal to C24hr for the 2 subjects
(for 3.5 mpk PFS), 1 subject (for 3.5 mpk IV) and 2 subjects (for 4.5 mpk PFS) missing the 24 hour PK 
sample and this value was used to replace the missing C24hr in order to calculate Cavg.
 
 
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Table 2
Summary of Posaconazole Plasma Steady State Pharmacokinetic Parameters for 
Dose Cohort #1 (3.5 mg/kg/d) and Dose Cohort #2 (4.5 mg/kg/d) by Age Group 
and Dose Formulation in PK Evaluable Subjects from MK-5592-097
Dose 
Cohort
Age 
Grou
p
Dose 
Type
N
Cmax
(ng/mL)
†
Tmax
(hr)‡
AUC0-24
(hr*ng/mL)†
C0
(ng/mL)†
Cmin
(ng/mL)†
Cavg
(ng/mL)†
1:  
3.5 
mg/kg
1
(2 to 
<7 yrs 
old)
IV§
11
1590 
(43.1)
1.78
(1.67 -
5.53)
17800 
(55.0)
424 
(82.4)
400
(81.3)
743
(55.0)
PFS§
5
884 
(44.4)
3.83
(1.92 -
4.25)
12300
(36.0)
262 
(40.4)
256
(45.4)
511 
(36.0)
2
(7 to 
17 yrs 
old)
IV
19
2450 
(72.7)
1.77
(0.00 -
3.50)
27300
(49.7)
802 
(90.4)
670 
(65.1)
1140
(49.7)
PFS
10
1340 
(30.8)
2.20
(1.92 -
6.03)
20700 
(33.7)
629 
(46.5)
579 
(44.9)
861
(33.7)
2:  
4.5 
mg/kg
1
(2 to 
<7 yrs 
old)
IV
13
2350 
(41.1)
1.75
(1.42 -
5.90)
25900 
(29.7)
536 
(62.9)
492
(59.0)
1080
(29.7)
PFS§
7
1590 
(43.5)
3.92
(1.88 -
5.92)
23400
(64.4)
615 
(174.3)
557 
(163.7)
976
(64.4)
2
(7 to 
17 yrs 
old)
IV
14
2380 
(40.1)
1.75
(1.52 -
1.80)
31500
(38.1)
882 
(57.3)
813 
(57.9)
1310
(38.1)
PFS
8
1670 
(28.5)
6.14
(1.98 -
7.98)
28700
(33.9)
827 
(54.3)
790
(48.2)
1190
(33.9)
†Geometric mean (%GCV); ‡median (min - max).  
§ Due to subjects being at steady state, the predose value was assumed to be equal to C24hr for the 2 subjects 
(for 3.5 mpk PFS), 1 subject (for 3.5 mpk IV) and 2 subjects (for 4.5 mpk PFS) missing the 24 hour PK 
sample and this value was used to replace the missing C24hr in order to calculate Cavg.
4.2.2.1
Starting Dose for This Trial
In this study, 3 different doses will be evaluated in 3 sequential cohorts, 3.5 mg/kg (Dose 
Cohort #1), 4.5 mg/kg (Dose Cohort #2), and 6 mg/kg (Dose Cohort #3). The starting dose is 
3.5 mg/kg.
All doses administered of the POS IV solution will be calculated based on the subject’s 
weight at Baseline. All doses administered of POS PFS will be calculated based on a
subject’s body weight as measured within 3 days prior to the first day of POS PFS treatment.
 
 
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Starting Dose for POS IV Solution:
The IV starting dose for this trial is 3.5 mg/kg in both age groups. For each subject, the IV 
solution will be given for the first 10 days, with a BID loading dose on Day 1, followed by 
once daily on Days 2-10. Thereafter, subjects should preferably switch to POS PFS (see 
below).
For subjects who are unable or unwilling to tolerate a transition to oral medication at Day 10 
of POS IV solution, the subjects may continue on POS IV solution and switch to POS PFS 
up through Day 18 at the discretion of the investigator or complete study treatment with POS 
IV solution.
Starting Dose for POS PFS: 
The oral PFS starting dose for this trial is 3.5 mg/kg in both age groups (after the subject 
completes at least 10 days of treatment with POS IV solution). For each subject, the POS 
PFS will be given once daily for 10-18 days. POS PFS may be continued beyond 10 days of 
treatment if the subject remains neutropenic.
In this study, the total maximum duration of POS, administered as either IV solution or PFS, 
is 28 days.
No comparator will be used in this trial. The primary goal of this study is to evaluate the PK 
of POS IV solution and POS PFS.
4.2.2.2
Maximum Dose/Exposure for This Trial
In this study, 3 different doses are to be studied. Two dosing cohorts have completed 
evaluation (3.5 mg/kg/day Dose Cohort #1, and 4.5 mg/kg/day Dose Cohort #2). A third 
Dose Cohort of 6 mg/kg/day (Dose Cohort #3), is to be the final dose cohort to be evaluated 
in this study.
Maximum dose by formulation:
POS IV solution:

6 mg/kg/day (up to a maximum of 300 mg) of POS administered as an IV solution on 
Days 1-10 (given BID on Day 1). Subjects may receive up to 28 days of POS IV 
solution if they are unable to transition to oral therapy (POS PFS).
POS PFS:

6 mg/kg/day POS (up to a maximum of 300 mg) after the subject completes at least 
10 days of treatment with POS IV solution. For each subject, the POS PFS will be 
given once daily for 10-18 days. POS PFS may be continued beyond 10 days of 
treatment if the subject remains neutropenic.

In this study, the total maximum duration of POS, administered as either IV solution 
or PFS, is 28 days.
 
 
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For a given subject, the maximum dose for an individual subject of either formulation is 
300 mg/day (following BID dosing on Day 1). No subjects will receive more than 
300 mg/day dosing (after 300 mg BID dosing on Day 1). The maximum total daily dosing 
established for this study reflects the approved adult dose for POS tablet and POS IV solution 
formulations, which is 300 mg BID on Day 1 followed by 300 mg once daily. Daily dosages 
above 300 mg/day will not be evaluated in this trial.
4.2.2.3
Rationale for Dose Interval and Trial Design
The dose interval and trial design were chosen based on target doses and PK profiles 
identified for adults enrolled in the POS IV solution and oral tablet studies. The duration of 
study therapy administration for each formulation is based on the minimum duration of POS 
required to achieve steady state (i.e., 7 – 10 days).
Rationale for Pharmacokinetic Targets
4.2.3
The minimum desired target level of the steady-state POS plasma concentration for this study 
is based on observations from earlier registration clinical trials conducted with the POS oral 
suspension in adult patients (Table 3).
Table 3
Posaconazole Exposures at Steady State During Treatment with Posaconazole 
Oral Suspension from Pivotal Trials Supporting Safety and Efficacy in Adult 
Patients
Mean Cavg
ng/mL
Lower Bound
2nd Quartile
ng/mL
99th
Percentile
ng/mL
Prophylaxis of IFIs (600 mg/day) 
    Neutropenic subjects (AML/MDS)
   GVHD subjects
583
1130
322
557
1920
3260
Treatment of IFIs (800 mg/day)
808
290
2990
Cavg = average plasma concentration; GVHD = graft-versus-host disease; IFI= invasive fungal infections; 
AML = acute myelogenous leukemia; MDS = myelodysplastic syndrome
In a controlled trial involving neutropenic adult subjects (study P01899), POS oral 
suspension was superior to standard azoles (fluconazole and itraconazole) in reducing the 
incidence of IFI, including aspergillosis and candidiasis, and in reducing 100-day all-cause 
mortality; in this study, the mean plasma concentration at steady state was 583 ng/mL. POS 
oral suspension was also found to be effective for the treatment of adult subjects with 
refractory IFI, including aspergillosis, and for the treatment of IFI in adult subjects who were 
intolerant to certain antifungals (study P00041). POS oral suspension showed a better 
response rate and survival benefit when compared to historical control cases; in this study, 
the mean plasma concentration was 808 ng/mL.
 
 
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There appeared to be an association between POS plasma concentration achieved with POS 
oral suspension at steady state and efficacy in these pivotal clinical trials.  In general, adult 
subjects with POS steady state exposures in the second quartile or higher had higher response 
rates than control (Table 4). Using these data and following receipt of regulatory guidance, a 
mean steady state Cavg exposure of approximately 1200 ng/mL with approximately 90% of 
subjects with values between 500 and 2500 ng/mL has been proposed as a target exposure for 
the POS pediatric program.
Since there is evidence that efficacy is correlated to exposure, with lower exposures being 
associated with poor outcomes, and the cumulative data to date does not suggest any 
toxicities are associated with Cavg >2500 ng/mL, the primary goal is to ensure that most 
pediatric subjects achieve a steady-state Cavg that is >500 ng/mL.
Table 4
Clinical Response Rates by Cavg Quartile Analyses from Pivotal Trials of POS 
Oral Suspension Supporting Safety and Efficacy in Adult Patients
CI98-316
Prophylaxis in GVHD
P01899
Prophylaxis in Neutropenia
(AML/MDS)
P00041
Treatment  - Aspergillosis
Quartile
Cavg Range
Clinical 
Failure
Cavg Range
Clinical 
Failure
Cavg Range
Clinical 
Success
Q1
21.5 – 557
44.4% 
28/63
89.6 – 322
54.7%
29/53
55 – 277
24%
4/17
Q2
557 – 915
20.6 %
13/63
322 – 490
37%
20/54
290 – 544
53%
9/17
Q3
915 – 1563
17.5%
11/63
490 – 734
46.3%
25/54
550 – 861
53%
9/17
Q4
1563 – 3650
17.5%
11/63
734 - 2200
27.8%
15/54
877 – 2010
71%
11/16
Control
--
35%
--
42%
--
26%
Shaded area = Targeted exposure in 90% of subjects
Cavg = average plasma concentration; GVHD = graft-versus-host disease; AML = acute myelogenous leukemia; MDS = myelodysplastic 
syndrome
Rationale for Endpoints
4.2.4
4.2.4.1
Efficacy Endpoints
There are no efficacy endpoints for this study.
4.2.4.2
Safety Endpoints
Safety will be assessed based on adverse events, physical examinations, vital signs, clinical 
laboratory test results, and electrocardiogram (ECG) results. All subjects who receive at least 
one dose of study treatment will be included in the safety analysis.
The occurrence of azole-associated toxicity will be evaluated.
 
 
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An external Data Monitoring Committee (eDMC) will be assembled at the onset of the study 
and will evaluate the accumulating available data for safety at the completion of Dose Cohort 
#1 for each age group, prior to each age group starting the next dosing group and at other 
time points as determined by the study team and eDMC.
4.2.4.3
Pharmacokinetic Endpoints
The primary endpoint will be Cavg for both the POS IV solution and POS PFS. The Cavg will 
be calculated by dividing the AUC with dosing interval. Additionally, Cmin, Cmax, Tmax, and 
AUC will also be calculated for patients in each age group per dose cohort.
4.2.4.4
Additional Endpoints
Palatability and acceptability parameters for the new POS PFS formulation will be assessed 
in all subjects (refer to Section 7.1.2.9 for further details of palatability assessment).
In addition, the PK of sulfobutylether-beta-cyclodextrin (SBEβCD) will also be assessed as 
an exploratory objective while on POS IV solution. This objective is included in support of a 
regulatory authority request to contribute data on pediatric cyclodextrin use, for which 
pediatric clinical trial data are lacking.
4.2.4.5
Planned Exploratory Biomarker Research
4.2.4.6
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on buccal swab DNA specimens 
collected during this clinical trial). Importantly, a subject may participate in the main trial 
without participating in the Future Biomedical Research portion of the study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
 
 
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5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male or female immunocompromised subjects who are between the ages of 2 years to 17 
years (inclusive) and have documented or anticipated neutropenia (ANC<500/mm3 [0.5 x 
109/L]) which is expected to last for at least 7 days following start of study treatment will be 
enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1) Be a child or adolescent of either sex and of any race, 2 to 17 years of age at the time 
of screening.
2) Have a parent/guardian or legally authorized representative who is willing to give 
written informed consent. Assent will be obtained from minors according to 
institutional practices. The guardian/subject may also provide consent/assent for 
Future Biomedical Research. However, the subject may participate in the main trial 
without participating in Future Biomedical Research.
3) Have documented or anticipated neutropenia (ANC < 500/mm 3 [0.5 x 109 /L]) 
expected to last for at least 7 days following start of study treatment in at least one of 
the following clinical situations:
a.
Acute leukemia,
b. Myelodysplasia,
c.
Severe aplastic anemia,
d. Recipients of Autologous HSCT,
e.
High risk neuroblastoma,
f.
Advanced stage non-Hodgkin’s lymphoma (NHL),
g. Recipients of allogeneic HSCT during the pre-engraftment (neutropenic) 
period,
h. Hemophagocytic lymphohistiocytosis
4) Must have a central line (e.g. central venous catheter, peripherally inserted central 
catheter, etc.) in place or planned to be in place prior to beginning IV study therapy.
 
 
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5) If the subject is of reproductive potential and is not surgically sterile (or their partner 
is not surgically sterile), must agree to remain abstinent* or use (or have their partner 
use) a medically accepted method of birth control starting from the time of consent 
through 1 month after the completion of the study. Acceptable methods of birth 
control‡ are: intrauterine device (IUD) with spermicide, diaphragm or cervical cap (if 
acceptable to local standard of care) with spermicide, contraceptive sponge with 
spermicide, condom with spermicide, and any registered and marketed hormonal 
contraceptive that contains an estrogen and/or progestational agent, including oral, 
subcutaneous, intrauterine or intramuscular agents that is used with a barrier method.
*
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.
‡
If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1) Has a proven or probable IFI, as defined by the 2008 European Organization for 
Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus 
group criteria, at the time of screening.
2) Has received POS (any formulation) within the past 10 days prior to screening.
3) Is receiving prohibited drugs (has not met the required washout periods as listed in 
Section 5.5.1) at the time of randomization or is expected to receive such prohibited 
medications during the course of study therapy.
4) Has laboratory results that are outside of normal limits at screening, as follows:
a) Moderate or severe liver dysfunction, as defined as:
•
Aspartate aminotransferase (AST) > 5 times the upper limit of normal (ULN),
OR
•
Alanine aminotransferase (ALT) > 5 times the ULN, OR
•
Serum total bilirubin >2.5 times the ULN, OR
•
AST or ALT > 3 times ULN with total bilirubin > 2 times ULN,
 
 
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b) Calculated creatinine clearance <30 mL/min. Creatinine clearance will be 
calculated using the following equation:
Creatinine clearance =    k X height (cm)
Serum creatinine (mg/dL)
Where k = 0.55 for male and female children 1-13 years old; k = 0.7 for 
adolescent males 13-18 years old, k= 0.55 for adolescent females 13-18 years old; 
(Schwartz equation)
5) Has QTc prolongation (either based on Fridericia or Bazett’s correction) at screening 
defined as :
a) Symptomatic QTc prolongation >450 msec (males) or >470 msec (females)
OR
b) Any QTc prolongation of >500 msec
6) Is pregnant or intends to become pregnant during the course of the study, or is 
breastfeeding at screening.
7) Has a history of anaphylaxis attributed to the azole class of antifungal agents.
8) Has any clinically significant condition or situation, other than the condition being 
studied that, in the opinion of the investigator, would interfere with the study, 
evaluations or optimal participation in the study including:
a) Not expected to receive a minimum of 10 days of POS IV solution
9) Has previously participated in this study
10) Has participated in any Phase 1 clinical study for a medication classified as an
Investigational New Drug (IND) within 30 days prior to enrollment or is expected to 
participate in such a study within 60 days following randomization. Participation in 
non-IND studies is permitted.
11) Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
5.2
POS study drug will be administered to patients with neutropenia associated with
chemotherapy given for a diagnosis of acute leukemia (newly diagnosed or relapsed), 
myelodysplasia, severe aplastic anemia, high risk neuroblastoma, advanced NHL, or 
hemophagocytic lymphohistiocytosis. In addition, recipients of an autologous HSCT or 
recipients of autologous HSCT during the pre-engraftment (neutropenic) period are eligible.
 
 
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The subject population will be divided into 2 age groups. Age Group 1 will be Young 
Children, who are aged 2 years to <7 years of age, and Age Group 2 will be 
Adolescents/Older Children, who are aged 7 to 17 years of age. 
The two formulations will be studied in all subjects in a sequential manner (POS IV solution, 
followed by POS PFS formulation). There will be three pre-specified dosage cohorts in this 
study. The decision to move to the next higher dose cohort may be done independent of 
complete enrollment of the other age group.
The first dosage cohort (Dose Cohort #1) will receive 3.5 mg/kg (up to a maximum of 
300 mg) BID of POS IV solution on Day 1, followed by 3.5 mg/kg/day (up to a maximum of 
300 mg) of POS IV solution administered once daily from Day 2 through Day 10; thereafter, 
treatment with the POS PFS formulation at a dose of 3.5 mg/kg/day will be initiated and 
administered for at least 10 additional days. Subjects who are unwilling or unable to tolerate 
a transition to oral therapy after Day 10 may continue on POS IV solution at the discretion of 
the investigator. Subjects who continue on POS IV solution beyond Day 10 may (a) 
transition to POS PFS at any time up through Day 18 that they are able to tolerate oral 
medication, or (b) complete study treatment with POS IV solution only. POS PFS may also 
be continued beyond 10 days of treatment if the subject remains neutropenic. The total 
maximum duration of POS, administered as either IV solution or PFS, is 28 days.
Preliminary PK data for each formulation will be reviewed upon completion of the first 
dosage cohort. If the PK exposure target is achieved in an age group in Dose Cohort #1, and 
an appropriate pediatric dose can be determined for both formulations, then the second 
dosage cohort may not be enrolled for that age group.
The second dosage cohort (Dose Cohort #2) will receive 4.5 mg/kg (up to a maximum of 
300 mg per administration) BID POS IV solution on Day 1, followed by 4.5 mg/kg/day of 
POS IV solution administered once daily from Day 2 through Day 10; thereafter, treatment 
with the POS PFS formulation at a dose of 4.5 mg/kg/day will be initiated and administered 
for at least 10 additional days. Subjects who are unwilling or unable to tolerate a transition to 
oral therapy after Day 10 may continue on POS IV solution at the discretion of the 
investigator. Subjects who continue on POS IV solution beyond Day 10 may (a) transition to 
POS PFS at any time up through Day 18 that they are able to tolerate oral medication, or (b) 
complete study treatment with POS IV solution only. The total maximum duration of POS, 
administered as either IV solution or PFS, is 28 days. The dose chosen for Dose Cohort #2
may be modified prior to enrollment based on preliminary review of PK data from the Dose 
Cohort #1 in order to optimize the achievement of the desired PK target.
The third dosage cohort (Dose Cohort #3) will receive 6 mg/kg (up to a maximum of 
300 mg) BID POS IV solution on Day 1, followed by 6 mg/kg/day (up to a maximum of 
300 mg) of POS IV solution administered once daily from Day 2 through Day 10; thereafter,
treatment with the POS PFS formulation at a dose of 6 mg/kg/day will be initiated and 
administered for at least 10 additional days. Subjects who are unwilling or unable to tolerate 
a transition to oral therapy after Day 10 may continue on POS IV solution at the discretion of 
the investigator. Subjects who continue on POS IV solution beyond Day 10 may 
(a) transition to POS PFS at any time up through Day 18 that they are able to tolerate oral 
 
 
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medication, or (b) complete study treatment with POS IV solution only. The total maximum 
duration of POS, administered as either IV solution or PFS, is 28 days.
The POS study treatments to be used in this trial are outlined below in Table 5.
Table 5
Trial Treatment
POS IV Solution Treatment Period
(minimum 10  days)
POS PFS Oral Treatment 
Period
(minimum 10 days)
Day 1
Day 2 through end of 
IV dosing
Age Group 1
Young Children  
(2 to  < 7 years old)
Dose 
Cohort # 1
3.5 mg/kg BID 
POS IV solution*
3.5  mg/kg once daily
POS IV solution*
3.5 mg/kg once daily
POS PFS *
Dose 
Cohort # 2
4.5 mg/kg BID 
POS IV solution*
4.5 mg/kg once daily
POS IV solution*
4.5 mg/kg once daily
POS PFS*
Dose 
Cohort # 3
6 mg/kg BID POS 
IV solution*
6 mg/kg once daily
POS IV solution*
6 mg/kg once daily
POS PFS*
Age Group 2
Adolescents/Older 
Children
(7 to 17 years old)
Dose 
Cohort # 1
3.5 mg/kg BID 
POS IV solution*
3.5 mg/kg once daily 
POS IV solution*
3.5 mg/kg once daily
POS PFS*
Dose 
Cohort # 2
4.5 mg/kg BID 
POS IV solution*
4.5 mg/kg once daily
POS IV solution*
4.5 mg/kg once daily
POS PFS*
Dose 
Cohort # 3
6 mg/kg BID POS 
IV solution*
6 mg/kg once daily
POS IV solution*
6 mg/kg once daily
POS PFS*
*Maximum dose of 300 mg per administration

Young children (Age Group 1, ages 2 to <7 years) and adolescents/older children Age Group 2, (ages 7-17 years) 
will be enrolling in parallel.

The duration of POS IV solution treatment may be extended beyond 10 days if subjects are unwilling or unable to 
transition to POS PFS.

The combined duration of POS treatment, either as POS IV solution or POS PFS, for each subject cannot exceed 28
days

Safety and PK data will be assessed separately for each dose cohort in 2 age groups.

Potential modifications to dosing based on preliminary study data are outlined in Section 4.2.2.
Trial Treatment should begin within 7 days of the screening visit. Subjects will receive a 
minimum of 10 days of POS IV solution. POS will be administered intravenously over 
approximately 1.5 hours via a central line. 
All supplies indicated in Table 5 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
 
 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
All doses of POS IV solution will be based on the subject’s age and the actual body weight as 
measured at Baseline (prior to receiving the first IV dose of POS). The IV dose will remain 
the same for all subsequent IV doses (through Day 10, or beyond Day 10, for subjects unable 
or unwilling to transition to POS PFS).
All doses of POS PFS will be based on the subject’s age and the actual body weight as 
measured on the first day of oral treatment (prior to receiving the first dose of POS PFS) or 
the subject’s weight within 3 days prior to the first dose of PFS. The oral dose will remain 
the same for all subsequent oral doses.
Doses should be continued through each treatment period as outlined in Table 5.
The rationale for the selection of doses to be used in this trial is provided in Section 4.2.2.
5.2.1.2
Dose Escalation
There is no dose escalation in this study for individual subjects. Dose escalation will be 
performed at the completion of each age group and dose cohort, for the subsequent dose 
cohort as outlined in Table 5.
Timing of Dose Administration
5.2.2

Each dose of POS IV solution will be administered approximately 12 hours apart 
on Day 1 and every 24 hours thereafter during IV treatment.

Each dose of POS PFS will be administered every 24 hours during the oral 
treatment period. POS PFS will be administered without regard to food intake;
however, information about food intake will be recorded in a food diary as 
outlined in Section 7.1.2.8.

Serial PK samples will be obtained prior to dosing or within 24 hours after the last 
dose of study drug administration for early discontinuation.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
study treatment administered.
Treatment Allocation
5.3
Subjects participating in this trial will be allocated by non-random assignment.
 
 
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Stratification
5.4
Treatment allocation will be stratified according to the following factors:
1. Age Group 1 (Young Children): 2 years to < 7 years of age
2. Age Group 2 (Older Children/Adolescents): 7 years to 17 years of age
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
All prior medication taken by the subject 14 days prior to study treatment initiation and all
medications (including chemotherapeutic medications) taken during study treatment, or 
during the 14 day safety follow-up period following therapy will be recorded on the 
appropriate electronic Case Report Form (eCRF). The identity of the therapy, the dates 
started or 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 subjects 
medical history.
Patients receiving other systemic (PO or IV) antifungal agents as prophylactic therapy must 
discontinue those treatments prior to study drug administration. No other systemic antifungal 
agents may be administered during the POS treatment phase without Sponsor approval.
In addition, nasal sprays of amphotericin B (AMB) and aerosolized AMB are viewed as 
systemic regimens and are prohibited during IV/oral POS study therapy (treatment phase). If 
subjects are on such treatment before study entry, such drugs must be discontinued prior to 
study drug administration. 
Topical non-absorbable antifungals may be used for the prophylaxis or treatment of 
oropharyngeal candidiasis, vaginal candidiasis, or cutaneous fungal infection. These include
the following medications: oral AMB, miconazole (oral or topical), nystatin (oral or topical), 
and clotrimazole (oral or topical). All other antifungal therapies must be approved by the 
Sponsor prior to use.
Investigational drugs under an IND (i.e., other drugs not yet approved for marketing by the 
FDA or local health authorities) administered in the 30 days prior to randomization are 
prohibited. Such investigational agents are also prohibited for 60 days following 
randomization.
Subjects should be monitored for 14 days after the last dose of POS for AEs, and all AEs 
should be reported in the eCRF.
Medications Prohibited Prior to Study Drug Administration and During the 
5.5.1
Study Treatment Phase
The medications prohibited prior to study drug administration and during the treatment phase 
of the study are listed in Table 6. This table also lists the recommended washout periods to be 
 
 
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observed for these prohibited medications prior to initiation of POS treatment. The washout 
period for POS after discontinuation is approximately 7 days.
Table 6
Prohibited Medications Prior to Study Drug Administration and During the Study 
Treatment Phase
Prohibited Medications During the Study Treatment Phase and Prior to Study 
Drug Administration
Minimum Washout 
Perioda
Other systemic antifungal therapy (oral, intravenous or nasal/inhaled) for the 
treatment of invasive fungal infections (IFI)
30 days
Other systemic antifungal therapy (oral, intravenous, or nasal/inhaled) for the 
prophylaxis of IFI
No washout required
Medications that are known to interact with azoles and may lead to life-threatening 
side effects:  astemizole, cisapride, ebastine, halofantrine, pimozide, quinidine, and 
terfenadine
10 days (astemizole)
24 hours (others)
Medications known to lower the serum concentration/efficacy of azole antifungals:  
barbiturates, carbamazepine, cimetidine, isoniazid, phenytoin, rifabutin, rifampin, 
and St. John’s Wort (hypericum perforatum)
24 hours
Vinca alkaloids (vincristine, vinblastine, or other licensed or investigational 
members of this class)
48 hours
Ergot alkaloids (ergotamine, dihydroergotamine or other licensed or investigational 
members of this class)
2 days
Sirolimus (CYP3A4 substrate)
48 hours
Anthracycline-based chemotherapy 
24 hours
Investigational drugs (new chemical or biological entities as part of an IND)
30 days
Trisenox (arsenic trioxides)
30 days
Disopyramide
4 days
Bepridil
10 days
Ibutilide
3 days
Haloperidol
10 days
HMG-CoA reductase inhibitors metabolized via CYP3A4 (e.g., simvastatin, 
lovastatin and atorvastatin)
24 hours
Cyclophosphamide
24 hours
Specific antiretroviral agents for the treatment of HIV including atazanavir, 
efavirenz, fosamprenavir, or ritonavir
24 hours
Kayexalate (sodium polystyrene sulfonate) b
No washout required
CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; QTc = QT interval corrected for rate; 
TdP = torsades de pointes.
a
These waiting times should be observed prior to study drug administration in subjects receiving a prohibited 
drug as prior therapy. No concurrent use of prohibited medications is permitted.  Deviations from these washout periods 
must be approved by the Sponsor prior to use of study drug or prohibited agent.
b
Administration of Kayexalate prohibited during oral (PFS) treatment phase only
Medications Allowed During the Study
5.5.2
All medications not listed in Table 6 are permitted in the study. Specific medications that are 
allowed with caution and/or monitoring are presented in Table 7.
 
 
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Medications Allowed With Caution and Clinical Monitoring
5.5.3
Clinical and/or QTc monitoring is recommended when the study drug is coadministered with 
one of the following drugs that have reported a potential risk of torsades de pointes: 

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 7. 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 drug, periodically during treatment, and after discontinuation of study drug:
Table 7
Medications Allowed During the Study that Require Monitoring
Medication Class
Medication Name*
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 drug, 
periodically during treatment, and after discontinuation of 
study drug.
Antiretroviral Therapy
Tenofovir
As HIV protease inhibitors and non-nucleoside reverse 
transcriptase inhibitors (NNRTIs) are CYP3A4 substrates, 
it is expected that POS will increase plasma levels of these 
antiretroviral 
agents. 
Patients 
should 
be 
carefully 
monitored for any occurrence of toxicity during the 
coadministration of POS and these agents. NOTE: 
Coadministration of POS with atazanavir, efavirenz, 
fosamprevanir, or ritonavir is not permitted during the 
treatment phase of the study.
 
 
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Medication Class
Medication Name*
Recommendation
Benzodiazepines
Alprazolam
Midazolam
Triazolam
POS 200 mg orally once daily increased the AUC of 
midazolam 
by 
83% 
following 
intravenous 
(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 
(e.g., 
diltiazem, 
nifedipine, 
nisoldipine, 
verapamil), frequent monitoring for AEs and toxicity 
related to calcium channel blockers is recommended 
during co-administration 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
Immunosuppressive
Cyclosporine
In heart transplant patients on stable doses of cyclosporine, 
POS 200 mg once daily 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 
upon 
initiation, 
during 
coadministration, and upon discontinuation of POS 
treatment, with adjustment of cyclosporine doses as 
necessary.
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 patients already receiving tacrolimus, the dose of 
tacrolimus dose should be reduced (e.g., to about one third 
of the current dose). Thereafter, blood levels of tacrolimus 
should be monitored carefully during coadministration, 
and upon discontinuation of POS, and the dose of 
tacrolimus should be adjusted as necessary.
Oral 
Hypoglycemic 
Agents/Sulfonylureas
Glipizide
Glucose concentrations decreased in some healthy subjects 
when glipizide was coadministered with POS.  Monitoring 
of glucose concentrations is recommended in diabetic 
patients.
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 drug, periodically during 
treatment, and after discontinuation of study drug.
* Not all medications from a specific medication class may be listed here.
 
 
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Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
There are no diet or activity restrictions for this study. Information on food intake relative to 
dose administration will be collected during the oral (PFS) phase of the study in a study 
medication/food diary. The data collected will include the time the dose was administered, 
the type of meal that was consumed (if any) and the timing of the meal relative to study 
medication administration.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Death;
In this trial, a subject may discontinue from treatment, but continue to participate in the 
regularly scheduled activities of the study as long as the subject does not withdraw consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

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;

Failure to comply with the dosing, evaluations, or other requirements of the study;

Request of the subject or subject’s parent or legally authorized representative 
(subjects have the right to discontinue treatment or the study at any time for any 
reason);

The subject has a confirmed positive serum pregnancy test;

Initiation of other systemic (IV, oral, or nasal/inhaled) antifungal agents for empiric, 
pre-emptive or definitive therapy of IFI, including agents containing amphotericin B 
 
 
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(AMB), echinocandins, azole and triazole antifungal agents, or other investigational 
antifungal drugs;

Subjects who, following Baseline require any of the prohibited medications listed in 
Table 6 of Section 5.5.1;

Any situation or condition which may threaten the subject’s health or well-being by 
continuing on study treatment;

Administrative (e.g. study termination);

An AST or ALT value that is greater than or equal to 3 X the ULN and an elevated 
total bilirubin value that is greater than or equal to 2 X the ULN and, at the same 
time, an alkaline phosphatase value that is less than 2 X the ULN, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.  
NOTE: Patients will be discontinued from study therapy but followed for safety until 
the abnormal value(s) has/have normalized, stabilized, or returned to baseline;

If the QTc interval change from Baseline is greater than 60 msec or the QTc interval 
is >500 msec (refer to Section 7.1.2.5 for details on ECG testing).
A subject who develops a superficial fungal infection (e.g., cutaneous fungal infection, thrush 
or candidal vaginitis) may be treated with topical antifungal agents (nystatin and/or azole 
formulations) and continued on study drug if in the judgment of the investigator there is no 
evidence of systemic involvement or more extensive mucosal involvement that would require 
more specific systemic antifungal therapy. Superficial candidiasis (including signs and 
symptoms and supportive laboratory findings) must be noted on the eCRF. It is the right and 
duty of the investigator or subinvestigator to interrupt treatment of any subject if he/she feels 
that study discontinuation is necessary to protect the subject, or that there are unmanageable 
factors, that may interfere significantly with the study procedures or interpretation of the 
results.
If a subject discontinues prior to completion of the study, the reason for the discontinuation 
will be obtained. The date of the last dose of study medication and the date of the last 
assessment and/or contact will be obtained. This information will be documented in the 
appropriate section of the eCRF. A follow-up contact (telephone or visit) will be arranged as 
appropriate.
At the time of discontinuation, every effort should be made to ensure all procedures and 
evaluations scheduled for the final study visit are performed (see Section 6.0, Trial Flow 
Chart). For all discontinued subjects, a trough sample should be collected within 24 hours of 
the last dose, AEs should be recorded and followed to outcome and medication compliance 
should be assessed.
Subject Replacement Strategy
5.9
If a subject in a given dose cohort and age group fails to complete 7 days of IV study therapy, 
a replacement subject will be entered at that dose cohort and age group. Subjects will not be 
re-enrolled in this study.
 
 
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Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
The Trial Flow Chart for this study has been split into two parts:
Part 1: Screening and POS IV solution treatment phase of the study (Visits 1-14)
Part 2: POS PFS and Follow-up Phases of the study (Visits 15-28)
PART 1: (Visits 1-14) SCREENING, BASELINE & POS IV SOLUTION VISITS
6.1
POS IV SOLUTION
TREATMENT PHASE
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Title:
Screening
Baseline
Day 
1
Day 
2
Day 3
Day 4
Day 5
Day 6
Day 
7
Day 
8
Day
9
Day 10 
Optional Use 
of POS IV 
Solution 
Day 11-28
Last Day of 
POS IV 
Solutiona
Scheduling window
Day -7 to < 
Day -1
Day-1
Administrative Procedures
Visits 15 - 28 
Continue on next 
table  (Part 2)
Obtain Informed Consent/Assent
X
Informed Consent for Future 
Biomedical Research (optional)
X
Review Inclusion/Exclusion 
Criteria
X
X
Issue Subject Identification Card
X
Medical History
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening Number Assignment
X
Randomization Number 
Assignment
X
Clinical 
Procedures/Assessments
Visits 15 - 28 
Continue on next 
table  (Part 2)
Complete physical examination
X
X
Focused  physical examinationb
X
X
X
X
X
Xb
X
Body Weight (kg)
X
X
Height (cm)
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogramc
X
Xc
Chest Radiographd
X
IV Study Drug Administration
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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POS IV SOLUTION
TREATMENT PHASE
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Title:
Screening
Baseline
Day 
1
Day 
2
Day 3
Day 4
Day 5
Day 6
Day 
7
Day 
8
Day
9
Day 10 
Optional Use 
of POS IV 
Solution 
Day 11-28
Last Day of 
POS IV 
Solutiona
Scheduling window
Day -7 to < 
Day -1
Day-1
Laboratory 
Procedures/Assessments
Pregnancy Test (Serum) e
X
X
Hematology/Serum Chemistry f, g
X
Xf
Xg
Xg
Xg
Xg
X
Absolute Neutrophil Count h
X
Xh
Xh
Xh
Xh
Xh
X
POS PK Trough Sampling i, j
Xi
Xj
POS Full PK Sampling k
Xk
Cyclodextrin (SBEβCD) PK 
samplingl
Xl
DNA/Buccal swab for Future 
Biomedical Research (optional)m
X
a. The last day of POS IV solution can occur anytime between the 10th and the 18 day of treatment with POS IV solution.
b. After Day 1, the focused physical exam should be performed 3 times per week until the last day of POS IV
c.
ECG may be performed on Day 6, 7, or 8
d. As clinically indicated to rule out fungal infection.
e. Pregnancy test will be done on females of childbearing potential. If a serum pregnancy test is performed at screening and the baseline visit occurs more than 2 days after screening, the serum pregnancy 
test should be repeated at the baseline visit. If the baseline visit occurs 2 days or less from the screening visit, serum pregnancy test is sufficient and a pregnancy test does not need to be repeated at the 
baseline visit. A urine pregnancy test may be substituted for a serum pregnancy test at the screening visit; however, if a urine pregnancy test is used for screening, it must be followed up with a 
confirmed negative serum pregnancy test within 48 hours.
f.
Hematology:  complete blood count (CBC) with differential; serum chemistry:  BUN, calcium, serum creatinine, potassium, sodium, glucose, AST, ALT, alkaline phosphatase, total bilirubin, albumin, 
total protein, magnesium, chloride, and bicarbonate. At Baseline, only repeat hematology, chemistry & ANC if > 2 days since screening labs.
g. Hematology and chemistry testing must be performed 2 times per week with at least 2 days in between samples.
h. Collect ANC 2 times per week while on POS IV solution with at least 2 days in between samples. 
i.
Plasma TROUGH sampling (POS only; 0.35 mL of blood per sample) pre-dose (0 hr) on Day 6 of IV treatment. The Day 6 sample may be collected on Day 5 to coincide with other labs. For 
premature discontinuations (prior to Day 7), a trough level sample will be taken approximately 24 hours post start of infusion of the last dose, and all other safety assessments will be performed 
according to the Last Day of POS IV solution schedule.
j.
For subjects continuing POS IV solution beyond Day 10 collect troughs once per week. 
k. POS PK sampling during POS IV solution administration:  Full PK sampling may be performed on any day from Day 7-10. Perform PK sampling at pre-dose (0 hour), within 15 minutes after the 
end of infusion, and at approximately 4, 6, 12 and 24 hours post start of infusion. 
l.
Cyclodextrin (SBEβCD) PK sampling during POS IV solution administration(0.35 mL of blood per sample):  PK sampling at pre-dose (0 hour), within 15 minutes after the end of infusion, and at 
approximately 4, 6 and 12 hours post start of infusion. May be performed on any day from Day 7-10 and should coincide with POS full PK.
m. Participation in future biomedical research is optional. Informed consent for future biomedical research must be obtained before the DNA Buccal swab samples. The DNA buccal swab should be 
collected on Day 1 on randomized subjects only or at a later date, as soon as the informed consent is obtained.
 
 
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PART 2: (VISITS 15-28) ORAL (PFS) TREATMENT AND FOLLOW-UP VISITS
6.2
POS PFS TREATMENT
FOLLOW-UP
Visit Number
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit Title:
1st
Day of 
POS PFSa
2nd
Day of 
POS 
PFS
3rd
Day of  
POS 
PFS
4th
Day
of POS 
PFS
5th
Day of 
POS 
PFS
6th
Day of 
POS 
PFS
7th
Day of 
POS 
PFS
8th
Day of 
POS 
PFS
9th
Day of 
POS
PFS
10th
Day of 
POS 
PFS
Optional
POS 
PFS
Day 11-
18b
EOT/
Last Day 
of POS 
PFSb
FOLLOW-
UP
14 Days 
after End 
of Therapy 
(EOT) 
(POS IV 
solution or 
POS PFS)
Survival 
Assessmentn
Scheduling window
Day after 
last IV 
Dose
EOT +14 
DAYS
Day 90-110
Administrative 
Procedures
Prior/Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Medication/Food
Diary Assessment c
X
X
X
X
X
X
X
X
X
X
X
X
Provide or collect Study 
Medication/Food Diary 
(outpatients)d
Xd
Xd
Xd
Xd
Clinical 
Procedures/Assessments
Focused physical exam e
X
X
X
X
X
X
Body Weight (kg)f
X
Vital Signse
X
X
X
X
X
X
Electrocardiogramg
Xg
Oral Study Drug 
Administration
Xa
X
X
X
X
X
X
X
X
X
X
X
Assessment of Palatability
X
X
X
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival Assessmentn
X
Laboratory 
Procedures/Assessments
Hematology/Serum 
Chemistry h,i
Xh i
Xh i
Xh i
Xh i
Xh i
Absolute Neutrophil j
Xj
Xj
Xj
Xj
X
POS PK Trough
Samplingk,l
Xk
X k, l
Xk
POS Full PK Samplingm
Xm
 
 
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a.
The first day of POS PFS formulation can occur any day after Day 10 of POS IV solution.
b.
The last day of POS PFS can occur anytime between the 10th through the 18th day of POS PFS (combined treatment with POS IV and POS PFS cannot exceed 28 days).
c.
Food information will be collected in study medication diaries for subjects receiving PFS. The timing and characteristics of food taken will be recorded for each dose. Outpatients will maintain the daily 
dosing record and will record the actual time of dosing at the time of administration and the timing and characteristics of meals.
d.
The SM/Food diary should be provided to outpatients and the completed diaries collected at least once a week at a scheduled outpatient visit.
e.
For inpatients, perform focused physical exam and record vital signs 2 times per week, at least 2 days apart while on POS PFS. For outpatients, perform focused physical exam, and record vital signs 
once per week while on POS PFS.
f.
The subject’s weight as measured within 3 days prior to the first dose of oral treatment (PFS) will be used to calculate the first and all subsequent doses of PFS.
g.
ECG may be performed on Day 8, 9, or 10 of PFS
h.
Hematology:  complete blood count (CBC) with differential; Serum Chemistry:  BUN, calcium, serum creatinine, potassium, sodium, glucose, AST, ALT, alkaline phosphatase, total bilirubin, albumin,
total protein, magnesium, chloride, and bicarbonate. The first sample after the first day of POS PFS should be collected no later than the 5th dose of POS PFS.
i.
For inpatients, hematology and chemistry testing must be performed 2 times per week with at least 2 days in between samples. For outpatients, lab testing must be performed once per week while on
POS PFS
j.
ANC must be drawn a minimum of twice a week for inpatients and once per week for outpatients while on POS PFS and during periods of neutropenia (ANC <500/mm3).  The first sample after the 
first day of POS PFS should be collected no later than the 5th dose of POS PFS.
k.
POS plasma trough sampling during POS PFS administration (0.35 mL of blood per sample): Collect trough sample pre-dose (0 hr) on the 6th day of POS PFS and at the end of POS therapy. For 
premature discontinuations, a trough level sample will be taken approximately 24 hours after administration of the last dose, and all other safety assessments will be performed according to the Last Day 
of POS PFS schedule. The trough may be collected at either the 5th or 6th day of POS PFS to coincide with other labs.
l.
For subjects continuing for more than 7 days of POS PFS treatment, POS trough samples should be collected once per week with other required labs.
m. PK full sampling during POS PFS administration (0.35 mL of blood per sample): If an inpatient, perform PK sampling at pre-dose (0 hour), and 2, 4, 6, 8, and 24 hours post-dose; if an outpatient, 
perform PK sampling at predose (0 hour) 2, and 4 hours post-dose. Full PK sampling may be performed anytime between the 7th through the 10th day of POS PFS treatment.
n.
Survival Assessment, if the subject is alive or dead, will be recorded on the electronic case report form (eCRF).  If the subject dies, the cause and date of death will be recorded. This assessment can be 
made by telephone or by medical records.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by th e 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the study.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
7.1.1.4
Medical History
A detailed medical history will be obtained by the investigator or qualified designee and 
recorded in the eCRF. The medical/disease history should include:

Identify the specific medical condition listed in Inclusion criteria #3 that qualified 
the subject for the study

Details regarding any ongoing or prior cancer diagnoses, immunosuppressive 
conditions (including HIV), and transplant procedures (BMT and solid organ)

Details of previous surgeries or trauma

Details of previous arrhythmias

Details regarding recent or ongoing bacterial infections 

Detail of any prior history of fungal infection

Any history of hepatitis

Any significant signs or symptoms related to underlying medical conditions

Results of any abnormal chemistry, hematology lab or imaging results performed 
within 7 days of starting the trial.
Any medical conditions found at the Screening and Baseline exams will be recorded on the 
eCRF in the Medical History module.  The status of the condition will be evaluated as 
“resolved”, “stable” or “unstable”.  Any unstable medical condition will require a comment.
 
 
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7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirements, and prohibited medications for the 14 days prior to 
initiation of POS treatment as outlined in Section 5.5.1 and listed in Table 6.

Record prior medication (prescription or over the counter) taken by the subject within 
14 days before starting the trial. It is important to also record any protocol-specified 
prohibited medications, as outlined in Section 5.5.1 (Table 6), received during the 14-
day period prior to enrollment.

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.

Patients receiving other systemic antifungal agents (IV, oral or nasal/inhaled) as 
prophylactic therapy must discontinue these treatments prior to study drug 
administration.  No other systemic antifungal agents may be administered during the 
study treatment phase (i.e., POS IV solution/PFS) without sponsor approval.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record all medications and therapeutic procedures  
taken by the subject during POS treatment and for the 14 days of safety follow-up. Of note, 
any protocol-specified prohibited medications (see Section 5.5.1 and Table 6) received 
during the 14-day follow-up period after POS had ended should also be recorded.

Parenteral nutrition products should be recorded as concomitant medication.
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. The use of any 
concomitant medication must relate to an AE or the subject’s medical history.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
 
 
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7.1.1.7
Assignment of Randomization Number
All eligible subjects will receive a randomization number.  The randomization number 
identifies the subject for all procedures occurring after randomization.  Once a randomization 
number is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
7.1.1.8
Trial Compliance (Medication)
Study medication compliance will be monitored by ongoing data review during the IV 
treatment phase (POS IV solution) of the study. Compliance during the oral treatment phase
(POS PFS) will be verified by review of the study medication/food diary.
Interruptions from the protocol specified treatment (defined as missing one or more doses)
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on subject management.
The shifting of the timing of a dose (within the window provided to accommodate a subject’s 
schedule) is not considered an interruption.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Physical Examination
The principal investigator or designee will perform a complete physical exam at the 
Screening & Baseline Visits and will perform directed (focused) physical exams at least two 
times a week thereafter as indicated in the Trial Flow Chart (Section 6.0). Any medical 
conditions found at the Screening and Baseline exams will be recorded on the eCRF in the 
Medical History module. The status of the condition will be evaluated as “resolved”, “stable”
or “unstable”. Any unstable medical condition will require a comment. An exacerbation of a 
pre-existing condition or any new finding that occurs during the study will be captured as an 
adverse event and recorded in the Adverse Event module of the eCRF.
7.1.2.2
Body Weight (kg)
Body weight at Baseline will be used to calculate the subject’s dose for the IV treatment 
phase of the study.  The subject’s weight measured within three days prior to the first dose of 
oral treatment should be used to calculate all oral treatment (PFS) doses. The actual weight 
measured should be recorded. Body weight should be obtained without shoes. At each 
required visit, it is preferred that the weight should be measured on the same scale for the 
same individual. Measurements should be recorded to the nearest tenth of a kg.
7.1.2.3
Height (cm)
Height measurements should be taken without shoes and be recorded to the nearest cm.
 
 
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7.1.2.4
Vital Signs
The pretreatment vital signs will be considered the Baseline values.
Vital signs will be obtained by the principal investigator or designee. Systolic and diastolic 
blood pressure (mm Hg), heart rate (bpm) and body temperature (°C or °F) will be obtained 
according to the local standard procedure and will be recorded.
If the scheduled time for vital sign measurements coincides with a blood collection, the vital 
signs should be performed prior to the blood collection or at least 5 minutes afterwards. The 
same timing for obtaining the vital signs (before or after blood collection) should be used for 
all vital sign measurements. 
Body temperatures obtained within one hour of blood product transfusions should not be 
included on the eCRF. On the required days, the maximum daily temperature (outside of 
blood transfusions) will be collected and recorded on the eCRF.
7.1.2.5
Electrocardiogram
Two baseline ECGs must be performed at least 5 minutes apart at the Baseline Visit for 
purposes of protocol eligibility.
Prior to study drug administration, all ECGs should be reviewed for clinically significant 
abnormalities and reported as normal (or with findings that are not clinically significant).
ECGs should also be performed on Day 6, 7 or 8 of POS IV solution treatment and on Day 8, 
9, or 10 of POS PFS treatment and as clinically indicated for the evaluation of AEs. 
ECGs performed after the Baseline Visit should be done at approximately the same time of 
day (AM or PM) that baseline ECGs were performed.
A standard 12-lead ECG, reporting ventricular rate, PR, QRS, QT, and QTc intervals, will be 
performed. Any clinically significant abnormality must be followed until stabilization or 
return to baseline. 
Any change in the QTc interval of greater than 30 msec post Baseline (when compared to 
Baseline) will require a repeat ECG, and a determination of serum potassium (K), calcium 
(Ca), magnesium (Mg), and electrolyte replacement, if necessary. Additional evaluation may 
be required, and the principal investigator should determine if discontinuation of study drug 
or other evaluation is required in consultation with the project physician. 
If the QTc interval change from Baseline is greater than 60 msec, study drug should be 
interrupted while evaluation and treatment of other etiologies is ongoing (Section 5.8,
Subject Discontinuation Criteria).
During the Treatment Phase, if a QTc interval is found to be abnormal (symptomatic QTc 
intervals greater than 450 msec [males] or 470 msec [females]) after repeated ECG for 
 
 
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confirmation a cardiology consultation is to be requested to determine possible etiologies in 
addition to or other than study drug should also be performed at the same time (e.g., review 
of other concomitant drugs, and determination of serum Mg, Ca, and K levels). The 
investigator will determine if discontinuation of study drug is warranted after clinical 
examination of the subject and pertinent laboratory evaluation, and discussion of the case 
with the Sponsor’s project physician.
ECGs performed will be transferred to a blinded third party for an evaluation of QT, QTc 
(Fredericia and Bazett), PR, and QRS intervals and ventricular rate, as well as an overall 
clinical interpretation. The final results of the third-party analysis will be considered the 
definitive ECG data and will be the only ECG data used in the analysis.
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 (e.g., morning) to reduce diurnal variation.
7.1.2.6
Chest Radiograph
A chest radiograph will be performed, as clinically indicated, to evaluate for fungal infection.
7.1.2.7
IV Study Drug Administration/Infusion Site Examination

The collection of blood specimens for safety labs and PK trough levels should 
preferably occur prior to the administration of POS IV solution.

The subject’s body weight at Baseline will be used to calculate all IV doses

IV infusions should be administered via a central line at approximately the same time 
each day. On the first day 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 (i.e., 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.

The infusion site should be examined prior to and at the end of the infusion according 
to local standard of care. Any adverse events observed at the infusion site or during 
the infusion will be recorded on the eCRF.
7.1.2.8
Oral Study Drug Administration (PFS)

The collection of blood specimens should preferably occur prior to the oral 
administration of POS PFS.
 
 
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
A subject’s body weight should be measured within 3 days prior to the first day of 
POS PFS treatment. The weight measured will be used to calculate all subsequent 
doses of POS PFS treatment. 

The POS PFS dose may be administered by oral syringe or via a feeding tube and 
should be prepared and administered using the Sponsor supplies as outlined in the 
Pharmacy Manual. Refer to the Pharmacy Manual for additional details on allowed 
dosing devices.

Doses of POS PFS should be administered 24 hours apart at approximately the same 
time each day. 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.

The Study Medication/Food Diary must be completed for every dose of PFS. If 
treatment is given as an outpatient, the subject or the subject’s guardian or caretaker 
will complete the study medication/food diary on a daily basis. The diary will be 
collected and entered by site study staff at the visits outlined in the trial flow chart
(Section 6.0).

Subjects who vomit within 30 minutes of POS PFS administration should be given a 
replacement dose as soon as possible. Repeated episodes of vomiting should be 
recorded on the Adverse Event (AE) eCRF and the Dosing eCRF.

Subjects should be observed for approximately 30 minutes after the first dose of PFS 
for tolerance. During this time, a palatability assessment should be performed as 
outlined in Section 7.1.2.9.
7.1.2.8.1 Outpatient Administration of Oral Study Medication (PFS)
It is preferred that the subject be administered their first dose of PFS before leaving the 
hospital so the patient and caregiver have an opportunity to observe or be observed preparing 
the first oral dose (PFS) for administration. If the investigator determines that the subject is 
able to be discharged from the hospital and will be able to continue treatment with POS PFS 
at home, the investigator should take the following steps:

Refer to the Trial Flow Chart and determine the number of days until the next PK 
collection timepoint and schedule the out-patient appointment (allowing enough 
time to perform PK blood sampling predose (0 hour), 2, and 4 hours post-dose).

Direct IVRS to dispense enough doses (including replacement doses if the subject 
is at risk of vomiting) for the subject to take home with them to last until their 
next clinical visit.

Instruct the subject not to take their daily dose of POS PFS prior to their 
scheduled appointment on clinic visit days. On the clinic visit days, doses of PFS 
should be administered in the clinic after the pre-dose PK blood sample is 
collected and recorded in the study medication/food diary.

Provide the subject/parent/caregiver with the study medication/food diary and the 
Palatability Assessment form and instruct them on how to complete both forms.
 
 
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
Instruct the subject/parent/caregiver to bring all medication (including empty 
packages), the palatability assessment form and the study medication/food diary
with them to all office visits.
These steps need to be repeated at every outpatient visit.
7.1.2.9
Assessment of Palatability (Taste)
All subjects will rate the palatability of the PFS formulation at three times during the PFS 
treatment phase of the study:

Immediately after the first oral dose (POS PFS).

Approximately 3-5 days later immediately after the subject has taken their oral dose.

At the End of Treatment (EOT), immediately after the last dose of oral treatment.
The palatability assessment questionnaire that will be used can be found in the 
Administrative Site Binder.
The palatability assessment should be completed for all subjects regardless of age or 
condition. The paper form may be completed by the subject, reported by the patient to an 
observer (caregiver or parent), or completed as observed by a parent/primary caretaker, nurse 
or member of the trial staff.
7.1.2.10 Adverse Event Monitoring
The monitoring for Adverse Events will occur at the visits outlined in the Trial Flow Chart 
following the guidelines in Section 7.2.
7.1.2.11 Survival Assessment
A survival assessment (if the subject is alive or dead) will be performed between Day 90 and 
Day 110 and will be recorded on the eCRF. In the event of death, the cause and date of death 
will also be recorded. This assessment can occur by telephone or by using medical records.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Appendix 12.4.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis & Other
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 8. These 
safety lab tests will be performed locally. The timing for these assessments are outlined
in the Trial Flow Chart (Section 6.0).
 
 
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
If the Baseline and Day 1 visits are combined, clinical lab tests should be drawn prior 
to the administration of study treatment. 

Blood specimens may be drawn either peripherally or via central venous catheter.

If during the trial any laboratory result is outside the reference range and is 
considered clinically significant by the investigator, the test should be repeated at 
appropriate time intervals until it returns to baseline or becomes a clinically 
insignificant finding.

If clinically indicated, safety lab tests may be repeated more often to evaluate clinical 
symptoms of AEs and must be followed until stabilization or return to baseline.
Table 8
Laboratory Tests
Hematology
Chemistry
Other
Hematocrit
Albumin
Serum β-human chorionic 
gonadotropin (β-hCG)1
Hemoglobin
Alkaline phosphatase
Platelet count
Alanine aminotransferase (ALT)
WBC (total and 
differential)
Aspartate aminotransferase (AST)
Absolute neutrophil 
count (ANC)
Bicarbonate
Calcium
Chloride
Creatinine
Glucose
Potassium
Sodium
Total Bilirubin  
Direct bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood urea nitrogen
Magnesium
If possible, lab samples should be collected in the fasting state (after an overnight fast for 
morning sample).
 
 
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7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
Plasma posaconazole concentration data will be used to estimate the following PK
parameters:

Cavg: Average steady-state plasma concentration

Cmin:
POS trough level immediately before a subject receives the dose on the day 
specified in the protocol

Cmax: Maximum plasma concentration

Tmax: Time of maximum plasma concentration

AUC: Area under the plasma concentration versus time curve 

CL:  Total body clearance

CL/F:  Apparent total body clearance
The current blood sampling schedule is an optimized schedule based on the adult steady-state 
PK data. For patients receiving IV therapy, if all blood samples can be collected at steady-
state as scheduled, the steady-state AUC will be calculated using the non-compartmental 
trapezoidal method. The Cavg will be calculated by dividing the AUC with dosing interval.
For patient receiving PFS, since sparse PK samples are collected for outpatients, a population 
PK analysis will be conducted and model-predicted plasma concentration-time profiles will 
be used to determine Cavg.
Plasma sulfobutylether-beta-cyclodextrin-containing (SBEβCD) concentration data will be 
used to estimate the following PK parameters:

Cmax: Maximum plasma concentration

Tmax: Time of maximum plasma concentration

AUC: Area under the plasma concentration versus time curve
7.1.3.2.1 Blood Collection for Plasma Posaconazole Levels of MK-5592
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Buccal swabs for genomics use
 
 
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Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit (EOT) should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. A PK trough sample should be collected approximately 24 hours 
after the last dose, and all other safety assessments will be performed. The investigator or 
trial coordinator must notify the Sponsor when a subject has been discontinued/withdrawn 
from the trial. If a subject discontinues for any reason at any time during the course of the 
trial, the subject may be asked to return to the clinic (or be contacted) for the End of Trial 
(EOT) approximately 72 hours after the last dose of trial drug is administered) to have the 
applicable procedures conducted. However, the investigator may decide to perform the End 
of Trial procedures at the time of discontinuation or as soon as possible after discontinuation.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
 
 
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suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained with the study 
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:

ECG machine

Refrigerated centrifuge

Freezer for storage of samples

Refrigerator
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
All screening procedures outlined in Section 6.0 must be performed within 7 days of 
enrollment into the study.  Prior to randomization, potential subjects must be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Only subjects 
with clinically acceptable results from all screening criteria are to be enrolled in the study.
Screening procedures may be repeated after consultation with the Sponsor.
At the Screening visit the following procedures will be performed:

The investigator or qualified designee shall discuss with the parents(s) or legal 
guardian of each subject, and with each subject as appropriate, the nature of the study, 
its requirements, and its restrictions. 

Written informed consent will be obtained from the parent or legal guardian of each 
subject prior to any study procedures being performed, and a signed copy will be 
given. Assent will be obtained from minors according to institutional practices. 

The inclusion/exclusion criteria will be reviewed

A subject identification card will be issued

Demographic profile

Complete medical history

Record all medications taken within the last 14 days 

Screening number will be assigned (after signing of study-specific informed consent)

Complete physical exam

Body weight

Height
 
 
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
Vital signs (blood pressure, heart rate and temperature)

Electrocardiogram. A single ECG or telemetry may be used to evaluate QTc for 
eligibility at the screening visit, however two 12 lead ECGs performed 5 minutes 
apart must be done at the Baseline Visit to confirmQTc criteria for study eligibility
before study drug dosing occurs.

Blood samples will be collected for evaluation of eligibility criteria and for safety 
assessments (e.g., pregnancy test, hematology, chemistry & absolute neutrophil 
count)
7.1.5.2
Baseline Visit
At the Baseline visit the following procedures will be performed:

Review the inclusion/exclusion criteria

Record all medications taken within the last 14 days. 

A complete physical examination

Body Weight

Vital signs

12-lead electrocardiogram (ECG). Two 12 lead ECGs performed 5 minutes apart 
must be done at the Baseline Visit to confirm QTc criteria for study eligibility-before 
study drug dosing occurs.

A chest radiograph (as clinically indicated for fungal infection)

Adverse Event Monitoring

Laboratory tests (including a pregnancy test on females of child-bearing potential, 
hematology, chemistry & absolute neutrophil count). Only repeat hematology, 
chemistry & ANC if it has been more than 2 days since the screening labs were 
performed. Only repeat pregnancy test if it has been more than 2 days since the 
screening pregnancy test was performed, or if a urine pregnancy test was conducted 
at screening.
7.1.5.3
Treatment Day(s)
Eligibility will be confirmed at Day -1 or pre-dose on Day 1 through review of pregnancy 
testing (females), a physical examination, ANC, vital signs, and concomitant 
medication/adverse event monitoring (see Section 6.0).
All subjects will be administered POS IV solution for a minimum of 10 days. Those subjects 
that are still neutropenic will then switch to oral treatment with the POS PFS for a minimum 
of 10 days; however, subjects may continue on POS IV solution beyond Day 10, if a subject 
cannot tolerate or refuses to take oral medication. Transition to POS PFS, rather than 
remaining on POS IV solution, is preferred.
 
 
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Blood samples for POS PK testing will be drawn prior to study treatment and as close as 
possible to the time points listed in the Trial Flow Chart (Section 6.0). The exact date/time of 
dosing and blood sampling will be recorded. 
Procedures performed during POS IV solution and POS PFS treatment are outlined 
separately below and should be performed as outlined in The Trial Flow Chart (Section 6.0):
7.1.5.3.1 POS IV Treatment Days
On IV treatment days the following procedures will be performed:
Day 1:

On Day 1 of IV treatment, POS IV solution will be administered twice. Each dose 
will be administered approximately 12 hours apart.

The exact date and time of each dose administration will be recorded on the 
appropriate eCRF. 

Review prior and concomitant medications

Perform a focused physical exam

Vital signs

Adverse event monitoring (examine the infusion site on a daily basis, prior to and at 
the end of infusion, according to local standard of care, for local adverse reactions).

A buccal swab will also be collected (If elected, the informed consent for future 
biomedical research but must be obtained before the DNA /Buccal swab is collected 
on Day 1 on randomized subjects only or at a later date, as soon as the informed 
consent is obtained)
Day 2 to Day 28:

Review concomitant medications

Vital signs

Perform a focused physical exam 3 times per week until the end of IV treatment as 
outlined in the Trial Flow Chart (Section 6)

Electrocardiogram (may be performed on Day 6, 7 or 8 of treatment)

Monitor for adverse events

Collect blood for laboratory safety tests (e.g., hematology, blood chemistries, ANC), 
according to the Trial Flow Chart (Section 6)

Administer study medication once daily at approximately the same time each day;
each dose should be administered approximately 24 hours apart

Record the exact date and time of each dose administration on the appropriate eCRF
 
 
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POS PK sample collection

Collect POS Cmin or trough samples (0.35 mL of blood per sample) prior to dosing 
(pre-dose (0 hr) on the 6th day of POS IV solution treatment; the Day 6 sample may 
be collected on Day 5 to coincide with other labs

Collect POS trough samples once per week for subjects continuing POS IV solution 
beyond Day 10

Perform full POS PK sampling on any day from Day 7-10 at pre-dose (0 hour), within 
15 minutes after the end of infusion, and at approximately 4, 6, 12 and 24 hours post 
start of infusion

Record the exact date and time that each sample is collected on the appropriate eCRF
Cyclodextrin PK sample collection

Cyclodextrin (SBEβCD) PK sampling should coincide with POS full PK on any day 
from Day 7-10 at pre-dose (0 hour), within 15 minutes after the end of infusion, and 
at approximately 4, 6, and 12 hours post start of infusion

Record the exact date and time that each sample is collected on the appropriate eCRF
For Premature Discontinuations:

Collect a POS trough level sample approximately 24 hours after administration of the 
last dose

Perform all other safety assessments according to the Last Day of POS IV schedule.

Update IVRS system with subject status.
7.1.5.3.2 POS PFS Treatment Days
Note: If the subject will be an outpatient during PFS treatment, the investigator staff should 
provide the subject with enough PFS to ensure study medication compliance until the next 
clinic visit and instruct the subject/caregiver in how to complete the Study Medication/ Food 
Diary Assessment form and the Assessment of Palatability form. Clinic Visits should be 
scheduled to coincide with lab safety and PK collection times.
On PFS treatment days the following procedures will be performed:

During POS PFS administration, administer each dose approximately 24 hours apart, 
at the approximately the same time each day

Record the exact date and time of each dose administration on the appropriate eCRF. 

Review concomitant medications

Vital signs

Perform a focused physical exam according to the Trial Flow Chart (Section 6)

Electrocardiogram (may be performed on Day 8, 9 or 10 of treatment)
 
 
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
Monitor for adverse events
o
Examine the infusion site on a daily basis, prior to and at the end of infusion, 
according to local standard of care, for local adverse reactions

Collect blood for laboratory safety tests (e.g., hematology, blood chemistries ANC), 
according to the Trial Flow Chart (Section 6).

Study Medication/Food Diary Assessment

Assessment of Palatability
POS PK sample collection:

Collect POS Cmin or trough samples prior to dosing on the 6th day of oral treatment 
(PFS) and at EOT; the Day 6 trough sample may be collected at either the 5th or 6th
day of POS PFS to coincide with other labs

Collect POS trough samples once per week for subjects continuing POS PFS beyond 
Day 7

Perform POS full PK sampling at pre-dose (0 hour), and 2, 4, 6, 8, and 24 hours post-
dose on any day from Day 7-10 for an inpatient

PK sampling for an outpatient will be performed on any day from Day 7-10 during 
oral treatment (PFS) at predose (0 hour), 2, and 4 hours post-dose of POS PFS 
treatment

Record the exact date and time that each sample is collected on the appropriate eCRF. 
For Premature Discontinuations:

Collect a POS trough level sample approximately 24 hours after administration of the 
last dose.

Perform all other safety assessments according to the End of Treatment (EOT)/Last 
Day of POS PFS schedule.

Update IVRS system with subject status.
7.1.5.4
Post-Trial/14 Day Follow-up
Subjects will be required to return to clinic approximately 14 days after the last dose of trial 
drug for the post-trial visit. If the post-trial visit occurs less than 14 days after the last dose of 
trial drug, a subsequent follow-up phone call should be made at 14 days post the last dose of 
trial drug to determine if any adverse events have occurred since the post-trial clinic visit.
7.1.5.5
Survival Assessment
A survival assessment, if the subject is alive or dead, will be performed any day from 
Day 90-110. If the subject dies, the date of death will be recorded. This assessment can be 
performed by telephone or by medical records.
 
 
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7.1.5.6
Critical Procedures Based on Trial Objectives: Timing of Procedure
For this trial, collection of blood samples for POS PK sampling is the critical procedure.
At any post-dose time point, the blood sample for POS needs to be collected as close to the 
specified time point as possible.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose occurs when the subject has taken (accidentally or intentionally) any 
drug administered as part of the protocol that exceeded the dose as prescribed by the 
protocol. All reports of overdose must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Sponsor Contact information can be found in the Investigator Trial 
File Binder.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 9 for additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
 
 
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7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
The following will not be considered SAEs in this study.
1. An event that results in hospitalization or prolongs an existing hospitalization will not 
be considered a serious adverse event if the only reason for the hospitalization was:
a.
administration of chemotherapy
b. transfusion of blood products
c.
administration of study procedures
d. placement of a permanent intravenous catheter
 
 
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e.
hospice placement for terminal care
f.
outpatient hospitalization for procedures such as elective day surgery or 
hospitalization due to convenience purposes (e.g., transportation difficulties)
2. Any Grade 3 or 4 leukopenia, absolute neutropenia, or thrombocytopenia (regardless 
of baseline value) will not be considered a serious adverse event, even in the event of 
medical intervention to prevent medically significant sequelae.
3. Any Grade 1, 2, or 3 decrease in hemoglobin will not be considered a serious adverse 
event.
If an abnormal laboratory value included in item numbers 2 or 3 resulted in a clinical event, 
then the clinical event and not the abnormal laboratory value must be recorded as an AE in 
the eCRF.  This clinical event must be reviewed to determine if it meets the criteria for an 
SAE.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 9. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 9 for instructions in evaluating adverse events.
 
 
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Table 9
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with 
Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, 
there
is 
a 
reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
External Data Monitoring Committee (eDMC)] regarding the trial.
Data Monitoring Committee
7.3.1
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (eDMC) will monitor the ongoing, accumulating safety data from this 
trial. The voting members of the committee are external to the Sponsor. The members of the 
eDMC must not be involved with the trial in any other way (e.g., they cannot be trial 
investigators) and must have no competing interests that could affect their roles with respect 
to the trial. 
The eDMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial. Also, the eDMC will review ongoing 
trial safety results, consider the overall risk and benefit to trial participants and recommend to 
the EOC if the trial should continue in accordance with the protocol.  The eDMC will 
evaluate the accumulating available data for safety at the completion of Dose Cohort #1 for 
each age group, prior to each age group starting the next dosing group (Dose Cohort #2), and 
at other time points as determined by the study team and eDMC.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
eDMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC. The eDMC will monitor the trial at an appropriate 
frequency, as described in the detailed eDMC charter.
The eDMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
 
 
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This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, along with an explanation as to when and why they 
occurred, will be listed in the Clinical Study Report (CSR) for the study.  Post hoc 
exploratory analyses will be clearly identified in the CSR. No separate Statistical Analysis 
Plan (SAP) will be issued for this study.
Pharmacokinetic Analyses
8.1.1
The primary PK population for POS IV solution will be all treated subjects who receive at 
least 7 days of POS IV solution therapy and complete the full POS PK sampling while on 
POS IV solution. The non-compartmental PK analysis will be used for the primary PK 
population. 
For POS PFS therapy, a population PK analysis will be conducted to determine the 
individual PK exposure since sparse PK samples will be collected for patients who are 
outpatients during the POS PFS treatment period.  Model-predicted individual concentration-
time profiles will be used to determine Cmax, Cmin, Cavg, and AUC. 
PK parameters (Cmax, Tmax, Cmin, Cavg, AUC, CL and CL/F) for both POS IV solution and 
POS PFS will be summarized using descriptive statistics as described in Section 8.2.1 below.
A non-compartmental PK analysis will be performed to determine the PK exposure of 
sulfobutylether-beta-cyclodextrin-containing (SBEβCD).  
Safety Analyses
8.1.2
The All-Subjects-as-Treated (ASaT) population will be employed for safety analyses, and 
consists of all subjects who took at least one dose of POS study therapy.
Efficacy Analyses
8.1.3
There are no efficacy analyses planned for this study.
Power and Sample Size
8.1.4
A total of approximately 120 subjects will be screened to obtain a minimum of 
72 PK-evaluable subjects in the PK analysis.
 
 
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Statistical Analysis Plan
8.2
Pharmacokinetic Analysis Plan
8.2.1
Only subjects who receive at least 7 days of POS IV solution therapy and complete the full 
POS PK sampling while on POS IV solution will be included in the non-compartmental PK 
analysis for the primary patient population. 
PK parameters for POS (Cmax, Cmin, Cavg, CL) will be listed and summarized by POS 
formulation, dose cohort, and age group using descriptive statistics.
For POS PFS therapy, a population PK analysis will be conducted to determine the 
individual PK exposure.  A population PK model will be developed using the plasma data 
collected from this study in combination with the adult PK data.  Model-predicted individual 
concentration-time profiles will be used to determine Cmax, Cmin, Cavg, AUC and CL/F for 
patients receiving POS PFS. Covariates of age group and dose cohort will be explored in the 
model.
Comparison of the exposure from previous experience in adults (from P05520 for the POS 
IV formulation; P05615 for the tablet formulation) will be conducted at steady state using 
graphics. Additionally, the proportion of subjects in PN097 with steady-state Cavg greater 
than or equal to 500 ng/mL (as well as the proportion of subjects with Cavg between 500-2500 
ng/mL) will be compared to the previous studies using descriptive statistics.
A non-compartmental PK analysis will be performed to determine the PK exposure of 
sulfobutylether-beta-cyclodextrin-containing (SBEβCD).  PK parameters for POS (Cmax, Tmax
and AUC) will be listed and summarized by POS dose cohort, and age group using 
descriptive statistics.
Safety Analyses
8.2.2
All subjects who receive at least one dose of study drug will be included in the safety 
analysis.
Adverse events (AEs) will be tabulated by age (2 to <7 years, 7 to 17 years) and POS 
treatment (IV solution, PFS). The number and percent of each event will be computed and 
summarized by body system organ class. Severity, duration, relationship to POS, and 
outcome of the events will also be recorded. ECGs and clinical safety laboratory values, such 
as hematology and serum chemistry, will be tabulated by age and treatment group and 
compared to baseline using summary statistics. Vital signs will be listed by date and time. 
Key toxicities, including hepatotoxicity and nephrotoxicity, will be tabulated by age and dose 
cohorts.
Additionally, survival at Day 100 (allowed range Day 90 -110) and Day 65 (allowed range 
Day 60-70) will be tabulated by age group and dose cohort.
 
 
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Efficacy Analyses
8.2.3
There are no efficacy analyses planned for this study.
Other Analyses
8.2.4
Compliance with study medication, including palatability/acceptability of the POS PFS 
formulation, will be summarized by age and treatment group.
Power and Sample Size
8.2.5
The sample size is not based on any formal power calculation.
The total sample size for the study is a minimum of 84 subjects (72 PK-evaluable subjects)
distributed across the 3 dose cohorts as follows:
Dose cohort #1 (a minimum of 24 PK evaluable subjects, divided 12 per Age Group).
Dose cohort #2 (a minimum of 24 PK evaluable subjects, divided 12 per Age Group).
Dose cohort #3 (a minimum of 36 subjects, divided as 12 PK evaluable subjects per Age 
Group and an additional 12 distributed across either Age Group).
The actual total number of enrolled subjects may be greater than 84 in order to ensure a 
minimum of 72 subjects that meet PK evaluability criteria.
At the time of this amendment (MK-5592-097-02), enrollment in Dose Cohorts #1 and #2 is 
complete. Therefore, the remaining target enrollment for this amendment is a minimum 
36 subjects in Dose Cohort #3 (12 PK evaluable subjects per age group and an additional 
12 distributed across either age group).
If successful dose selection is defined as at least 10 out of 12 (82.2%) patients per age/dose 
group achieving a Cavg >500 ng/mL, the chance of achieving success is at least 89%, based 
on a sample size of 12 patients in each age/dose cohort using a binomial distribution (n=12, 
p=0.90), where p = probability of success.
Interim Analysis
8.2.6
Interim Analysis for Dose Cohorts #1 and #2
For the 2 dose cohorts (3.5 mg/kg and 4.5mg/kg) which have completed enrollment at the 
time of this amendment, a pre-planned interim summary of PK and safety data was 
conducted in order to inform the decision to advance to the next higher dose cohort. Because 
these data summaries did not involve formal tests of hypotheses, they did not affect type I 
error.
 
 
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Interim Analysis for Dose Cohort #3
There is no formal interim analysis planned for the third dose cohort (6 mg/kg).
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10.
Table 10
Product Descriptions
Product Name & Potency
Dosage Form
Posaconazole 300 mg
IV Solution (sterile)
Posaconazole 300 mg
Powder for Oral Suspension
Ora-Blend® SF
Oral Suspension
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label posaconazole vials (IV solution) or posaconazole sachets
(PFS).  On Day 1 of POS IV solution, subjects will be dispensed 2 vials which are to be 
taken as 2 separate doses to be administered 12 hours apart (BID). This will be followed by 
1 vial daily on days 2-10, or until IV treatment is completed. Vials will not be kitted.
Subjects switching to POS PFS will receive kitted sachets to allow for daily dosing until the 
end of treatment. In addition, Ora-Blend® SF will be provided for the purposes of 
reconstituting the POS PFS.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
 
 
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Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
 
 
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By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
 
 
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The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
 
 
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The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
 
 
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Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
 
 
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authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
 
 
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submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1. Rosen GP, Nielsen K, Glenn S, Abelson J, Deville J, Moore TB. Invasive fungal 
infections in pediatric oncology patients: 11-year experience at a single institution. J 
Pediatr Hematol Oncol 2005; 135-40.
2. Hovi, L, Saarinen-Pihkala UM, Vettenranta K, Saxen H. Invasive fungal infections in 
pediatric bone marrow transplant recipients: single center experience of 10 years. Bone 
Marrow Transpl 2000;26:999-1004.
3. Dvorak CC, Steinbach WJ, Brown JM, Agarwal R. Risks and outcomes of invasive 
fungal infections in pediatric patients undergoing hematopoietic cell transplantation. 
Bone Marrow Transpl 2005;36:621-9.
4. Castagnola E, Cesaro S, Giacchino M, Livadiotti S, Tucci F, Zanzazzo G, et al. Fungal 
infections in children with cancer. A prospective, multicenter surveillance study. Ped Inf 
Dis J 2006;25:634-9. 
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name. 
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA (buccal swab) specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug/vaccine.  The DNA (buccal swab)
specimen(s) will be stored to provide a resource for future trials conducted by Merck 
focused on the study of biomarkers responsible for how a drug/vaccine enters and is 
removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may 
interact with, or other aspects of disease.  The specimen(s) may be used for future assay 
development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Buccal swab specimens for DNA isolation will be obtained at a time when the subject 
is having other trial procedures conducted. Specimens like tissue and bone marrow 
will usually be obtained at a time when the subject is having such a procedure for 
clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
 
 
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key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
 
 
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
 
 
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9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Buccal swab 
specimens will be collected inside the cheek with no associated venipuncture to obtain 
the specimen. Therefore, there will not be an additional risk for the subject.
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
 
 
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be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15;
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Trial Visit:
Screening
& Baseline
POS IV
Solution
Treatment 
POS Oral
(PFS)
Treatment
Post 
Treatment 
Follow-up
Total 
Collections
mL per 
collection
Total 
mL/test
Visits 1-2
Visit 
3-14
Visits
15-26
Visits
27-28
Approximate Blood Volume 
Lab Safety 
Tests
Hematology/C
hemistry
2
4
5
0
11
4
44
ANC
2
4
5
0
11
4
44
Serology
Serum β-
Human 
Chorionic 
Gonadotropin 
(β-hCG)a
1
0
0
0
1
1
1
Study Drug
POS Full PK
*(0 hour), , 
within 15 
minutes after 
the end of 
infusion, and at 
approximately 
4, 6, 12 and 24 
hours post start 
of infusion.)
0
6*
6*
0
12
.35
4.2
POS PK 
Trough
(0.35 ml
/sample)
0
3
3
0
6
0.35
2.1
SBEβCD
Cyclodextrin 
PK
(0.35ml
/sample)
0
5
0
0
5
.35
1.75
a Serum pregnancy tests only applies to sexually active females of childbearing potential 
 
 
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List of Abbreviations
12.5
Abbreviation
Definition
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
AMA
American Medical Association
AMB
Amphotericin B
AMB-R
Amphotericin B Resistant
AML
Acute myelogenous leukemia
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Asia Pacific
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
AUC(tf)
Area under the plasma concentration versus time curve from time 0 to the time of 
the final quantifiable sample
β-hCG
Serum β-human chorionic gonadotropin (β-hCG)
BID
bis in die; twice a day
BMT
Bone Marrow Transplantation
BPM
Beats Per Minute
BUN
Blood urea nitrogen
°C
Celsius
Cavg
Average steady-state plasma concentration
CBC
Complete Blood Count
CHMP
Committee for Medicinal Products for Human Use
CFR
Code of Federal Regulations
CL/F
Apparent total body clearance
cm
Centimeter
Cmax
Maximum observed plasma concentration
Cmin
Minimum observed plasma concentration
CRU
Clinical Research Unit
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Minimum observed plasma concentration
CYP
Cytochrome P450
DBS
Dried Blood Spot
DILI
Drug Induced Liver Injury
dL
Deciliter
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
 
 
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ECI
Event of Clinical Interest
eCRF
Electronic Case Report Form
eDMC
External Data Monitoring Committee
EEA
European Economic Area
EEMEA
Eastern Europe, Middle East and Africa
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of treatment/Last Study Visit
ERC
Ethics Review Committee
EU
European Union
°F
Fahrenheit
F
Female
FDA
Food and Drug Administration, USA
FLZ
Fluconazole
FLZ-R
Fluconazole Resistant
GCP
Good Clinical Practice
GVHD
Graft versus host disease
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methylglutaryl coenzyme A
HPMCAS
hypromellose acetate succinate
HSCT
Hematopoietic stem cell transplantation
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IDSA
Infectious Disease Society of America
IEC
Independent Ethics Committee
IFI
Invasive fungal infection
IND
Investigational New Drug Application; legal instrument in the USA that allows 
study of unapproved, investigational new drugs in human subjects
IRB
Institutional Review Board
ITZ
Itraconazole
ITZ-R
Itraconazole resistant
IUD
Intrauterine Device
IV
Intravenous
IVRS/IWRS
Interactive Voice Response System
kg
Kilogram
L
Liter
LA
Latin America
M
Male
 
 
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MDS
Myelodysplastic syndrome
mg
Milligram
min
Minute
mL
Milliliter
mm3
Cubic millimeter
MSG
Mycoses Study Group
NHL
Non-Hodgkin’s Lymphoma
NNRTI
Non-nucleoside reverse transcriptase inhibitors
OGS
Oral granules for suspension
PD
Pharmacodynamic
PFS
Powder for oral suspension
PGt
Pharmacogenetic
PK
Pharmacokinetics
PO
Per OS (by mouth)
POS
Posaconazole
QTc
QT interval corrected for rate
RBC
Red blood cell
RNA
Ribonucleic Acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBEβCD
Sulfobutylether-beta-cyclodextrin
SCT
Stem cell transplantation
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT) 
SOP
Standard Operating Procedure
TdP
Torsade de pointes
Tmax
Time to maximum observed plasma concentration
ULN
Upper limit of normal
US
United States
VOR
Voriconazole
VOR-R
Voriconazole Resistant
WBC
White blood cell 
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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