Conditions: Fungal Infections Invasive Pulmonary Aspergillosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 585
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of posaconazole (POS) versus voriconazole (VOR) in the treatment of adults and adolescents with invasive aspergillosis (IA). The primary hypothesis is that the all-cause mortality through Day 42 in the POS treatment group is non-inferior to that in the VOR treatment group.

Detailed description:

Arms:
arm 1: Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment. arm 2: Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.

Interventions: intervention 1: Posaconazole intervention 2: Voriconazole intervention 3: Placebo
Intervention descriptions: intervention 1: POS IV: Day 1: 300 mg BID Day 2-84: 300 mg QD POS oral: Day 1: 300 mg BID Day 2-84: 300 mg QD intervention 2: VOR IV: Day 1: 6 mg/kg per body weight administered BID Day 2-84: 4 mg/kg per body weight administered BID VOR oral: Day 1: 300 mg BID Day 2-84: 200 mg BID intervention 3: Matching placebo received for Posaconazole (IV and oral) or Voriconazole (oral)

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT01782131 
Document Date: 
07-FEB-2019
A Phase 3 Randomized Study of the Efficacy and Safety of
Posaconazole versus Voriconazole for the Treatment of Invasive
Aspergillosis in Adults and Adolescents


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1.0 TITLE PAGE
Title
A Phase 3 Randomized Study of the Efficacy and Safety of 
Posaconazole versus Voriconazole for the Treatment of Invasive 
Aspergillosis in Adults and Adolescents (Phase 3; Protocol No. MK-
5592-069)
Sponsor
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Sponsor’s Address
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
IND No.
75,061; 51,316
EudraCT No.
2011-003938-14
Trial Physician
Global Clinical Research, Infectious Diseases
Phase
3
Date of Finalization of This Current 
Version of the Protocol
07-FEB-2019– PROTOCOL AMENDMENT#5
Previous Version(s) of the Protocol
01-AUG-2016– Protocol Amendment#4
08 JAN 2015 – Protocol Amendment#3
26 JUN 2013 – Protocol Amendment#2
12 DEC 2012 – Protocol Amendment#1
15 NOV 2012 – Initial Protocol
Protocol Template Approval Date
13 OCT 2011
 
 
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C O N F I D E N T I A L
TRIAL PROTOCOL
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR 
PRODUCT IS PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF 
THIS DRUG OR PRODUCT AND IS SUBJECT TO RECALL AT ANY TIME.  THE 
INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH 
DISCLOSURE IS REQUIRED BY APPLICABLE LAW OR REGULATIONS.  
SUBJECT TO THE FOREGOING, THIS INFORMATION MAY BE DISCLOSED 
ONLY TO THOSE PERSONS INVOLVED IN THE TRIAL WHO HAVE A NEED TO 
KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS 
INFORMATION.  THESE RESTRICTIONS ON DISCLOSURE WILL APPLY 
EQUALLY TO ALL FUTURE ORAL OR WRITTEN INFORMATION SUPPLIED TO 
YOU BY THE SPONSOR OR ITS AFFILIATES OR REPRESENTATIVES THAT IS 
DESIGNATED AS “PRIVILEGED” OR “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.
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT: This amendment has clarified aspects of the planned protocol 
and statistical analyses for the study. Key elements of the analyses for the study that have been modified include 
approximate sample size and power calculation, time windows allowed for the assessment of all-cause mortality 
and global clinical response, and the elimination of some secondary objectives for which data analyses are no 
longer planned.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.0, 2.2
Synopsis, Trial 
Flow Chart
Oral tablet acceptability text in adolescent subject 
exploratory analysis has been deleted.  
A footnote was added under the trial flow chart:
t       Visit 7 window (Week 6, Day 30-54) is slightly different 
from the window for the Global Clinical Response 
assessment at Week 6 (± 2 weeks)
Removal of text to align 
with final planned 
protocol analyses as an 
insufficient number of 
adolescent subjects 
have been enrolled to 
conduct sub-analysis.
The footnote was 
added to clarify the flow 
chart Week 6 visit 
window is different from 
the window for the 
Week 6 Global Clinical 
Response assessment
2.0, 5.2
Synopsis, Subject 
Population 
Rationale
Following text deleted:
At least 30 FAS-evaluable adolescents will be enrolled in 
this study
Text removed as it is no 
longer planned to have 
enrollment of at least 
30 adolescents in the 
study. 
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.0, 8.7.2
Synopsis, Sample 
Size and Power 
for Efficacy 
Analyses
Added underlined text:
This sample (approximately 300 randomized subjects in 
each azole arm) will have ~ 82.7% power (with 1-sided 
alpha=0.025) to show non-inferiority of POS compared to 
VOR using a 10% margin assuming an all-cause mortality 
through Day 42 of 23% for both treatment groups.
Text updated to clarify 
sample size and related 
power calculation 
statements
2.2 
Trial Flow Chart
Underlined text from footnote ‘u’ was modified:
All subjects randomized and treated are to be followed for 
mortality assessment throughout the study period until Visit 
9Day 114, regardless of whether the subject discontinues 
study therapy prior to Visit9 8 D85 Day 84
Text updated to clarify 
the specific study day 
through which mortality 
analyses will be 
planned to be 
conducted.
2.0, 6.2, 
8.2.2, 8.5.1
Synopsis, 
Secondary 
Objectives, 
Secondary Trial 
Objectives, 
Statistical 
Methods for 
Efficacy Analyses
Removed the word Key from Secondary 
Objectives/Endpoints
Done for simplification 
purposes and to align 
with the planned 
endpoint analysis.
2.0, 8.2.2
Synopsis, 
Secondary 
Objectives
The secondary objective to evaluate the all-cause mortality 
for POS vs. VOR through Day 84 was separated into 2 
objectives, one in the ITT and the other in the FAS
population
Update text to align 
with the planned 
endpoint analyses 
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.0, 6.2, 
8.2.2, 8.5.1
Synopsis, Other 
Secondary Trial 
Objectives, 
Secondary 
Objectives, Other 
Secondary 
Objectives, 
Statistical 
Methods for 
Efficacy Analyses
Other secondary objectives (previously Sections 6.3 and 
8.2.3) were merged with Secondary objectives. Table 13,
Analysis Strategy for Key Efficacy Variables, in Section 8.5.1 
was updated
Merged the 2 sets of 
secondary objectives 
for simplification 
purposes
7.7.1.2, 
7.7.1.3
Secondary 
Endpoints, Other 
Endpoints
Other Endpoints merged with Secondary Endpoints
Merged other endpoints 
with secondary 
endpoints for 
simplification purposes
2.0, 6.2, 
7.7.1.3, 
8.2.3
Synopsis, 
Secondary Trial 
Objectives, Other 
Endpoints, 
Secondary
Following text deleted:

To evaluate the time to global clinical response for 
POS versus VOR in the FAS population

Time to global clinical response at Weeks 2, 4, 6, and 
12 in the FAS population.

To evaluate the global clinical response at Weeks 6 
and 12 in subjects with a diagnosis of possible, 
probable, or proven IA receiving POS vs. VOR in the 
ITT population
Modified text to align 
with the planned 
endpoint analyses
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.0, 6.2, 
8.2.3
Synopsis, 
Secondary Trial 
Objectives, 
Secondary
Added underlined text:
To evaluate, in the subset of subjects that have 
pharmacokinetic data and food intake records, the 
pharmacokinetic profile of POS and VOR, including an 
evaluation of the effect of food intake on the POS tablet 
steady state pharmacokinetic profile, and to evaluate the 
exposure-response (efficacy and safety endpoints) 
relationships of POS and VOR in a subset of subjects with 
available data.
Modified the text to 
align with the planned 
study analysis
2.0, 6.1, 
6.2, 7.1, 
7.7.1.1, 
7.7.1.2, 
8.2.1, 
8.2.2, 8.5.1
Synopsis, Primary 
Trial Objective, 
Secondary Trial 
Objectives, 
Overall Trial 
Design, Primary 
Endpoint, Key 
Secondary 
Endpoints, 
Primary Objective, 
Secondary 
Objectives, 
Statistical 
Methods for 
Efficacy Analyses
Added “through Day 42 and Day 84” as replacement text for 
“Week 6 and Week 12,” for mortality endpoint analysis 
throughout the protocol.
Added, to specifically 
indicate the actual 
endpoint for mortality 
analysis 
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
7.4.1.5.8, 
8.10, 
Investigational 
Medicinal Product 
Accountability, 
Compliance 
(Medication 
Adherence)
Following text was modified in Investigational Medicinal 
Product Accountability and Compliance sections:
In this study, as part of the routine recording of the amount 
of study treatment taken by each patient, at each site, the 
volume of infusion administered and the number of 
tablets/capsules dispensed and returned will be counted, 
reviewed, and recorded at regular intervals at the local level. 
Pharmacy records of dispensing and return of study 
medication will be recorded using local documentation 
records and will be monitored and reviewed by unblinded 
study monitors throughout the study period. Pharmacy 
records will be retained at the local pharmacy and available 
for Sponsor review.  Site records will be used to ensure and 
document study medication compliance.  Study medication 
dosing will be recorded in the electronic case report for each 
study medication component (IV or oral, placebo or active 
drug) based upon local documentation records.  
Text was modified to 
clarify the procedures 
followed to assess drug 
accountability and 
compliance in the study
7.7.1.2
Secondary 
Endpoints
Modified the following text primary:
For the primary global clinical response endpoint (6 weeks) 
the assessment would need to be ± 2 weeks.
Text modified to align 
with study endpoints 
and to clarify that the 
secondary endpoint of 
clinical response would 
include study windows 
of +/- 2 weeks.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
7.7.3.1
Pharmacogenetics 
Endpoints
Following text deleted:

Any significant PGt relationships to outcome will 
require validation in future clinical trials
Added underlined text:

Exploratory analysis genetic testing of the CYP2C19 
polymorphisms and PK/PD, safety and efficacy 
relationships may be conducted as the data allow.
Modified text to align 
with the planned study 
analyses, and to omit 
the requirement for 
future clinical trials to 
further assess PGt 
relationship.
7.7.4
Other Endpoints
Added underlined text:
These PK samples should be collected via peripheral 
venipuncture and not be drawn from the central catheter.
PK/PD correlation tests assessing achievable serum drug 
levels of POS and VOR vs. minimum inhibitory 
concentrations for Aspergillus isolates and global clinical 
response will be conducted on all randomized subjects with 
available data.  Exposure/response assessments will be 
conducted including an exploration of the relationship 
between PK/PD indices with efficacy and safety timepoints 
as available data allow.
Text added to clarify 
the scope of the PK/PD 
data analyses as the 
data allow
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
8.2.3
Exploratory 
Objectives
Added underlined text regarding exploratory objectives:
Please note: The analyses to test the above three 
exploratory objectives may be conducted at a later date, as 
data allow 
Added the text, to 
clarify that the analysis 
of pharmacogenomic 
data may be conducted 
at a future date as data 
allow. 
8.4.1
Efficacy Analysis 
Populations
Added the following underlined text:  
The FAS population consists of all randomized subjects who 
have been classified as having proven or probable IA (based 
upon independent adjudication assessment) using the 
modified 2008 EORTC/MSG definitions, and receive at least 
one dose of study drug  
Language updated to 
clarify the FAS study 
population for analysis 
purposes
8.5.1
Statistical 
Methods for 
Efficacy Analyses
Added the following underlined text:

Mortality will be evaluated through Day 42 and 
through Day 84 with no time window applied either 
before or after the target day.

Global clinical response at Week 6 and Week 12 will 
be evaluated to include the completion of the 
response components within the visit windows, ±2 
weeks for Week 6 and ±4 weeks for Week 12.
Modified Table 13 to align with the planned endpoint 
analyses.
Text updated to align 
with the planned 
endpoint analyses
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
8.5.2
Statistical 
Methods for 
Safety Analyses
Added the underlined text:

Adverse experiences (specific terms as well as 
system organ class terms) and predefined limits of 
change in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 
endpoints prior to database lock will be classified as 
belonging to "Tier 2" or "Tier 3", based on the number 
of events observed.  

CNS and visual safety: Treatment-emergent adverse 
events (TEAEs) of visual abnormalities (including:  
terms related to visual hallucination, diplopia, 
nystagmus, photophobia, photopsia, 
dyschromatopsia, scotoma, hemianopia, optic 
neuritis, uveitis, optic disc disorder, visual impairment, 
vision blurred, visual acuity reduced, blindness, optic 
atrophy, papilledema, and optic neuropathy); 
confusion, hallucination, altered mental status, 
cognitive disturbance, dizziness, altered level of 
consciousness, depressed level of consciousness, 
asterixis, tremor, seizures, or encephalopathy. 
Text modified to 
indicate that a final 
review of the reported 
AE terms will be 
conducted prior to 
database lock to 
determine additional 
related terms that may 
be added to the Tier 1 
evaluations
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
8.5.3
Summaries of 
Baseline 
Characteristics, 
Demographics, 
and Other 
Analyses
Deleted Population PK Analyses
Deleted population PK 
analyses section as 
these analyses will not 
be conducted as a part 
of the planned study 
analysis
8.7.2
Sample Size and 
Power for Efficacy 
Analyses
Modified the following underlined text:
Table 17 summarizes the study power for assumed VOR 
mortality rates ranging between 18% and 28%, for different 
numbers of subjects in each arm, with the POS mortality rate 
ranging from -2% to +2% from the VOR rate.  

For example, if the VOR mortality is assumed to be 
18% and the POS mortality is assumed to be 19% 
with 600 subjects (300/arm) in ITT population, then
this current study design has 80.4% power to 
demonstrate non-inferiority with a 10% margin. 

Alternatively, if the VOR mortality is assumed to be 
22% and the POS mortality is assumed to be 21% 
with 540 subjects (270/arm), then this study design 
has 87.2% power to demonstrate non-inferiority with a 
10% margin.  

If an all-cause mortality rate of 23% is observed in 
270 VOR patients (23%=62/270), the largest 
observed all-cause mortality rate that could be 
observed among POS patients and still meet the non-
inferiority criterion would be 26% (69/270). In this 
Text modified to 
provide supportive 
information and to 
clarify sample size and 
power calculation for 
the statistical analysis
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
instance, the observed difference in mortality rates 
would be again 3.0 percentage points (POS minus 
VOR) with a 95% CI of (-4.7, 9.8).  
Modified Table 17 to include 570 (285/arm) and 540 
(270/arm) subjects.
8.7.3
Sample Size and 
Power for Safety 
Analyses
Added underlined text: 
Table 18 gives the difference in percentage points (POS 
minus VOR) that can be ruled out with different power levels 
and 95% confidence when there are 300 or 285 or 270
randomized subjects in each treatment group. The true 
frequency of subjects experiencing an AE on POS arm is 
assumed the same as that in the VOR arm. For a 
reasonably common adverse experience which occurs in 
20% of subjects receiving either POS or VOR, the study with 
300 randomized subjects in each arm has 90% power to 
declare, with 95% confidence that the true difference 
between group proportions is no more than 12.7 percentage 
points. 
Modified Table 18 to include 570 (285/arm) and 540 
(270/arm) subjects.
Text added to provide 
supportive information 
for the statistical 
analysis
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
8.8
Subgroup 
Analyses and 
Effect of Baseline 
Factors
Following text deleted:

Adolescents (≥13 years to <18 years) and Adults (≥18 
years)

Patients population: (1) proven vs. probable IA; (2) 
probable IA due to galactomannan EIA vs. all other 
probable/proven IA; (3) site of IA infection (lung, 
sinus, multiple sites, etc.); (4) underlying disease; (5) 
neutropenic status at baseline [ANC <500 vs. >500]
Text modified to 
remove the subgroups 
that will no longer be 
included in the planned 
study analyses
8.10
Compliance 
(Medication 
Adherence)
Modified section with underlined text:
For IV study therapy, on each day, each patient should take 
a certain number of infusions/injections encompassing both 
the assigned treatment and any matching placebo (sham 
infusions).  A day within the study will be considered an “On-
therapy” day if the patient receives at least one infusion. 
For oral therapy, on each day, each patient should take a 
certain number of tablets and capsules encompassing both 
the assigned treatment and any dummy placebo tablets or 
capsules. A day within the study will be considered an “On-
Therapy” day if the patient takes one capsules/tablet.  
Text was modified to 
clarify how drug 
accountability and 
compliance will be 
evaluated in the study 
analyses
 
 
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2.0 SYNOPSIS
TITLE OF TRIAL:  A Phase 3 Randomized Study of the Efficacy and Safety of Posaconazole 
versus Voriconazole for the Treatment of Invasive Aspergillosis in Adults and Adolescents (Phase 
3; Protocol No. MK-5592-069).
OBJECTIVES:
Primary Trial Objective:  To compare the all-cause mortality for posaconazole (POS) compared 
to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) through Day 42 in all 
randomized subjects who received at least one dose of study treatment (in the ITT [Intention to 
Treat] population). The hypothesis to be tested is that the all-cause mortality at through Day 42 in 
the POS treatment group is non-inferior to that in the VOR treatment group.
Secondary Trial Objectives:  

To evaluate the all-cause mortality for POS vs. VOR through Day 42 in the FAS population.

To evaluate the all-cause mortality for POS vs. VOR through Day 84 in the ITT populations.

To evaluate the all-cause mortality for POS vs. VOR through Day 84 in the FAS populations.

To evaluate the adjudicated global clinical response for POS vs. VOR at Week 12 in the FAS 
population.

To evaluate the adjudicated global clinical response for POS vs. VOR at Week 6 in the FAS
population.

To evaluate the time to death (all causes) for POS vs. VOR in the FAS population.

To evaluate mortality due to IA through Day 42 and through Day 84 for POS vs. VOR in the 
FAS population.

To evaluate the safety and tolerability of POS and VOR by analyzing Tier 1 Safety events and 
all adverse events.

To evaluate the safety of POS compared to VOR therapy in the All-Patients-as-Treated 
(APaT) population.

To evaluate, in the subset of subjects that have pharmacokinetic data and food intake 
records, the pharmacokinetic profile of POS and VOR, including an evaluation of the effect of 
food intake on the POS tablet steady state pharmacokinetic profile, and to evaluate the 
exposure-response (efficacy and safety endpoints) relationships of POS and VOR. 
Exploratory Objectives:

To explore the effects of CYP2C19 polymorphisms and predicted metabolic enzyme activity 
on POS and VOR plasma concentration.

To explore pharmacogenetic endpoints and their association with key efficacy and safety 
parameters.

To explore the effect of treatment on serological biomarkers (e.g., serum galactomannan EIA, 
beta-D-glucan).
 
 
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Rationale:  
Current guidelines for the treatment of IA recommend the use of VOR as primary therapy [10], 
[23].  Early initiation of antifungal therapy is recommended while the definitive diagnostic 
evaluation is in process.  The duration of azole treatment is not yet well defined; current 
recommendations call for a minimum duration of 6 to 12 weeks in immunocompromised subjects.  
These recommendations are based upon the findings of controlled clinical studies that found initial 
treatment with VOR to be superior to amphotericin B deoxycholate (AmB) in the treatment of 
acute IA.  In an open-label controlled study after 12 weeks of therapy, the global clinical response 
to therapy was 53% in subjects who were randomized to receive VOR with a survival rate of 71% 
compared to a response rate of 32% for AmB and a survival rate of 58% [2] Invasive aspergillosis 
is a serious, life-threatening disease that occurs among patients with prolonged and/or severe 
impairment of the immune system. Without the initiation of antifungal therapy, the acute mortality 
rate has been shown to exceed 85% (Appendix 2). With early diagnosis and the prompt initiation 
of therapy, the mortality rate of patients treated with a mold-active antifungal agent has improved. 
A meta-analysis of all-cause mortality at through Day 42 based on historical data of VOR 
treatment of IA found a mortality rate of 23% [27].  In 2015, a recently completed prospective 
clinical study of isavuconazole(ISA) vs VOR given to patients with invasive aspergillosis reported 
through Day 42 all-cause mortality rate of 18.6% and 20.2, ISA and VOR treatment arms, 
respectively. In the same clinical study, with the use of the 2008 EORTC/MSG guidelines for the 
evaluation of clinical response among subjects with proven or probable IA, a successful clinical 
response at the end of therapy was noted to be 35% and 38.9%, ISA and VOR treatment arms, 
respectively [27].
More effective or safer antifungal therapy is sought for patients with IA.  POS is a highly active 
triazole with the potential to have at least similar efficacy to VOR based on animal model data, 
and some potential advantages in terms of tolerability and drug interactions.  POS was shown to 
be effective in an open label, externally controlled salvage therapy trial of 107 patients with 
proven/probable aspergillosis.  The global clinical response rate (complete and partial response) 
at the end of therapy was 42% in POS treated subjects, compared to 26% in external controls 
receiving standard therapy [5].  In addition, POS has activity against Aspergillus spp. other than A. 
fumigatus, and importantly, against Zygomycetes, which can mimic the clinical presentation of 
aspergillosis in high risk patients.  In this study of refractory IA, there was an exposure response 
association; subjects in the highest quartile with the highest POS exposure (mean Cavg of 1250 
ng/mL) had a higher response (approximately 75%) compared to lower concentration quartiles.
This study will investigate two extended spectrum azoles (POS and VOR) in subjects with proven,
probable or possible IA based on modified EORTC/MSG definitions [1, 10].  Subjects with proven 
invasive fungal infection (IFI) will have confirmed infection based upon detection of the fungus by 
histological analysis or culture of a specimen taken from sterile material from a site of infection.  
Subjects with probable IFI will require the presence of appropriate host factors, clinical criterion, 
and a mycological criterion including both direct tests and indirect tests including galactomannan 
antigen detection.  Subjects with possible IA will meet the criteria for a host factor and a clinical 
criterion, but without confirmatory mycological criterion.  Subjects who are enrolled with a 
diagnosis of possible IA will undergo additional diagnostic work-up to confirm proven or probable 
IA post-randomization.  Subjects with possible IA diagnosis will continue in the study, and all 
randomized subjects who receive at least one dose of study drug will be evaluated as the ITT 
study population. Subjects with a diagnosis of proven or probable IA (based on modified 
EORTC/MSG definitions) will be considered part of the FAS population.  By enrolling subjects as 
early as possible, it is hoped that better outcomes overall will be achieved, based on data 
indicating that early intervention improves survival [11, 26]. Subjects enrolled into this study may 
be randomized to treatment with either POS IV or POS tablet formulations.  Merck has developed
and registered IV and oral tablet formulations of POS that are able to achieve a higher exposure 
target with reduced variability compared to POS oral suspension [6, 29]. Phase 1B/3 studies have 
been conducted in patients treated with POS IV solution and POS oral tablet given as antifungal 
prophylaxis. In patients, the mean steady state Cavg exposure for POS IV solution 300 mg QD 
was 1430 ng/ml; the mean steady state Cavg exposure for POS tablet 300 mg QD was 1460 
ng/ml [29].  With these new formulations, the desired exposure target for the treatment of invasive 
 
 
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aspergillosis (Cavg at least 1250 ng/mL) will be more rapidly and more consistently achieved.  In 
the strategy employed by this protocol, a sufficient number of subjects with well documented IA 
can be enrolled within a reasonable time, following treatment paradigms which reflect clinical 
practice and provide data to support the safety and efficacy of POS versus VOR in the treatment 
of patients who have suspected or documented aspergillosis.
Trial Design
Overview:  This is a Phase 3, randomized, double-blind study of POS versus VOR in subjects with 
IA as defined by modified EORTC/MSG consensus criteria.  Subjects with features consistent with 
proven, probable, or possible IA will be enrolled.  All randomized subjects who receive at least 
one dose of study drug will be included in the primary ITT population.  Subjects who are enrolled 
with a diagnosis of possible IA will undergo additional diagnostic work-up to confirm proven or 
probable IA post-randomization are to be included in the secondary FAS population.
At the time of study enrollment, subjects will be randomized to receive one of two possible 
treatment arms: POS or VOR for a maximum total duration of therapy of 12 weeks.  In general, 
most subjects should receive the full 12 weeks of study therapy.  Subjects will be randomized to 
POS or VOR in a 1:1 ratio.  Overall, approximately 600 subjects will be enrolled, randomized and 
treated in the study will comprise the primary ITT population (approximately 300 ITT-eligible
subjects per treatment arm).  The study will also evaluate subjects whose diagnosis of proven or 
probable IA as confirmed by an independent Clinical Adjudication Committee (CAC) will comprise 
the secondary FAS study population.  The FAS further requires subjects to have received at least 
one dose of study drug and have at least one post-randomization observation for the analysis 
endpoint subsequent to at least one dose of study treatment (and have baseline data for those 
analyses requiring baseline data).
Most subjects will begin antifungal azole (VOR or POS) therapy via the IV route; however, some 
may begin therapy via the oral route.  Azole therapy will be switched from IV route to the oral 
route when the subject is considered clinically stable and able to take oral medication.  The 
assigned azole treatment (POS or VOR) will be provided in a double-blind manner.  All subjects 
will be treated with study drug for up to 12 weeks. The primary study objective is to evaluate 
mortality through Day 42 in the ITT study population. The final study visit (follow-up evaluation) 
will be done 1 month (Day 114 following randomization) after the end of treatment visit.  
Ultimately, subjects who complete 12 weeks of study treatment will participate in the study for a 
total of approximately 16 weeks post-randomization.
Overview of Active Study Drug Dosing by Treatment Arms
Treatment Arms
IV Therapya
Oral Therapy
Arm 1 – Posaconazole (POS)
POS IV:
Day 1b: 300 mg BID
Day 2-84c: 300 mg QD
POS oral: 
Day 1b: 300 mg BID
Day 2-84c: 300 mg QD
Arm 2 – Voriconazole (VOR)
VOR IV:
Day 1b: 6 mg/kg per body 
weight administered BID
Day 2-84c: 4 mg/kg per body 
weight administered BID
VOR oral: 
Day 1b:  300 mg BID
Day 2-84c: 200 mg BID
a Subjects will begin IV study drug and then step down/transition to oral study drug.  If clinically 
indicated, some subjects may begin study drug with oral therapy instead of IV therapy.
bDay 1 refers to the first day of subject taking either IV or Oral therapy.  Subjects will only take 
one formulation, either IV or oral at a time
c The planned duration of study therapy is 12 weeks (84 days) with a maximum allowable 
duration of up to 98 days. IV=intravenous; POS=posaconazole; VOR=voriconazole
Diagnostic and efficacy data from all subjects will be reviewed by an independent Clinical 
Adjudication Committee (CAC) who will be blinded to the assigned treatment arm.  The CAC will 
determine acceptability of the diagnostic criteria according to modified MSG/EORTC consensus 
criteria [9].  Subjects who are randomized and receive at least one dose of study drug will 
 
 
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comprise the ITT dataset. In addition, subjects whose diagnosis of proven or probable IA is 
confirmed post-randomization by the CAC will comprise the FAS dataset.  The CAC will 
adjudicate classification of the global clinical response to treatment (as per modified 2008 
EORTC/MSG guidelines) at 6 weeks and at 12 weeks/end-of therapy (EOT) post-randomization.  
A successful global clinical response will be defined as an FAS-evaluable subject who is judged 
by the CAC to be alive and have a complete or partial response at the time points of interest.  The 
CAC will also adjudicate IFI-attributable mortality through Day 42 and Day 84 in subjects as data 
allow.
The primary analysis will test for non-inferiority of all-cause mortality for POS compared to VOR
through Day 42.  The primary analysis will be conducted in the ITT population.  
Secondary analyses will include a comparison of global clinical response at Week 6 in the FAS 
data set. The FAS population consists of all randomized subjects who have confirmed proven or 
probable IA (based on modified 2008 EORTC/MSG definitions) post-randomization and who 
receive at least one dose of study treatment and have at least one post-randomization 
observation for the analysis endpoint subsequent to at least one dose of study treatment (and 
have baseline data for those analyses requiring baseline data).  Additional secondary analyses 
include all-cause mortality through Day 42 and Day 84 in the FAS population, global clinical 
response at both Week 6 and Week 12 in the FAS population and all-cause mortality through Day 
84 in the ITT population. Safety will also be evaluated for both treatment groups using an All-
Patients-as-Treated (APaT) population, which includes all subjects who received at least one 
dose of study treatment. 
The primary endpoint, corresponding to the primary trial objective, is all-cause mortality through 
Day 42 in subjects in the ITT population. The primary analysis is to compare the POS arm to the 
VOR arm. The difference in mortality rate between arms (POS minus VOR) and the associated 
95% confidence interval (CI) on the difference will be calculated using Miettinen and Nurminen’s 
method [13] stratified by risk for mortality/poor outcome (high risk, not high risk).  If the upper limit 
of that CI is less than 10% (the non-inferiority margin), then non-inferiority of POS will be declared.  
If non-inferiority is declared, it can be further concluded that POS is superior to VOR if the lower 
limit of the CI exceeds zero.  Due to the principle of closed testing, no adjustment for multiplicity is 
required since non-inferiority can always be concluded whenever the data also supports 
superiority.  Summary statistics and a tabulated treatment comparison will be provided.
Number of Trial Centers:  Up to155 global centers will be selected for inclusion.
Duration of Participation:  Each subject will participate in the trial for approximately 16 weeks from 
the time the subject signs the Informed Consent Form (ICF) through the final contact.  After a
screening phase of up to 7 days, each subject will be receiving assigned treatment for a maximum 
of 12 weeks.  In general, most subjects should receive the full 12 weeks of study therapy.   After 
the Week 12 visit, each subject will have a final study visit 4 weeks after the Week 12 visit.
Duration of Trial:  Approximately 4 years to complete study enrollment and 4 months (16 weeks) 
to complete study treatment and follow-up.
 
 
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Key Inclusion/Exclusion Criteria:  
Key Inclusion Criteria:
1.
Each subject must be willing and able to provide written informed consent for the trial.  The 
legal representative (e.g., parent or guardian) for a subject under the age of legal consent or 
who otherwise is unable to provide independent consent may provide written informed 
consent for the subject.  Each subject of the age of assent must be willing and able to provide 
assent in addition to consent from the legal representative to participate in the trial.  
2.
Each subject must be ≥13 years of age weighing >40 kg [88 lb] and ≤150 kg [330 lb] at the 
time of randomization. Each subject between 13 and 14 years of age must weigh ≥50 kg [110 
lb]. Subjects may be of either sex and of any race/ethnicity.  For those sites that do not have 
the ability to enroll adolescents, subjects must be greater than ≥18 years of age.
3.
Each subject must meet the criteria for proven, probable, or possible IA as per 2008 
EORTC/MSG disease definitions at the time of randomization.  Proven IA will include those 
subjects with the demonstration of fungal elements (by cytology, microscopy, or culture) in 
diseased tissue (sterile sampling).  Probable IA includes subjects with at least 1 host factor, 
clinical criteria, as well as mycological criteria including both direct and indirect (i.e., detection 
of serum, or BAL fluid Aspergillus galactomannan antigen by sandwich EIA) methods.  Two 
consecutive serum galactomannan EIA values ≥0.5 or a single value of ≥1.0 may be used as 
the sole microbiological criterion for probable IA.  A single galactomannan EIA value of ≥1.0 in 
a BAL sample may be used to meet the microbiological criteria for probable IA.  For subjects 
receiving piperacillin/tazobactam within 72 hours of serum galactomannan sampling, serum 
galactomannan criteria for probable IA will not meet the criteria for probable IA.  Possible IA 
includes subjects with at least 1 host factor and clinical criteria but without mycological criteria.  
A modification to the 2008 EORTC/MSG criteria regarding risk factors has been made to allow
for the inclusion of subjects with any duration of neutropenia as an acceptable inclusion host 
factor. See Appendix 3 for tables of diagnostic criteria.
4.
Each subject with possible IA at time of randomization must be willing or be in process of an 
ongoing diagnostic work up which is anticipated to result in a mycological diagnosis of proven 
or probable IA post-randomization.
5.
Each subject 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.
Subjects without central catheter access must be clinically stable and able to receive oral 
study therapy.  
6.
Each subject must have acute IA defined as duration of clinical syndrome of <30 days.
7.
Each subject must be willing to adhere to dosing, study visit schedule, and mandatory 
procedures as outlined in the protocol.  The subject must be willing to continue on study 
therapy for up to 12 weeks and remain in the study through the 1-month follow-up.
8.
The subject must have the ability to transition to oral study therapy during the course of the 
study.
9.
Female subjects of child-bearing potential must be using a medically accepted method of birth 
control before beginning study-drug treatment and agree to continue its use for 30 days after 
stopping the medication, or have been surgically sterilized (e.g., hysterectomy or tubal 
ligation).  For those subjects using oral or injectable hormonal contraception, a barrier method 
of birth control (e.g., condom in combination with spermicide) is necessary.  Female subjects 
of childbearing potential should be counseled in the appropriate use of birth control while in 
this study.  Vasectomy of the partner and tubal ligation should each be considered effective 
methods of birth control.
Female subjects who are not currently sexually active must agree and consent to use one of 
the above-mentioned methods should they become sexually active while participating in the 
study.
10. To participate in the pharmacogenetic analysis, the subject must be willing to give written 
 
 
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informed consent for the pharmacogenetic testing and able to adhere to dose and visit 
schedules.  Note:  A subject unwilling to sign the informed consent for pharmacogenetic 
testing may be included in the trial; however, pharmacogenetic samples must not be obtained.
11. Subject is not taking prohibited antifungal prophylaxis or treatment as defined by the protocol.  
Examples of allowable Antifungal Therapy Allowed Prior to Randomization are shown in 
Figure 1.
Key Exclusion Criteria:
1.
The subject has chronic (>1-month duration) IA, relapsed/recurrent IA, or refractory invasive 
aspergillosis which has not responded to prior antifungal therapy.
2.
The subject has chronic pulmonary aspergillosis, pulmonary sarcoidosis, aspergilloma, or 
allergic bronchopulmonary aspergillosis (ABPA).
3.
The subject has a known mixed invasive mold fungal infection including Zygomycetes, and/or 
a known invasive Aspergillus fungal infection in which either study drug may not be 
considered active.
4.
The subject has received any systemic (oral, intravenous, or inhaled) antifungal therapy for 
this infection episode for 4 or more consecutive days (≥96 hours) immediately prior to 
randomization.  
5.
The subject has developed the current episode of IA infection (possible, probable, or proven 
infection) during the receipt of more than 13 days of an azole or polyene antifungal agent 
given for prophylaxis that is considered to be a mold-active, antifungal agent (including 
itraconazole, posaconazole, voriconazole, isavuconazole, inhaled or systemic amphotericin or 
lipid-associated amphotericin), Any duration of echinocandin antifungal use is allowed (prior to 
randomization).
6.
The subject has received POS or VOR as empirical treatment for this infection for 4 days (96 
hours) or more within the 15 days immediately prior to randomization. 
7.
The subject has received any treatment specifically listed in Table 2 which is more recent 
than the indicated washout period prior to randomization.
8.
A subject must not have any condition that, in the opinion of the investigator, may interfere 
with optimal participation in the study, i.e., any condition requiring the use of prohibited drugs 
or unstable medical conditions other than the hematological disorder such as cardiac or 
neurologic disorder or impairment expected to be unstable or progressive during the course of 
this study (e.g., seizures or demyelinating syndromes, acute myocardial infarction within 
3 months of study entry, myocardial ischemia, or unstable congestive heart failure, unstable 
arrhythmias, atrial fibrillation with ventricular rate <60/min, or history of torsades de pointes, 
symptomatic ventricular or sustained arrhythmias, unstable electrolyte abnormalities [e.g., 
Grade 2 hypokalemia or hypomagnesemia]).
9.
The subject has known hypersensitivity or other serious adverse reaction to any azole 
antifungal therapy, or to any other ingredient of the study medication used.
10. The female subject is pregnant, intends to become pregnant, or is nursing at the time of 
randomization.
11. The subject has any known history of Torsade de Pointes, unstable cardiac arrhythmia or 
proarrhythmic conditions, or a history of recent myocardial infarction within 90 days of study 
entry.
12. The subject has QTc (either Fridericia or Bazett’s correction) interval ≥500 msec on 
electrocardiogram performed at screening or baseline.
13. The subject has significant liver dysfunction (defined as total bilirubin > 1.5 times upper limit of 
normal AND AST or ALT > 3 times upper limit of normal with normal alkaline phosphatase 
[ALP] on screening labs) at the time of randomization.
14. The subject has hepatic cirrhosis or a Child-Pugh score of C (severe hepatic impairment) at 
the time of randomization.   See Appendix 4 for Child-Pugh Classification.
15. The subject has severe renal insufficiency (estimated creatinine clearance <20 mL/min) or on 
 
 
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hemodialysis at the time of randomization or is likely to require dialysis during the study.
16. The subject has a known hereditary problem of galactose intolerance, Lapp lactase 
deficiency, or glucose-galactose malabsorption.
17. The subject has acute symptomatic pancreatitis within 6 months of study entry or has a 
diagnosis of chronic pancreatitis at the time of randomization.
18. The subject has an active skin lesion consistent with squamous cell carcinoma at the time of 
randomization, or a current or prior history of malignant melanoma within 5 year of study 
entry.
19. The subject is on artificial ventilation or receiving acute Continuous positive airway pressure 
(CPAP)/ Bilevel Positive Airway Pressure (BPAP) at the time of randomization.
20. A subject has known or suspected Gilbert’s disease at the time of randomization.
21. The subject requires treatment with other medications that cannot be stopped and for which 
there is a known contraindication to co-administration of one or more of the study drugs.
22. The subject is not expected to survive for at least 1-week post-randomization.
23. The subject must not have prior enrollment in this study.  The subject must not have prior 
enrollment in other POS studies within 90 days of study entry.
24. The subject or a family member is among the personnel of the investigational or sponsor staff 
directly involved with this trial.
INVESTIGATIONAL PRODUCT, DOSE, MODE OF ADMINISTRATION
Investigational Product:  

POS IV Loading dose (Day 1):  300 mg IV Q 12 hours (BID) for 2 doses.

POS IV Maintenance dose (Beginning with the third dose): 300 mg IV Q 24 hours (once daily)

POS Oral (through Week 12): POS tablet 300 mg QD to begin following transition from POS 
IV.
Transition to oral therapy may occur when the subject is considered clinically stable and able to 
take oral medication.  If clinically indicated, some subjects may begin therapy with oral 
medication.  If this occurs, a loading dose of POS 300 mg BID will be taken for the first day only.  
Subjects who are randomized to receive reference product (VOR Oral) will receive a double-
dummy tablet with appearance consistent with POS tablet when transition to oral therapy.
IV infusions will be masked to blind the differences in appearance of study drug.  Matching 
placebo infusions of 5% dextrose in water will be used for the additional daily doses in subjects 
randomized to POS to make the number of infusions per day (2) similar in the 2 treatment arms.
Reference Product:  

VOR IV Loading dose (Day 1): 6 mg/kg of body weight administered IV Q 12 hour (BID).

VOR IV Maintenance dose (Beginning on Day 2): 4 mg/kg of body weight administered IV Q 
12 hours (BID).

VOR Oral (through Week 12):  VOR oral capsule 200 mg BID to begin following transition 
from VOR IV.
Transition to oral therapy may occur when the subject is considered clinically stable and able to 
take oral medication.  If clinically indicated, some subjects may begin therapy with oral 
medication.   If this occurs, a loading dose of VOR 300 mg BID will be taken for the first day only.  
Subjects who are randomized to receive investigational product (POS Oral) will receive a double-
dummy capsule with appearance consistent with VOR capsule when transition to oral therapy.
IV infusions will be masked to blind the differences in appearance of study drug.
 
 
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STATISTICAL METHODS:  
Type of Blinding: Double-Blind, Double-Dummy (for Oral Administration)
Only the investigational pharmacists or qualified medical personnel responsible for preparing the 
study drug will have knowledge of the treatment identity and will prepare study medications 
according to the protocol guidelines; all other study personnel will be blinded to study treatment.  
The unblinded pharmacists will not be involved in any post-treatment assessments for the 
subjects enrolled in this trial.  Preparation of IV study therapy will be done by study personnel who 
are not otherwise involved in the clinical assessment (efficacy and safety assessments) of the 
subject.  In order to maintain the blind, preparation of the intravenous study drugs must be 
performed by someone other than the persons who will evaluate the subject for clinical response 
and presence of adverse experiences.
IV infusions will be masked to blind the appearance of the IV study drugs.  Matching placebo 
infusions of 5% dextrose will be used for the additional daily doses to make the number of 
infusions per day (2) similar in both treatment arms.
Oral POS tablets and oral VOR capsules will be administered using a double-dummy, double-
blind method to blind study personnel and subjects as to the assigned treatment arm.  Oral VOR 
will be given as over-encapsulated tablets with each capsule containing 100 mg of VOR or a 
placebo to VOR. The POS oral tablet will also be blinded by use of a dummy tablet with each 
tablet containing 100 mg of POS or a placebo to POS.
As VOR labeling recommends, dosage adjustment based upon hepatic insufficiency will be made.  
Appropriate dosing modifications will be included in the trial design in a blinded fashion.  There is 
no planned dose reduction or dose adjustment of POS IV or POS oral tablet or POS dummy 
tablet.
This study will be conducted using in-house blinding procedures.
The primary hypothesis will be evaluated through Day 42 and the additional efficacy and safety 
data will be evaluated at Week 12, and 4 weeks following the Week 12 visit. All subjects will be 
followed for the entire study duration. For the final analyses, all data will be screened, 
discrepancies resolved, and protocol violators identified before the data are unblinded.  All data-
handling guidelines and actions will also occur prior to data unblinding according to sponsor’s 
SOP for double-blind studies with in-house blinding.
Subject Replacement Strategy:  Subjects will not be replaced in this study.
Randomization:  Subjects will be randomly assigned (in a 1:1 ratio) to receive either POS or VOR 
according to a computer-generated randomization schedule using the interactive voice response 
system (IVRS).
Stratification:  Subjects will be stratified prior to treatment assignment by risk status for 
mortality/poor outcome.
High Risk: Any one of the following are present at Baseline or in the patient’s medical history:
•
Allogeneic hematopoietic stem cell transplant (HSCT).
•
Relapsed leukemia, undergoing salvage chemotherapy.
•
Liver transplant recipients [12].
Not High Risk: Any other eligible subject (none of the high-risk criteria are present at Baseline or 
in the subject’s medical history)
 
 
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Data Sets to be Analyzed:  The primary analysis will be performed on the ITT population.   The 
ITT population consists of all randomized subjects who have received at least one dose of study 
drug.  Secondary analyses will be based on the FAS population which includes subjects with 
confirmed proven or probable IA (based on 2008 modified EORTC/MSG definitions) and who: 1) 
receive at least one dose of study treatment; 2) have at least one post-randomization observation 
for the analysis endpoint subsequent to at least one dose of study treatment; 3) have baseline 
data for those analyses that require baseline data.  Safety analyses will be based on the all-
patients-as-treated (APaT) population, which includes all subjects who received at least one dose 
of study treatment. The FAS population consists of all randomized subjects who have at least one 
post-randomization observation for the analysis endpoint subsequent to at least one dose of study 
treatment (and have baseline data for those analyses requiring baseline data).  
Sample Size:  Approximately 600 subjects will be enrolled in this study, receive study drug and 
be randomly assigned in a 1:1 ratio to receive either POS or VOR. This sample (approximately 
300 randomized subjects in each azole arm) will have ~ 82.7% power (with 1-sided alpha=0.025) 
to show non-inferiority of POS compared to VOR using a 10% margin assuming an all-cause 
mortality through Day 42 of 23% for both treatment groups.  This assumed rate is based on a 
meta-analysis of historical VOR mortality data [27].  If the criteria for non-inferiority are met, then a 
superiority analysis of POS over VOR will be assessed.
Efficacy Analysis:  
The primary analysis will be performed on the ITT population, which consists of all randomized 
subjects who received at least one dose of study treatment. 
The primary endpoint in this study is all-cause mortality through Day 42 and which will be 
compared between the POS arm and the VOR arm for the ITT population.  The primary analysis 
will be assessed using a non-inferiority margin of 10%.  Ninety-five percent Confidence Intervals 
(CI), adjusted for stratification factors for the difference in success rates (POS minus VOR) will be 
computed.  If upper limit of that CI is less than 10%, then non-inferiority of POS will be declared.  
If non-inferiority is declared, then superiority of POS over VOR will be assessed and will be 
declared if the lower limit of the CI is greater than 0.
Secondary endpoints include the global clinical response at Week 6 and Week 12 in the FAS 
population, all-cause mortality through Day 42 and Day 84 in the FAS population and all-cause 
mortality through Day 84 in the ITT population.  All will be evaluated using a similar methodology 
as that for the primary analysis.  
Other endpoints (i.e., time to death [all causes] in the FAS population; and mortality due to IA at 
Weeks 6 and 12 in the FAS population) will also be analyzed. Adjudicated global clinical response 
Weeks 6 and 12 in subjects with possible, probable, or proven IA subjects (ITT population) will 
also be assessed as a secondary endpoint. 
Survival will be assessed using a Kaplan Meier estimates and will be compared between the two 
arms using the Log-Rank test.
Other analyses:  Sparse pharmacokinetic (steady state trough) sampling will be performed on all 
subjects throughout the treatment period.   Data regarding food intake relative to posaconazole 
tablet administration will be collected and the effect of food on the steady state pharmacokinetics 
of posaconazole tablet will be evaluated.  Plasma concentrations over time in individual subjects 
including adolescents will be evaluated including an evaluation of plasma concentrations at the 
time of adverse events. In subjects receiving IV study therapy, at the time of maximum 
concentration, data regarding ECG parameters will be evaluated.  Exploratory analysis may be 
conducted on pharmacogenomic endpoints and their association with key efficacy and safety 
parameters at a later date, as data allow. 
 
 
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Safety Analysis:  The incidence of serious adverse events (SAEs), incidence of treatment-
emergent and treatment-related AEs (overall, treatment-related, and selected AEs of interest) as 
well as other safety endpoints will be summarized by treatment groups.
The analysis of safety results will follow a tiered approach.  The tiers differ with respect to the 
analyses that will be performed.  The following four categories are Tier 1 events:
•
Hepatic safety:  Elevated AST or ALT lab value that is ≥3 x the upper limit of normal (ULN) 
and an elevated total bilirubin lab value that is ≥2 x ULN and, at the same time, an alkaline 
phosphatase lab value that <2 ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing;
•
CNS and visual safety:  Treatment-emergent adverse events (TEAEs) related to CNS or 
visual disturbances.  See Section 8.5.2 for a list of terms;
•
Dermatologic reactions:  TEAEs including rash and photosensitivity rash;
•
Adrenal steroidogenesis:  TEAEs indicating adrenal insufficiency or temporally associated 
TEAEs of hypotension.
The following are Tier 2 events based on specific AE categories:  (1) proportion of subjects with at 
least one adverse experience; (2) proportion of subjects with at least one drug related adverse 
experience; (3) proportion of subjects with at least one serious adverse experience; (4) proportion 
of subjects with at least one serious and drug related adverse experience; (5) proportion of 
subjects who discontinued study therapy due to an adverse experience.  95% confidence intervals 
(Tier 2) will be provided for between-treatment differences in the percentage of subjects with 
events; these analyses will be performed using the Miettinen and Nurminen method, an 
unconditional, asymptotic method.
The APaT population will be used to assess safety in this study.  All patients who received at least 
one dose of study treatment will be included in the APaT population.
Pharmacogenetics:  Exploratory analysis may be conducted on pharmacogenomic endpoints 
and their association with key efficacy and safety parameters at a later date, as data allow
eDMC:  Safety will be monitored by the external Data Monitoring Committee (eDMC) on an 
ongoing basis and the eDMC will make recommendations to the Sponsor as appropriate.
 
 
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2.1
Trial Design Diagram
 
 
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2.2
Trial Flow Chart
Study Procedures
Screening
Baseline
Treatment Phase
Follow-Up
Unscheduled
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
UW       
Day Relative to First 
Dose of Study Drug
Days -7 to 
-1
Day 1
Day 
3 
(± 1 
day)
Week 
1
[Day 
4 to 8]
Week 
2 
[Day 9 
to 15]
Week 
4
[Day 
16 to 
29]
Week 
6 
[Day 
30 to 
54]
Week 12 
/ EOTa
[Day 84  
(±4 
weeks)]
30 Days 
Posttherapy 
(±2 weeks)
Unscheduled        
Informed Consent/assent
X
Review 
Inclusion/Exclusion 
Criteria
X
X
Issue Subject 
Identification Card
X
Collect Subject 
Identification Card
X
Medical/Disease History
X
Pharmacogenetics 
Sampling (optional)b
X
Stratification and 
Randomization by IVRS
X
Problem Focused 
Physical Examination
X
X
X
X
X
X
X
X
X
Weight
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
Recording of Previous 
Treatmentsd
X
X
Assessment of Clinical 
Signs and Symptoms of 
Invasive Aspergillosis
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (ECG)z
X
Xe
X
X
Xf
X
Hematologyg
X
X
X
X
X
X
X
X
X
X
Serum Chemistryh
X
X
X
X
X
X
X
X
X
X
Serum hCG Pregnancy 
Testi
X
X
 
 
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Study Procedures
Screening
Baseline
Treatment Phase
Follow-Up
Unscheduled
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
UW       
Day Relative to First 
Dose of Study Drug
Days -7 to 
-1
Day 1
Day 
3 
(± 1 
day)
Week 
1
[Day 
4 to 8]
Week 
2 
[Day 9 
to 15]
Week 
4
[Day 
16 to 
29]
Week 
6 
[Day 
30 to 
54]
Week 12 
/ EOTa
[Day 84  
(±4 
weeks)]
30 Days 
Posttherapy 
(±2 weeks)
Unscheduled        
Serum for Aspergillus
Galactomannan EIAj, x
X
X
X
X
X
X
X
X
X
X
Serum for Beta-D-Glucan 
Assayj
X
X
X
X
X
X
X
X
X
X
Mycology Testingk
X
X
X
X
X
X
X
X
Blood for CYP 2C19 
genotypingl
X
Diagnostic Imagingm, x
X
Xn
Xn
Xn
Xo
X
Xp
X
Study Drug Dosingq
X
X
X
X
X
X
X
X
Concomitant Treatmentsr
X
X
X
X
X
X
X
X
X
Assess Global Clinical 
Response
Xt
X
Plasma Pharmacokinetic 
Assessments
X
X
X
X
X
X
X
Collect Unused 
Medications
X
X
X
X
X
X
X
Study Medication Diary/ 
Dosing Compliance 
Assessment y
X
X
X
X
X
X
X
Drug Accountability 
Inventory
X
X
X
X
X
X
X
Safety (Adverse Events) 
Evaluation
X
X
X
X
X
X
X
X
X
X
l /  IFI Assessmentu
X 
X    
X 
Mortality Assessment u
X
X
X
X
X
X
X
X
 
 
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Study Procedures
Screening
Baseline
Treatment Phase
Follow-Up
Unscheduled
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
UW       
Day Relative to First 
Dose of Study Drug
Days -7 to 
-1
Day 1
Day 
3 
(± 1 
day)
Week 
1
[Day 
4 to 8]
Week 
2 
[Day 9 
to 15]
Week 
4
[Day 
16 to 
29]
Week 
6 
[Day 
30 to 
54]
Week 12 
/ EOTa
[Day 84  
(±4 
weeks)]
30 Days 
Posttherapy 
(±2 weeks)
Unscheduled        
a        Subjects who receive less than 12 weeks of therapy, must complete the End of Therapy (EOT) procedures.  The planned duration of study therapy is 
12 weeks (84 days) with a maximum allowable duration of up to 98 days.
b
Informed consent for pharmacogenetic samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on 
Day 1 (or with the next scheduled blood draw), as the last sample drawn, on randomized subjects only, or at a later date as soon as the informed consent 
is obtained.  DNA samples for future use should be collected after informed consent for Pharmacogenetics sampling has been obtained.
c
Vital signs should be recorded in the eCRF daily for hospitalized subjects and on scheduled days, if outpatient.  While subjects are on IV treatment, 
vital signs should be collected daily.  Temperature recorded should be highest temperature (maximum temperature) for each day.  For screening period, 
daily maximum temperature for 5 days prior to Day 1 should be recorded.
d
A record of all prior medication (prescription or over the counter) taken by the subject within 7 days before starting the study is to be obtained and 
recorded in the subject's eCRF.  A record of chemotherapeutic agents used for any chemotherapy regimen within 30 days of Enrollment is to be obtained.  
A record of all prior immunosuppressive therapies and antifungal therapy should be recorded for 30 days prior to Baseline through Day 1.  
e
The Day 1 ECG should be performed prior to initiation of study treatment.
f
Assessments to be performed for early termination due to treatment failure or premature discontinuation due to adverse events (AEs) where the exam 
would be pertinent (i.e., ECG for cardiac AE, etc.).
g
The hematology panel will include: red blood cell count (RBC), white blood count (WBC), WBC differential, absolute neutrophil count (ANC), 
hemoglobin, hematocrit, and platelet count.
h
The following serum chemistry tests should be performed:  calcium, magnesium, albumin, glucose, potassium, sodium, chloride, creatinine, total 
protein, lactate dehydrogenase (LDH), uric acid, blood urea nitrogen (BUN) or urea, total bilirubin, alkaline phosphatase (ALK-P), AST (or SGOT), and 
ALT (or SGPT).
i
A serum beta-hCG test should be performed at screening for all women of childbearing potential.
j
Serum for Aspergillus Galactomannan enzyme immunoassay (EIA) and Beta-D-Glucan should be collected at all requested timepoints. The 
quantitative value and time of collection of the galactomannan sample should be documented for all galactomannan tests performed on patients. The 
results of all galactomannan samples taken during the period from screening to the 1 month follow up visit should be provided. Broncho-alveolar lavage 
fluid should be collected for the Aspergillus galactomannan assay, as necessary; however, the use of Plasma-Lyte for the bronchoscopy is not allowed.  
Galactomannan EIA serological test results may not be used to confirm a probable diagnosis of invasive aspergillosis if subjects are taking 
piperacillin/tazobactam within 72 hours of serum sampling.
k
Mycology testing includes standard fungal cultures from all sites of suspected Aspergillus infection, as clinically appropriate.  Unless clinically 
inappropriate or not warranted due to the patient’s health, condition or disease progression/ regression, mycology testing should occur at the following 
visits: screening/ baseline, Week 6 and Week 12.  Additional mycology testing will be done as clinically indicated and should correlate with potential 
disease regression/progression.  Repeated sampling of infected sites (e.g., repeated lung biopsies) to evaluate for response to therapy may not be 
feasible or clinically warranted.  Identification to species level and minimum inhibitory concentration (MIC) testing will be done by a central reference 
laboratory on subcultures provided by each investigative site.  All fungal isolates clinically relevant to infection should be stored locally for shipment to a 
central laboratory.
l          Blood for DNA will be obtained as a mandatory sample to determine CYP2C19 genotype status.   
 
 
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Study Procedures
Screening
Baseline
Treatment Phase
Follow-Up
Unscheduled
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
UW       
Day Relative to First 
Dose of Study Drug
Days -7 to 
-1
Day 1
Day 
3 
(± 1 
day)
Week 
1
[Day 
4 to 8]
Week 
2 
[Day 9 
to 15]
Week 
4
[Day 
16 to 
29]
Week 
6 
[Day 
30 to 
54]
Week 12 
/ EOTa
[Day 84  
(±4 
weeks)]
30 Days 
Posttherapy 
(±2 weeks)
Unscheduled        
m
At screening/ baseline, Week 6 and Week 12, Diagnostic imaging required of all attributable infected sites of disease.  High-resolution CT scan 
required for all subjects with pulmonary sites of infection.  A chest X-ray is deemed insufficient for assessment of pulmonary IA.
n
Imaging will only be performed at this visit if the clinical infectious condition changes relative to the previous assessment and repeat imaging is judged 
warranted by the clinician.
o
Imaging for the Week 6 visit can be performed at Week 6 ± 2 weeks.
p
Imaging for this visit will only be performed if there is relapse or worsening of the clinical infectious condition relative to the end-of-treatment 
assessment.
q
Study drug dosing (POS or VOR) will occur on every day from Day 1 through Day 84 (maximum allowable duration of up to 98 days).  While 
hospitalized, the timing of dosing will be recorded in the dosing record at the time of dosing.  While outpatient, subjects will maintain daily dosing record 
with recording of actual time of dosing at the time of administration.  While receiving IV treatment, vital signs should be collected daily. While receiving 
POS tablet or POS tablet placebo, the timing and characteristics of food taken should be recorded in the study medication diary and eCRF for each tablet 
dose.
r
All concomitant treatments, include medications and therapeutic procedures, should be recorded in the eCRF.
s
Plasma samples will be collected in all subjects including adolescents prior to the first dose of study treatment at Baseline, and at pre-dose on Day 7, 
Week 2, Week 4, Week 6, and Week 12 (EOT).  For adult subjects on IV therapy, at the Week 1 visit an additional plasma sample will be collected at the 
time of completion of the 90-minute infusion (i.e. at the time of anticipated Cmax). This PK sample should be collected via peripheral venipuncture and not 
be drawn from the central catheter. For adolescents on IV therapy, plasma samples will be collected at the time of completion of their 90-minute infusion 
at Day 7, Week 2, Week 4, Week 6 and Week 12 (EOT). These PK samples should be collected via peripheral venipuncture and not be drawn from the 
central catheter. Subjects who are receiving oral study therapy at the week 1 study visit do not need to collect the additional PK sample.  If a subject 
discontinues early, a PK sample (predose, if possible) should be collected at the time of study therapy discontinuation with the time of PK sample noted.  
t       Visit 7 window (Week 6, Day 30-54) is slightly different from the window for the Global Clinical Response assessment at Week 6 (± 2 weeks)u       All 
subjects randomized and treated are to be followed for mortality assessment throughout the study period until Day114, regardless of whether the subject 
discontinues study therapy prior to Visit 8 Day 84.
W    Labs and Procedures at unscheduled visits should only be performed as clinically appropriate.
x    All imaging results and galactomannan testing performed within 7 days of randomization should be recorded. For imaging and galactomannan testing, 
if the procedure is performed prior to screening a patient for the study and meets protocol requirements.  The results can be used for screening 
procedures as long as procedures were done within 7 Days of randomizing the patient.
y    Food information will be collected in study medication diaries for patients receiving POS tablet or POS tablet placebo, the timing and characteristics of 
food    taken should be recorded in the eCRF for each tablet dose. 
z    For subjects on IV therapy an ECG will be performed at the Week 1 study visit following the completion of the 90-minute infusion. At this time, a plasma 
sample will also be collected (see footnote “s”) Subjects who are receiving oral study therapy at the week 1 study visit may have the ECG performed 
without regard to the timing of study therapy.
 
 
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3.0 TABLE OF CONTENTS
1.0 TITLE PAGE....................................................................................................... 1
SUMMARY OF CHANGES ....................................................................................... 3
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT: ............................................ 3
2.0 SYNOPSIS ....................................................................................................... 14
2.1
Trial Design Diagram............................................................................. 24
2.2
Trial Flow Chart...................................................................................... 25
3.0 TABLE OF CONTENTS ................................................................................... 29
3.1
List of Tables.......................................................................................... 34
3.2
List of Appendices................................................................................. 35
4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.......................... 36
5.0 INTRODUCTION .............................................................................................. 39
5.1
Therapeutic Rationale ........................................................................... 39
5.2
Subject Population Rationale ............................................................... 40
5.2.1
Preclinical data Relative to Inclusion of Adolescent patient 
population with IV solution .............................................................. 41
5.3
Dose and Administration Rationale ..................................................... 42
5.3.1
Posaconazole Dose Rationale........................................................ 42
5.3.2
Voriconazole Dose Rationale.......................................................... 42
6.0 TRIAL OBJECTIVES ....................................................................................... 43
6.1
Primary Trial Objective.......................................................................... 43
6.2
Secondary Trial Objectives................................................................... 43
6.3
Exploratory Objectives.......................................................................... 44
7.0 INVESTIGATIONAL AND ANALYSIS PLAN................................................... 44
7.1
Overall Trial Design ............................................................................... 44
7.2
Beginning and End of the Trial............................................................. 46
7.3
Trial Population...................................................................................... 47
7.3.1
Subject Inclusion Criteria ................................................................ 48
7.3.2
Subject Exclusion Criteria............................................................... 51
7.3.3
Subject Discontinuation Criteria...................................................... 54
7.3.4
Replacement of Subjects................................................................ 55
7.4
Treatments ............................................................................................. 55
7.4.1
Trial Treatments.............................................................................. 55
7.4.1.1
Treatments Administered....................................................... 55
7.4.1.2
Method of Treatment Assignment, Randomization, and/or 
Stratification ........................................................................... 57
7.4.1.3
Selection and Timing of Dose for Each Subject..................... 57
Selecting the Dose for Each Subject............................. 57
 
 
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Determining the Timing of Dose Administration for 
Each Subject................................................................. 58
7.4.1.3.2.1
Posaconazole ...................................................... 58
7.4.1.3.2.1.1
POS IV Solution .......................................... 58
7.4.1.3.2.1.2
Posaconazole Tablet................................... 59
7.4.1.3.2.2
Voriconazole ........................................................ 60
7.4.1.3.2.2.1
Voriconazole IV ........................................... 61
7.4.1.3.2.2.2
Voriconazole Capsule ................................. 62
7.4.1.4
Blinding Trial Treatments ....................................................... 62
7.4.1.5
Investigational Medicinal Products......................................... 63
Identity of Investigational Medicinal Products ............... 63
Source........................................................................... 63
Labeling ........................................................................ 64
Packaging ..................................................................... 64
Storage ......................................................................... 64
Dispensing .................................................................... 65
Replacement of Investigational Product........................ 65
Investigational Medicinal Product Accountability........... 65
7.4.2
Non-Trial Treatments...................................................................... 66
7.4.2.1
Prior and Concomitant Medications ....................................... 66
Medications, Supplements, and Other Substances 
Prohibited Prior to Randomization and During the 
Trial............................................................................... 66
Concomitant Medications, Supplements, and Other 
Substances Allowed During the Trial ............................ 67
7.4.2.2
Other Treatments................................................................... 68
7.4.3
Procedures for Monitoring Subject Compliance With 
Administration of Trial Treatments .................................................. 69
7.5
Trial Schedule ........................................................................................ 69
7.6
Trial Procedures .................................................................................... 69
7.7
Assessments.......................................................................................... 78
7.7.1
Efficacy Assessments..................................................................... 78
7.7.1.1
Primary Endpoint ................................................................... 78
7.7.1.2
Secondary Endpoints............................................................. 78
7.7.2
Safety Monitoring and Assessments............................................... 79
7.7.2.1
Safety Endpoints.................................................................... 79
7.7.2.2
Definition of Terms................................................................. 80
Adverse Event............................................................... 80
Serious Adverse Event.................................................. 80
 
 
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Events of Clinical Interest.............................................. 80
Overdose ...................................................................... 81
Clinical Supply Complaint ............................................. 81
Planned Hospitalization................................................. 82
7.7.2.3
Monitoring .............................................................................. 82
Monitoring Adverse Events ........................................... 82
Monitoring Laboratory Assessments............................. 84
7.7.2.4
Assessment of Adverse Events ............................................. 84
Assessment of Severity................................................. 84
Assessment of Causality............................................... 85
Reference Safety Information (RSI) for the 
Assessment of Expectedness of Adverse Events......... 85
Known Potential Toxicities of Investigational Products . 85
Known Adverse Events Relating to the Underlying 
Clinical Condition .......................................................... 86
7.7.2.5
Reporting Safety Observations by the Investigator to the 
Sponsor.................................................................................. 86
Expedited Reporting of Safety Observations by the 
Investigator to the Sponsor ........................................... 86
Expedited Reporting by the Sponsor to a Regulatory 
Health Authority ............................................................ 87
Protocol-Specific Exceptions to (Serious) Adverse 
Event Reporting to Global Safety and Other Points to 
Consider........................................................................ 87
7.7.2.6
Discontinuation, Treatment Interruption, and Unblinding of 
Blinded Treatment Due to Safety Observations..................... 88
Discontinuation ............................................................. 88
Temporary Interruption of Treatment for a Subject ....... 88
Modification of Dose and/or Administration of 
Investigational Product for a Subject............................. 88
Unblinding Treatment for a Subject During the Trial ..... 88
7.7.3
Pharmacogenetics .......................................................................... 89
7.7.3.1
Pharmacogenetics Endpoints ................................................ 89
7.7.3.2
PD/PGt, PK/PGt and Safety/PGt Analysis ............................. 89
7.7.4
Other Endpoints.............................................................................. 89
7.8
Criteria for Early Termination of the Trial............................................ 90
8.0 STATISTICAL AND ANALYTICAL PLAN ....................................................... 90
8.1
Responsibility for Analyses/In-House Blinding .................................. 90
8.2
Hypotheses/Estimation ......................................................................... 91
8.2.1
Primary ........................................................................................... 91
 
 
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8.2.2
Secondary....................................................................................... 91
8.2.3
Exploratory...................................................................................... 92
8.3
Analysis Endpoints................................................................................ 92
8.3.1
Efficacy/Pharmacokinetics Endpoints ............................................. 92
8.3.2
Safety Endpoints............................................................................. 92
8.4
Analysis Populations............................................................................. 93
8.4.1
Efficacy Analysis Populations ......................................................... 93
8.4.2
Safety Analysis Populations............................................................ 94
8.5
Statistical Methods ................................................................................ 94
8.5.1
Statistical Methods for Efficacy Analyses........................................ 94
8.5.2
Statistical Methods for Safety Analyses.......................................... 96
8.5.3
Summaries of Baseline Characteristics, Demographics, and
Other Analyses ............................................................................... 99
8.6
Multiplicity.............................................................................................. 99
8.7
Sample Size and Power Calculations................................................... 99
8.7.1
Justification of Non-inferiority Margin for Response Rate ............... 99
8.7.1.1
Summary of Historical Response Data for VOR in IA .......... 100
8.7.1.2
Percentage Effect Size Retained with Selected Margin ....... 102
8.7.2
Sample Size and Power for Efficacy Analyses ............................. 104
8.7.3
Sample Size and Power for Safety Analyses................................ 106
8.8
Subgroup Analyses and Effect of Baseline Factors......................... 107
8.9
Interim Analyses .................................................................................. 107
8.10
Compliance (Medication Adherence)................................................. 107
8.11
Extent of Exposure .............................................................................. 108
8.12
Data Monitoring Committee................................................................ 108
9.0 ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS ....................................................................................... 108
9.1
Ethical Conduct of the Trial ................................................................ 109
9.1.1
Independent Ethics Committee or Institutional Review Board ...... 109
9.1.2
Subject Information and Consent.................................................. 109
9.1.3
Subject Identification Card............................................................ 110
9.1.4
Registration of the Trial................................................................. 110
9.1.5
Compliance with Law, Audit, and Debarment ............................... 110
9.1.6
Quality Control and Quality Assurance ......................................... 112
9.2
Reporting Trial Data to the Sponsor .................................................. 112
9.2.1
Data Collection Forms .................................................................. 112
9.2.2
Preparing Case Report Forms for All Subjects ............................. 112
9.2.3
Preparing Case Report Forms for Subjects Who Fail Screening.. 113
9.3
Publications and Other Rights ........................................................... 113
 
 
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9.3.1
Rights to Publish by the Investigator............................................. 113
9.3.2
Use of Proprietary or Confidential Information in a Publication..... 114
9.3.3
Use of Trial Information in a Publication ....................................... 114
9.3.4
Authorship of Publications ............................................................ 114
9.4
Trial Documents and Records Retention........................................... 115
10.0INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE................ 116
10.1
Sponsor ................................................................................................ 116
10.2
Investigators ........................................................................................ 116
10.2.1
Selecting Investigators.................................................................. 116
10.2.2
Financial Disclosure Requirement ................................................ 116
10.2.3
Clinical Study Report Coordinator Investigator ............................. 116
10.3
Central Organizations.......................................................................... 117
10.3.1
Scientific Advisory Committee ...................................................... 117
10.3.2
Clinical Adjudication Committee.................................................... 117
10.3.3
Data Monitoring Committee .......................................................... 117
11.0REFERENCES ............................................................................................... 118
APPENDICES........................................................................................................ 122
INVESTIGATOR SIGNATURE PAGE................................................................... 160
 
 
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3.1
List of Tables
Table 1
Overview of Active Study Drug Dosing by Treatment Arms...... 45
Table 2
Prohibited Medications Prior to Start of Study Treatment and 
During Study Treatment............................................................ 51
Table 3
Overview of Active Study Drug Dosing by Treatment Arms...... 56
Table 4
Summary of POS IV Therapy ................................................... 58
Table 5
Summary of POS Tablet Therapy............................................. 58
Table 6
Summary of VOR IV Therapy ................................................... 60
Table 7
Summary of VOR Capsule Therapy ......................................... 61
Table 8
Medications, Supplements, and Other Substances Allowed 
During the Trial ......................................................................... 67
Table 9
Laboratory Tests- Hematologic Studies.................................... 73
Table 10
Laboratory Tests- Serum Chemistries ...................................... 73
Table 11
Global Clinical Response Definitions from the 2008 
MSG/EORTC Guidelines .......................................................... 78
Table 12
Mapping Causality for SAE from EDC to Safety Data 
Reporting form 1727 ................................................................. 87
Table 13
Analysis Strategy for Key Efficacy Variables ............................ 96
Table 14
Analysis Strategy for Safety Parameters .................................. 98
Table 15
Meta-Analysis (3 studies)........................................................ 102
Table 16
Percentage (%) of Effect Size  Retained with 10% Margin ..... 103
Table 17
Power (%) Under Various Assumptions of All-cause Mortality 
Through 42 days (10% Non-inferiority Margin) ....................... 105
Table 18
Difference in AE Proportions (POS minus VOR)† That Can 
Be Ruled Out With Different Number of Randomized Subjects 
in Each Group......................................................................... 106
 
 
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3.2
List of Appendices
Appendix 1
Code of Conduct for Clinical Trials ......................................... 123
Appendix 2
Defining Opportunistic Invasive Fungal Infections (European 
Organization for Research and Treatment of Cancer/Invasive 
Fungal Infections Cooperative Group, National Institute of 
Allergy and Infectious Diseases Mycoses Study Group) ........ 124
Appendix 3
Criteria for Diagnosis of Invasive Aspergillosis ....................... 134
Appendix 4
Child-Pugh Scoring and Classification.................................... 138
Appendix 5
DNA Sampling and Pharmacogenetic Analysis Procedures... 140
Appendix 6
Summary of Imaging Charter.................................................. 147
Appendix 7
Additional Details on Statistical Methods ................................ 149
Appendix 8
Terminology Criteria for Adverse Events (CTCAE) lab grading 
criteria -  Investigations System Organ Class.  Please refer to 
the most recent complete CTCAE version and guidelines, if 
applicable................................................................................ 151
Appendix 9
Estimated blood volumes collected during the Study.............. 158
 
 
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4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
ABPA
Allergic bronchopulmonary aspergillosis
AE
Adverse event
AIDS
Acquired Immune Deficiency Syndrome
AMA
American Medical Association
AmB
Amphotericin B deoxycholate
APaT
All-Patients-as-Treated
ALT
Alanine serum transaminase (or SGPT)
ALP
Alkaline phosphatase (or ALK-P)
AML
Acute myelogenous leukemia
ANC
Absolute neutrophil count
AST
Aspartate serum transaminase (or SGOT)
AUC
Area under the curve
BAL
Broncho-alveolar lavage
BID
Twice daily dosing
BUN
Blood urea nitrogen
CAC
Clinical adjudication committee
Cavg
Average concentration
CHMP
Committee for Medicinal Products for Human use
CI
Confidence interval
CFR
Code of Federal Regulations
Cmax
Maximum concentration
CNS
Central nervous system
CRF
Case report form
CSR
Clinical study report
CT
Computed Tomography
CTCAE
Common terminology criteria for adverse events
CTD
Clinical trial directive
CYP2C19
Cytochrome P450 2C19
CYP2C9
Cytochrome P450 2C9
CYP3A4
Cytrochrome P450 3A4
DAO
Data as observed
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDMC
External data monitoring committee
 
 
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Term
Definition
EDC
Electronic data capture
EIA
Enzyme immunoassay
EMEA
European Medicines Agency
EOC
Executive oversight committee
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of therapy
ERC
Ethics review committee
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good clinical practice
hCG
Human chorionic gonadotropic
HESDE
Historical evidence of sensitivity to drug effects
HIV
Human immunodeficiency virus
HMG-CoA
Beta-hydroxy-beta-methylglutaryl-CoA
HSCT
Hematopoietic stem cell transplant
IA
Invasive Aspergillosis
ISA
Isavuconazole
ICF
Informed Consent Form
ICH
Internal Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
IEC
Independent ethics committee
IFI
Invasive Fungal Infection
IMP
Investigational Medicinal Product
IND
Investigational new drug
IRB
Institutional review board
ITT
Intention to treat
IV
Intravenous
IVRS
Interactive voice response system
LDH
Lactate dehydrogenase
MDS
Myelodysplastic syndrome
MIC
Minimum inhibitory concentration
mITT
Modified Intention to Treat
MRI
Magnetic resonance imaging
MSG
Mycoses study group
NCI
National Cancer Institute
NI
Non-inferior
 
 
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Term
Definition
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NSAID
Non-steriodal anti-inflammatory drug
PD
Pharmacodynamic
PDLC
Pre-defined limit of change
PGt
Pharmacogenetic (or PG)
PK
Pharmacokinetic
PO
Oral administration
POS
Posaconazole
PND
Post-natal day
PP
Per-protocol
PQC
Product quality complaint
Q12h
Every 12 hours
Q24h
Every 24 hours
QD
Once daily
QT interval
Interval from the beginning of the QRS complex to the end of the T wave on an 
electrocardiogram that represents the time during which contraction of the ventricles 
occurs
QTc interval
QT interval corrected for heart rate
RBC
Red blood cell count
RNA
Ribonucleic acid
RSI
Reference safety information
SAC
Scientific advisory committee
SAE
Serious adverse event
SAP
Statistical analysis plan
SmPC
Summary of product characteristics
SOC
System organ class
SOP
Standard operating procedure
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States
USA
United States of America
VOR
Voriconazole
WBC
White blood count
 
 
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5.0 INTRODUCTION
5.1
Therapeutic Rationale
Current guidelines for the treatment of IA recommend the use of VOR as primary 
therapy [10], [23].  Early initiation of antifungal therapy is recommended while the 
definitive diagnostic evaluation is in process.  The duration of azole treatment is not 
yet well defined; current recommendations call for a minimum duration of 6 to 12 
weeks in immunocompromised subjects.  These recommendations are based upon 
the findings of controlled clinical studies that found initial treatment with VOR to be 
superior to amphotericin B deoxycholate (AmB) in the treatment of acute IA.  In an 
open-label controlled study after 12 weeks of therapy, the global clinical response to 
therapy was 53% in subjects who were randomized to receive VOR with a survival 
rate of 71% compared to a response rate of 32% for AmB and a survival rate of 58% 
[2]. Invasive aspergillosis is a serious, life-threatening disease that occurs among 
patients with prolonged and/or severe impairment of the immune system. Without 
the initiation of antifungal therapy, the acute mortality rate has been shown to 
exceed 85 % (Appendix 2). With early diagnosis and the prompt initiation of therapy, 
the mortality rate of patients treated with a mold-active antifungal agent has 
improved [26]. A meta-analysis of all-cause mortality through Day 42 based on 
historical data of VOR treatment of IA found a mortality rate of 23 % [27]. In 2015, a 
recently completed prospective clinical study of ISA vs VOR given to patients with 
invasive aspergillosis reported through Day 42 all-cause mortality rate of 18.6% and 
20.2, ISA and VOR treatment arms, respectively. In the same clinical study, with the 
use of the 2008 EORTC/MSG guidelines for the evaluation of clinical response 
among subjects with proven or probable IA, a successful clinical response at the end 
of therapy was noted to be 35% and 38.9%, ISA and VOR treatment arms,
respectively [27].    
More effective or safer antifungal therapy is sought for patients with IA [26, 28].  
POS is a highly active triazole with the potential to have at least similar efficacy to 
VOR based on animal model data.  POS demonstrates a more potent in vitro activity 
compared to VOR against the most common clinical isolates including Aspergillus 
fumigatus and A. flavus [3].  POS may also have some potential advantages in 
terms of tolerability, drug interactions, and safety.  The most common treatment-
related adverse events for VOR are visual disturbances, with approximately 21% of 
subjects experiencing abnormal vision, color changes, and/or photophobia.  Similar 
visual disturbances are observed in ≤ 2% of subjects who have received POS.  
VOR is metabolized primarily by the human hepatic cytochrome P450 enzyme 
CYP2C19.  This enzyme exhibits genetic polymorphism, which can cause large 
differences in the pharmacokinetics of VOR.  Individuals are classified as either 
extensive metabolizers or poor metabolizers of this enzyme, and the distribution of 
these genotypes varies greatly across different populations.  Poor metabolizers have 
shown, on average, a 4-folder higher VOR exposure compared to the extensive 
metabolizers.  This variability can have significant clinical impact, since VOR 
exposure can vary greatly between individuals and data suggests that visual 
 
 
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disturbances may be associated with higher VOR plasma concentrations [4].  POS is 
not affected by genetic polymorphisms since it primarily circulates in plasma as 
parent compound, and of the circulating metabolites, the majority are formed via 
UDP glucuronidation.
POS was shown to be effective in an open label, externally controlled salvage 
therapy trial of 107 patients with proven/probable aspergillosis.  The global clinical 
response rate (complete and partial response) at the end of therapy was 42% in 
POS treated subjects, compared to 26% in external controls receiving standard 
therapy [5].  In addition, POS has activity against Aspergillus spp. other than A. 
fumigatus, and importantly, against Zygomycetes, which can mimic the clinical 
presentation of aspergillosis in high risk patients.  In this study of refractory IA, there 
was an exposure response association; subjects in the highest quartile with the 
highest POS exposure (mean Cavg of 1250 ng/mL) had a higher response 
(approximately 75%) compared to lower concentration quartiles.
Merck has developed new IV and oral formulations of POS that are able to achieve a 
higher exposure target with reduced variability compared to POS oral suspension 
[6].  POS IV Solution is an aqueous injectable solution containing 18 mg/mL of POS 
to be diluted in 5 % dextrose in water prior to IV administration.  The primary 
excipient in POS IV Solution and VOR IV is sulfobutylether--cyclodextrin 
(SBECD).  The administration of this excipient to subjects with impaired renal
function has been associated with potential limitations; however, a recent study with 
VOR has suggested that there is no difference between IV or oral administration and 
the impact on renal function [7].  POS tablet is designed to maximize systemic 
absorption and overcome the food-effect limitations of the oral suspension 
formulation.  This study will utilize both the IV and tablet formulations for POS and 
VOR for the treatment of subjects with IA.
5.2
Subject Population Rationale
The primary study population is the intent-to-treat (ITT) population, which includes all 
randomized subjects who received at least one dose of study drug.  However, of 
further interest in this study is the subset of subjects with a diagnosis of proven or 
probable invasive aspergillosis (IA) based on modified 2008 EORTC/MSG 
definitions [10].  Subjects with possible IA may also be enrolled into the study with 
further evaluation of proven or probable IA, which must be confirmed post-
randomization to be included in the FAS analysis on the secondary endpoints.  
(Note, inclusion in the FAS further requires subjects have at least one post-
randomization observation for the analysis endpoint subsequent to at least one dose 
of study treatment [and have baseline data for those analyses requiring baseline 
data]).
Subjects with proven invasive fungal infection (IFI) will have confirmed infection 
based upon detection of the fungus by histological analysis or culture of a specimen 
taken from sterile material from a site of infection.  Subjects with probable IFI will 
require the presence of appropriate host factors, clinical criterion, and a mycological 
 
 
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criterion including both direct tests and indirect tests including serum galactomannan 
antigen detection.  Host factors include: recent history of neutropenia temporally 
related to a fungal disease (Any duration of neutropenia is also acceptable for 
possible criteria in this study), receipt of an allogeneic HSCT, treatment with T-cell 
immune suppressants, prolonged corticosteroid use, and inherited severe 
immunodeficiency.  See Appendix 3 for the criteria for diagnosing invasive 
aspergillosis.
Subjects selected for this study will be 13 years of age or greater.  Subjects between 
13 and 14 years of age must weigh ≥ 50 kg [110lb].  
5.2.1
Preclinical data Relative to Inclusion of Adolescent patient population
with IV solution
POS IV Solution was evaluated in two studies in juvenile dogs, one in pre-weaning 
dogs post-natal 2-8 weeks of age during POS IV Solution administration and one 
study in post-weaning dogs aged 10-22 weeks during POS IV Solution 
administration.  
Well-characterized POS toxicities (the same as those seen in adult animals) were 
observed in both studies.  In addition, in the pre-weaning study following 6 weeks of 
POS IV administration (animals exposed to POS IV from post-natal day 14 through 
post-natal day 56) enlargement of the lateral ventricles in the brain was observed 
compared to concurrent placebo and saline control groups.  Plasma exposure to 
POS in these juvenile dogs was approximately 5x human therapeutic AUC with POS 
IV (300 mg IV).  No difference in the incidence of brain ventricular enlargement 
between control and treated animals was observed following a 5-month treatment-
free period, consistent with complete resolution.  There were no neurologic or 
behavioral abnormalities in the dogs with this finding.  This finding was not seen with 
administration of POS IV Solution to post-weaning dogs (aged 10-22 weeks) or with 
oral POS administration to juvenile dogs throughout development (from PND 4 days 
through 9 months of age), or in juvenile rats.  The finding of brain ventricular dilation 
observed in pre-weaning juvenile dogs after 6 weeks of POS IV Solution 
administration is considered to be equivalent to the period of development in 
humans from an age of 3 months to approximately two years of age.  
Findings of ventricular dilation in the brain were not observed in young adult dogs 
administered POS IV Solution for three months or in young adult monkeys 
administered POS IV Solution for 1 month, in which similar or higher POS exposures 
were attained compared to the juvenile study.  
This data supports allowing the inclusion of adolescent patients, 13 years of age and 
up. As a result of this data, the study population has been expanded to include the 
enrollment of adolescents outside of the European Union (i.e., in those regions with 
an approved indication for use of oral POS in the adolescent age population (13 
years of age and older). 
 
 
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Details about specific benefits and risks for subjects participating in this clinical trial
may be found in the accompanying Investigators Brochure and Informed Consent 
documents.  
5.3
Dose and Administration Rationale
At the time of study enrollment, subjects will be randomized in a 1:1 ratio to receive 
one of two possible treatment arms: POS or VOR.  All IV therapy must be 
administered via a central line (e.g., central venous catheter, peripherally-inserted 
central catheter, etc.).  Further details around IV dosing can be found in 
Section 7.4.1.3.2.
Both IV and oral therapy are given to treat IA.  In general, patients receive IV therapy 
at the beginning of treatment and transition to oral therapy when able. If patients are 
clinically stable and able to take oral medication, they may begin treatment on oral 
therapy.  In this study, both the IV and oral formulations will be used.  Most subjects 
will begin on IV therapy and transition to oral; however, some subject may start the 
study receiving oral therapy.  For IV therapy, study drug will be blinded and 
administered via central line.  Peripheral dosing will not be possible for this study, 
since each IV study drug has different infusion times.  Dosing duration is 90 minutes.   
The dosing of study drug via peripheral venous administration may not occur due to 
the potential occurrence of thrombophlebitis when IV study drug is given via 
peripheral route.  For oral therapy, study drug will be blinded using double-dummy 
tablets or capsules to mask study drug identity.
5.3.1
Posaconazole Dose Rationale
Subjects enrolled into this arm of the study will be treated with POS IV and/or tablet 
formulations.  A dose of POS 300 mg QD has been selected for this study based 
upon prior clinical development of POS.  Merck has developed new IV and oral 
formulations of POS that are able to achieve a higher exposure target with reduced 
variability compared to POS oral suspension [6]. Phase 1B/3 studies have been 
conducted in patients treated with POS IV solution and POS tablet given as 
antifungal prophylaxis [31]. In patients, the mean steady state Cavg exposure for 
POS IV solution 300 mg QD was 1430 ng/ml; the mean steady state Cavg exposure 
for POS tablet 300 mg QD was 1460 ng/ml [29].  With these new formulations, the 
desired exposure target (Cavg at least 1250 ng/mL) will be more rapidly and more 
consistently achieved.  This target concentration is associated with higher response 
rates in subjects with IA [5].  Subjects will receive a loading dose of 300 mg POS 
BID on Day 1, followed by 300 mg QD thereafter.  Most subjects will start therapy via 
the IV route and transition to the oral route when able to tolerate oral medications.  
5.3.2
Voriconazole Dose Rationale
Subjects enrolled in this arm of the study will be treated with VOR IV and/or capsule 
formulations.  The dose selected for the study is consistent with the current VOR 
prescribing information and recommendations for patients with invasive 
 
 
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aspergillosis.  The most recent guidelines of the Infectious Diseases Society of 
America (2008) and the American Thoracic Society (2011) for the treatment of 
invasive aspergillosis recommend IV VOR 6 mg/kg every 12 hour for one day 
followed by 4 mg/kg every 12 hours until improvement, followed by oral VOR 200 mg 
every 12 until resolution or stabilization of all clinical and radiographic manifestations 
[10], [23]. This dosage of VOR was also used in the most recent clinical study of 
invasive aspergillosis [27]. These guidelines are consistent with the current VOR 
labeling as well as 2012 recommendations by the American Society of Health 
System Pharmacists [18].  Controlled clinical trials have not shown a benefit of 
higher dosing of VOR; higher VOR dosing may lead to higher drug exposure which 
has been associated with an increased risk of hepatic or visual adverse events [8].  
According to the current guidelines, VOR is the current recommended therapy for 
subjects with IA [10], [23].  When on IV therapy, subjects will receive a loading dose 
of 6 mg/kg BID on Day 1, followed by a maintenance dose of 4 mg/kg BID.  If the 
subject is on oral therapy, a loading dose of 300 mg BID will be given on Day 1, and 
200 mg BID thereafter.  Most subjects will start therapy via the IV route and 
transition to the oral route when able to tolerate oral medications. The dose to be 
used for VOR IV and oral is the standard dose recommended for administration.  
With this dose at steady state most subjects will achieve drug concentrations within 
the range considered to be therapeutic (1-5.5 ug/mL). In a study by Pascual et al 
(2008) of patients treated with VOR for invasive mycoses including aspergillosis, the 
lack of a response to therapy was more frequent in patients with VOR 
concentrations < 1 ug/mL, and VOR concentrations > 5.5 ug/mL were associated 
with more frequent neurotoxicity [8].  VOR product labeling indicates that the oral 
maintenance dose of 200 mg achieves a VOR exposure similar to 3 mg/kg IV and a 
300 mg oral maintenance dose achieves an exposure similar to 4 mg/kg IV.  If 
clinically indicated, the subject may switch back to IV therapy if the subject is taking 
oral therapy and their clinical condition is not improving. Please refer to VOR EU 
product circular for full details [32].   
6.0 TRIAL OBJECTIVES
6.1
Primary Trial Objective
To compare the all-cause mortality for posaconazole (POS) compared to 
voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) through
Day 42 in all randomized subjects who received at least one dose of study treatment
(in the ITT [Intention to Treat] population). The hypothesis to be tested is that the all-
cause mortality through Day 42 in the POS treatment group is non-inferior to that in 
the VOR treatment group.
6.2
Secondary Trial Objectives
•
To evaluate the all-cause mortality for POS vs. VOR through Day 42 in the FAS 
population.
 
 
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•
To evaluate the global clinical response for POS vs. VOR at Week 12 in the FAS 
population.
•
To evaluate the all-cause mortality for POS vs. VOR through Day 84 in both the 
FAS and ITT populations.
•
To evaluate the global clinical response for POS vs. VOR at Week 6 in the FAS.
•
To evaluate the time to death (all causes) for POS vs. VOR in the FAS 
population.
•
To evaluate mortality due to IA through Day 42 and Day 84 for POS vs. VOR in 
the FAS population.
•
To evaluate the safety and tolerability of POS and VOR by analyzing Tier 1 
Safety events and all adverse events. 
•
To evaluate the safety of POS compared to VOR therapy in the All-Patients-as-
Treated (APaT) population.
•
To evaluate, in the subset of subjects that have pharmacokinetic data and food 
intake records, the pharmacokinetic profile of POS and VOR, including an 
evaluation of the effect of food intake on the POS tablet steady state 
pharmacokinetic profile, and to evaluate the exposure-response (efficacy and 
safety endpoints) relationships of POS and VOR in a subset of subjects with 
available data.
6.3
Exploratory Objectives
•
To explore the effects of CYP2C19 polymorphisms and predicted metabolic 
enzyme activity on POS and VOR plasma concentration.
•
To explore pharmacogenetic endpoints and their association with key efficacy 
and safety parameters.
•
To explore the effect of treatment on serological biomarkers (e.g., serum 
galactomannan EIA, beta-D-glucan).
7.0 INVESTIGATIONAL AND ANALYSIS PLAN
7.1
Overall Trial Design
This is a Phase 3, randomized, double-blind study of POS versus VOR in subjects 
with IA as defined by modified 2008 EORTC/MSG consensus criteria.  Subjects with 
features consistent with proven, probable, or possible IA will be enrolled.  Subjects 
who are enrolled with a diagnosis of possible IA will undergo additional diagnostic 
work-up to confirm proven or probable IA post-randomization to be included in the 
secondary FAS population.  All randomized subjects who receive at least one dose 
of study drug will be included in the primary ITT population.  
 
 
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At the time of study enrollment, subjects will be randomized to receive one of two 
possible treatment arms: POS or VOR for a maximum total duration of therapy of 12 
weeks.  In general, most subjects should receive the full 12 weeks of study therapy.  
Subjects will be randomized to POS or VOR in a 1:1 ratio.  Overall, approximately 
600 subjects will be enrolled in the study to obtain 300 ITT-evaluable subjects per 
arm.  Subjects who are randomized and receive at least one dose of study drug will 
comprise the primary analysis population (ITT dataset).
Most subjects will begin antifungal azole (VOR or POS) therapy via the IV route; 
however, some may begin study therapy via the oral route.  Subjects who may begin 
study therapy via the oral route may include subjects with renal insufficiency 
(creatinine clearance < 50 ml/min), or subjects without central venous catheter 
access.  Azole therapy will be switched from IV route to the oral route when the 
subject is considered clinically stable and able to take oral medication.  See Table 1
for an overview of the two treatment arms.  The assigned azole treatment (POS or 
VOR) will be provided in a double-blind manner.  A follow-up evaluation will be done 
1 month after treatment completion.  Ultimately, subjects who complete 12 weeks of 
study treatment will participate in the study for a total of approximately 16 weeks 
post-randomization.
Table 1 Overview of Active Study Drug Dosing by Treatment Arms
Treatment Arms
IV Therapya
Oral Therapy
Arm 1 – Posaconazole (POS)
POS IV:
Day 1b: 300 mg BID
Day 2-84c: 300 mg QD
POS oral: 
Day 1b: 300 mg BID
Day 2-84c: 300 mg QD
Arm 2 – Voriconazole (VOR)
VOR IV:
Day 1b: 6 mg/kg per body weight 
administered BID
Day 2-84c: 4 mg/kg per body 
weight administered BID
VOR oral: 
Day 1b:  300 mg BID
Day 2-84c: 200 mg BID
a Subjects will begin IV study drug and then step down/transition to oral study drug. If clinically indicated, 
some subjects may begin study drug with oral therapy instead of IV therapy.
b Day 1 refers to the first day of subject taking either IV or Oral therapy.  Subjects will only take one 
formulation, either IV or oral at a time
c The planned duration of study therapy is 12 weeks (84 days) with a maximum allowable duration of up to 
98 days. IV=intravenous; POS=posaconazole; VOR=voriconazole
Diagnostic, attributable mortality, and efficacy data from all subjects will be reviewed 
by an independent CAC who will be blinded to the assigned treatment arm.  The 
CAC will determine acceptability of the diagnostic criteria of a proven or probable IFI 
according to modified MSG/EORTC consensus criteria [9].  Subjects who are 
randomized receive at least one dose of study drug and whose diagnosis of proven 
or probable IA is confirmed by the CAC will comprise the FAS dataset.  (The FAS 
further requires subjects to have received at least one dose of study drug and have 
at least one post-randomization observation for the analysis endpoint subsequent to 
at least one dose of study treatment [and have baseline data for those analyses 
requiring baseline data]).  The CAC will adjudicate the global clinical response to 
 
 
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treatment (as per 2008 EORTC/MSG guidelines) at 6 weeks and at 12 weeks post-
randomization.  A successful global clinical response will be defined as an FAS-
evaluable subject who is judged by the CAC to be alive and have a complete or 
partial response at the time point of interest.  The CAC will also adjudicate IFI-
attributable mortality through Day 42 and Day 84 in subjects as data allow.
The primary analysis will be performed on the ITT population. The ITT population 
consists of all randomized subjects who received at least one dose of study 
treatment. 
The primary endpoint in this study is all-cause mortality through Day 42 between the 
POS arm and the VOR arm for the ITT population.  The primary analysis will be 
assessed using a non-inferiority margin of 10%.  Ninety-five percent Confidence 
Intervals (CI), adjusted for stratification factors for the difference in success rates 
(POS minus VOR) will be computed.  If upper limit of that CI is less than 10%, then 
non-inferiority of POS will be declared.  If non-inferiority is declared, then superiority 
of POS over VOR will be assessed and will be declared if the lower limit of the CI is 
greater than 0.  
The secondary endpoints include the global clinical response at Week 6 and Week 
12 in the FAS population and all-cause mortality through Day 42 and Day 84, in the 
FAS and ITT populations.  All will be evaluated using a similar methodology as that 
for the primary analysis.  Survival will be assessed using a Kaplan Meier estimates 
and will be compared between the two arms using the Log-Rank test.  
7.2
Beginning and End of the Trial
Each subject is considered to be enrolled in the trial when the subject (or the 
subject’s legal representative) has provided written informed consent.
Each subject is considered to have ended participation in the trial when he/she has 
completed the last protocol-specified contact (e.g., visits or telephone contacts) or 
prematurely discontinues from the study.
A subject is considered to have completed the trial after he/she has completed the 
end of therapy visit and follow-up assessments.
A subject is considered to have discontinued after he/she has withdrawn consent or 
has been discontinued under the conditions specified in Section 7.3.3.
A subject is considered to have been lost to follow-up if he/she is unable to be 
contacted by the investigator.  The end of participation for a subject lost to follow-up 
is the last known contact (e.g., visit or telephone contact).
The overall trial begins when the first subject is enrolled (i.e., signs the informed 
consent form).  The overall trial ends when the last remaining subject has ended 
participation in the trial, by completing the trial, being discontinued from the trial, or 
being lost to follow-up.
 
 
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Each subject will be monitored for the occurrence of SAEs immediately after the 
subject has signed informed consent.  Each subject will be followed for serious 
adverse events for up to and including 30 days after the last dose.  Follow-up 
procedures related to pregnancy or SAEs may continue beyond the end of the 
clinical trial.  Of note, all subjects are to be followed for mortality for the entire study 
period (i.e., until the final study visit at 16 weeks) regardless of the duration of study 
treatment.
Once a subject has ended participation in the trial, the investigational products from 
the trial will no longer be available to the subject and any future care will be provided 
according to the subject's personal physician.
A subject is considered to have completed study treatment if the subject has 
recovered from IA during a maximum of 12 weeks of study treatment.  All subjects 
who are randomized to the study and receive at least one dose of study drug must 
complete the Week 6 and the Week 12 visits and will be followed for 4 weeks 
following the Week 12 visit.  Each subject will participate in the trial for approximately 
16 weeks from the time the subject signs the Informed Consent Form (ICF) through 
the final contact.  After a screening phase of up to 7 days, each subject will be 
receiving assigned treatment (Section 7.4.1.1) for a maximum of 12 weeks.  In 
general, most subjects should receive the full 12 weeks of study therapy.  After the 
Week 12 visit each subject will have a final study visit at approximately 4 weeks (30 
days) following the Week 12 visit for a total duration of study of approximately 16 
weeks.
7.3
Trial Population
This study will investigate two extended spectrum azoles (POS and VOR) in 
subjects with proven or probable IA based modified 2008 EORTC/MSG definitions 
[10].  Subjects with possible IA may also be enrolled into the study with further 
evaluation of proven or probable IA, which must be confirmed post-randomization to 
be included in the FAS study population.  
Subjects with proven invasive fungal infection (IFI) will have confirmed infection 
based upon detection of the fungus by histological analysis or culture of a specimen 
taken from sterile material from a site of infection.  
Subjects with probable IFI will require the presence of appropriate host factors, 
clinical criterion, and a mycological criterion.  Mycological criteria include:

Direct test (cytology, direct microscopy, or culture)

Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus 
aspirate samples, indicated by the presence of fungal elements indicating 
a mold, or recovery by culture of a mold (e.g., Aspergillus species).
 
 
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
Indirect tests of aspergillosis (detection of antigen or cell-wall constituents) 
include:  galactomannan antigen detected in serum or bronchoalveolar lavage 
fluid.
If using the galactomannan test for diagnosis, a positive test result is defined as two
consecutive serum values of ≥0.5 or a single serum value ≥1.0.  Similarly, a single 
value of ≥1.0 in a BAL sample would qualify the subject for meeting the criteria as 
probable IA.  For subjects receiving piperacillin/tazobactam within 72 hours of serum 
galactomannan sampling, serum galactomannan criteria for probable IA will not 
meet the criteria for probable IA.  Patients with hematologic malignancy or recipients 
of HSCT who have a positive serum galactomannan assay without clinical or 
radiologic findings should not be enrolled, or if enrolled, should be excluded from the 
analysis of efficacy.  The quantitative value and time of measurement of the 
galactomannan index should be documented.  
Subjects with possible IA will meet the criteria for a host factor and a clinical 
criterion, but without confirmatory mycological criterion.  Subjects who are enrolled 
with a diagnosis of possible IA will undergo additional diagnostic work-up to confirm 
proven or probable IA post-randomization.  Subjects with possible IA diagnosis will 
continue in the study, however these subjects will not be considered part of the FAS
population.  All enrolled subjects who receive at least one dose of study drug will be 
part of the ITT population. By enrolling subjects as early as possible, it is hoped that 
better outcomes overall will be achieved, based on data indicating that early 
intervention improves survival [11, 26].  A subject under the age of legal consent or 
who otherwise is unable to provide independent consent may participate provided 
that a legal representative (such as a parent or legal guardian) provides written 
informed consent on his/her behalf.  Any minor must provide assent prior to entering 
into the study.
7.3.1
Subject Inclusion Criteria
A subject must meet all the criteria listed below to participate in the trial.
1. Each subject must be willing and able to provide written informed consent for 
the trial.  The legal representative (e.g., parent or guardian) for a subject 
under the age of legal consent or who otherwise is unable to provide 
independent consent may provide written informed consent for the subject.  
Each subject of the age of assent must be willing and able to provide assent 
in addition to consent from the legal representative to participate in the trial.  
2. Each subject must be ≥13 years of age weighing >40 kg [88 lb] and ≤150 kg 
[330 lb] at the time of randomization. Each subject between 13 and 14 years 
of age must weigh ≥50 kg [110 lb]. Subjects may be of either sex and of any 
race/ethnicity.  For those sites who do not have the ability to enroll 
adolescents, subjects must be greater than ≥18 years of age.
 
 
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3. Each subject must meet the criteria for proven, probable, or possible IA as 
per 2008 EORTC/MSG disease definitions at the time of randomization.  
Proven IA will include those subjects with the demonstration of fungal 
elements (by cytology, microscopy, or culture) in diseased tissue (sterile 
sampling).  Probable IA includes subjects with at least 1 host factor, clinical 
criteria, as well as mycological criteria including both direct and indirect (i.e., 
detection of serum, or BAL fluid Aspergillus galactomannan antigen by 
sandwich EIA) methods.  If using the galactomannan test for diagnosis, a 
positive test results is defined as two consecutive serum values of ≥0.5 or a 
single serum value ≥1.0.  Similarly, a single value of ≥1.0 in a BAL sample 
would qualify the subject for meeting the criteria as probable IA. For subjects 
receiving piperacillin/tazobactam within 72 hours of serum galactomannan 
sampling, serum galactomannan criteria for probable IA will not meet the 
criteria for probable IA.  Possible IA includes subjects with at least 1 host 
factor and clinical criteria but without mycological criteria.  A modification to 
the 2008 EORTC/MSG criteria regarding risk factors allows for the inclusion 
of subjects with any duration of neutropenia as an acceptable inclusion host 
factor. See Appendix 3 for tables of diagnostic criteria.
4. Each subject with possible IA at time of randomization must be willing or be in 
process of an ongoing diagnostic work up which is anticipated to result in a 
mycological diagnosis of proven or probable IA post-randomization.
5. Each subject 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. Subjects without central catheter access 
must be clinically stable and able to receive oral study therapy.
6. Each subject must have acute IA defined as duration of clinical syndrome of 
<30 days.
7. Each subject must be willing to adhere to dosing, study visit schedule, and 
mandatory procedures as outlined in the protocol.  The subject must be 
willing to continue on study therapy for up to 12 weeks and remain in the 
study through the 1-month follow-up visit.  
8. The subject must have the ability to transition to oral study therapy during the 
course of the study.
 
 
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9. Female subjects of child-bearing potential must be using a medically 
accepted method of birth control before beginning study-drug treatment and 
agree to continue its use for 30 days after stopping the medication, or have 
been surgically sterilized (e.g., hysterectomy or tubal ligation).  For those 
subjects using oral or injectable hormonal contraception, a barrier method of 
birth control (e.g., condom in combination with spermicide) is necessary.  
Female subjects of childbearing potential should be counseled in the 
appropriate use of birth control while in this study.  Vasectomy of the partner 
and tubal ligation should each be considered effective methods of birth 
control.
Female subjects who are not currently sexually active must agree and 
consent to use one of the above-mentioned methods should they become 
sexually active while participating in the study.
10.To participate in the pharmacogenetic analysis, the subject must be willing to 
give written informed consent for the pharmacogenetic testing and able to 
adhere to dose and visit schedules.  Note:  A subject unwilling to sign the 
informed consent for pharmacogenetic testing may be included in the trial; 
however, pharmacogenetic samples must not be obtained.
11.Subject is not taking prohibited antifungal prophylaxis or treatment as defined 
by the protocol.  Examples of allowable Antifungal Therapy Allowed Prior to 
Randomization are shown in Figure 1.
Figure 1Mold Active Antifungal Therapy Allowed Prior to Randomization
 
 
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7.3.2
Subject Exclusion Criteria
A subject meeting any of the exclusion criteria listed below must be excluded from 
participating in the trial:
1.
The subject has chronic (>1-month duration) IA, relapsed/recurrent IA, or 
refractory IA which has not responded to prior antifungal therapy.
2.
The subject has pulmonary sarcoidosis, aspergilloma, or allergic 
bronchopulmonary aspergillosis (ABPA).
3.
The subject has a known mixed invasive mold fungal infection including 
Zygomycetes, and/or a known invasive Aspergillus fungal infection in which 
either study drug may not be considered active.
4.
The subject has received any systemic (oral, intravenous, or inhaled) antifungal 
therapy for this infection episode for 4 or more consecutive days (≥96 hours)
immediately prior to randomization.  
5.
The subject has developed the current episode of IA infection (possible, 
probable, or proven infection) during the receipt of more than 13 days of an azole 
or polyene antifungal agent given for prophylaxis that is considered to be a mold-
active, antifungal agent(including itraconazole, posaconazole, voriconazole, 
isavuconazole, inhaled or systemic amphotericin or lipid-associated 
amphotericin), Any duration of echinocandin antifungal use is allowed (prior to 
randomization).
6.
The subject has received POS or VOR as empirical treatment for this infection for 
4 days (96 hours) or more within the 15 days immediately prior to randomization.
7.
The subject has received any treatment specifically listed in Table 2 which is 
more recent than the indicated washout period prior to randomization.
Table 2 Prohibited Medications Prior to Start of Study Treatment and During Study Treatment
Prohibited Medications Prior to Start of Study Treatment and During 
Study Treatment
Washout Perioda
Systemic antifungal therapy (oral, intravenous or inhaled) for > 3 consecutive 
days (≥96 hours) for treatment of this infection.
Not eligible to participate in 
the study
Systemic antifungal therapy (oral, intravenous or inhaled) for ≤3 consecutive 
days (<96 hours) for treatment of this infection.
Discontinue at 
Randomization
Investigational drugs (new chemical or biological entities):  Investigational 
use of approved products or chemotherapy regimens may be permitted with 
the approval of the sponsor’s project physician prior to use.
30 daysc
Prophylaxis of IFI with azole or polyene antifungal drugs.  This includes 
itraconazole, posaconazole, voriconazole, isavuconazole, inhaled or 
systemic amphotericin or lipid-associated amphotericin)
Discontinue at 
randomization
Nasal sprays of amphotericin B and aerosolized amphotericin B
Discontinue at 
randomization
 
 
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Prohibited Medications Prior to Start of Study Treatment and During 
Study Treatment
Washout Perioda
Medications that are known to interact with azoles and may lead to life-
threatening side effects:  astemizole, cisapride, ebastine, halofantrine, 
pimozide, quinidine, and terfenadine.
10 days (astemizole)
24 hours (others)
Ergot alkaloids (ergotamine, dihydroergotamine or other licensed or 
investigational members of this class).
2 days
Medications that are known to result in a false positive galactomannan EIA 
result:  amoxicillin/clavulanate, and Plasma-Lyte.e
Prohibited during screening 
phase
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
HMG-CoA reductase inhibitors metabolized via CYP3A4 (e.g., simvastatin, 
lovastatin, and atorvastatin).
24 hours
Cyclophosphamideb, d
24 hours
Fosamprenavir, Ritonavir and efavirenz
24 hours
Vinca Alkaloids d
24 hours
Sirolimus
7 days
a     These waiting times should be observed prior to start of study treatment and during study treatment in 
subjects receiving a prohibited drug as prior therapy or should be observed after study drug is stopped 
before the prohibited medication is prescribed.  No concurrent use is permitted.  Deviations from these 
washout periods must be approved by the sponsor prior to use of study drug or prohibited agent.
b         Low dose cyclophosphamide use is allowed during the treatment period with a temporary interruption
of study therapy on the day of cyclophosphamide dosing.
c         Investigational use of MK-8228 will require a 14-day washout period (rather than 30 days)
d         Concomitant use of Cyclophosphamide and vinca alkaloids is prohibited on study therapy.  Subjects
can remain on study if use of cyclophosphamide or vinca alkaloids therapies is needed but a washout 
of study drug for 24 hours must occur.
e         Medications that are known to result in a false positive galactomannan EIA result can be used on 
study, but when used do not allow for galactomannan to contribute to a confirmatory probable IA 
diagnosis. Please refer to figure 2.1 for additional details.
HMG-CoA=beta-hydroxy-beta-methylglutaryl-CoA; IFI = invasive fungal infection
8.
A subject must not have any condition that, in the opinion of the investigator, may 
interfere with optimal participation in the study, i.e., any condition requiring the 
use of prohibited drugs or unstable medical conditions other than the 
hematological disorder such as cardiac or neurologic disorder or impairment 
expected to be unstable or progressive during the course of this study 
(e.g., seizures or demyelinating syndromes, acute myocardial infarction within 
3 months of study entry, myocardial ischemia, or unstable congestive heart 
failure, unstable arrhythmias, atrial fibrillation with ventricular rate <60/min, or 
history of torsades de pointes, symptomatic ventricular or sustained arrhythmias, 
unstable electrolyte abnormalities [e.g., Grade 2 hypokalemia or 
hypomagnesemia]).
9.
The subject has known hypersensitivity or other serious adverse reaction to any 
azole antifungal therapy, or to any other ingredient of the study medication used.
 
 
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10. The female subject is pregnant, intends to become pregnant, or is nursing at the 
time of randomization.
11. The subject has any known history of Torsade de Pointes, unstable cardiac 
arrhythmia or proarrhythmic conditions, or a history of recent myocardial 
infarction within 90 days of study entry.
12. The subject has QTc (either Fridericia or Bazett’s correction) interval ≥500 msec 
on electrocardiogram performed at screening or baseline.
13. The subject has significant liver dysfunction (defined as total bilirubin > 1.5 times 
upper limit of normal AND AST or ALT > 3 times upper limit of normal with 
normal alkaline phosphatase [ALP] on screening labs) at the time of 
randomization.
14. The subject has hepatic cirrhosis or a Child-Pugh score of C (severe hepatic 
impairment) at the time of randomization.  See Appendix 4 for Child-Pugh 
Classification.
15. The subject has severe renal insufficiency (estimated creatinine clearance <20 
mL/min) or on hemodialysis at the time of randomization or is likely to require 
dialysis during the study.
16. The subject has a known hereditary problem of galactose intolerance, Lapp 
lactase deficiency, or glucose-galactose malabsorption.
17. The subject has acute symptomatic pancreatitis within 6 months of study entry or 
has a diagnosis of chronic pancreatitis at the time of randomization.
18. The subject has an active skin lesion consistent with squamous cell carcinoma at 
the time of randomization, or a current or prior history of malignant melanoma 
within 5 year of study entry.
19. The subject is on artificial ventilation or receiving acute Continuous positive 
airway pressure (CPAP)/ Bilevel Positive Airway Pressure (BPAP) at the time of 
randomization.
20. A subject has known or suspected Gilbert’s disease at the time of randomization.
21. The subject requires treatment with other medications that cannot be stopped 
and for which there is a known contraindication to co-administration of one or 
more of the study drugs.
22. The subject is not expected to survive for at least 1-week post-randomization.
23. The subject must not have prior enrollment in this study.  The subject must not 
have prior enrollment in other POS studies within 90 days of study entry.
 
 
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24. The subject or a family member is among the personnel of the investigational or 
sponsor staff directly involved with this trial.
7.3.3
Subject Discontinuation Criteria
A subject may discontinue from the clinical trial at any time for any reason.
It is the right and the duty of the investigator or sub-investigator to stop treatment in 
any case in which emerging effects are of unacceptable risk to the individual subject.  
In addition, the investigator or sub-investigator is to stop treatment of any subject 
with unmanageable factors that may interfere significantly with the trial procedures 
and/or the interpretation of results.
In this trial, a subject may discontinue from treatment, but continue to participate in 
the regularly scheduled activities as long as the subject does not withdraw consent.  
Discontinuation from treatment is “permanent”:  once a subject is discontinued 
treatment, even though he/she continues to be monitored in the trial, he/she shall 
not be allowed to begin treatment again.
At a minimum collect the following information when a subject discontinues:
1.
The reason the subject discontinued;
2.
The date of the last dose of test products from the trial;
3.
The date of the last assessment and/or contact.  A follow-up contact (telephone 
or visit) will be arranged as appropriate;
4.
(Serious) Adverse events;
5.
Compliance with the test product administration as specified in this protocol;
6.
Final Assessments:
Every effort should be made to ensure that all procedures and evaluations 
scheduled for the final trial visit are performed (Section 2.2, Trial Flow Chart);
7.
Retrieve all investigative products and test articles from the subject.
A subject must be discontinued from treatment for any of the following reasons:
1.
The subject or legal representative (such as a parent or legal guardian) 
withdraws consent;
2.
Adverse event criteria as specified in Section 7.7.2.3.1.
3.
Request of the subject (subjects have the right to discontinue treatment at any 
time for any reason);
 
 
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4.
Pregnancy;
5.
Subjects with a prolonged QTc interval on a manual measurement of their post 
baseline ECG: greater than 500 msec.  Study drug should be interrupted while 
evaluation and treatment of other etiologies is ongoing, and restarted within 5 
days if QTc is within normal limits (less than or equal to 500 msec);
6.
Subjects that develop clinically indicated visual problems (Grade 3 and/or Grade 
4);
7.
Subjects that develop an exfoliative cutaneous reaction, develops a skin lesion 
consistent with squamous cell carcinoma or melanoma.
8.
Subjects who, during the course of the study, it is determined that they have a 
mold fungal infection caused by an organism that may be insufficiently covered 
by the current study therapy, or some other infection that requires combination 
antifungal therapy.  Subjects who develop candidemia on study therapy may
receive an echinocandin agent in addition to study therapy for a maximum 
duration of 14 days. A subject who needs a longer duration than 14 days of 
echinocandin therapy should discontinue study therapy.
7.3.4
Replacement of Subjects
A subject who discontinues from the trial will not be replaced.
7.4
Treatments
7.4.1
Trial Treatments
7.4.1.1
Treatments Administered
Treatment should be started as close as possible to the date in which randomized 
treatment is assigned, preferably on the same day.
Upon acceptance into the study, once all of the inclusion and exclusion criteria are 
met, at Baseline/Day 1 subjects will be stratified into two strata; high risk or not high 
risk (see Section 7.4.1.2 for details).  Within each stratum, subjects will be randomly 
assigned to one of two possible treatment arms: POS or VOR for a total duration of 
therapy of 12 weeks. The planned duration of study therapy is 12 weeks (84 days) 
with a maximum allowable duration of up to 98 days. Subjects will be randomized to 
POS or VOR in a 1:1 ratio.  Table 3 provides an overview of the treatment arms.
 
 
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Table 3 Overview of Active Study Drug Dosing by Treatment Arms
Treatment Arms
IV Therapya
Oral Therapy
Arm 1- Posaconazole (POS)
POS IV: 
Day 1b: 300 mg BID
Day 2-84c: 300 mg QD
POS oral: 
Day 1b: 300 mg BID
Day 2-84c: 300 mg QD
Arm 2 – Voriconazole (VOR)
VOR IV: 
Day 1b: 6 mg/kg per body weight 
administered BID
Day 2-84c: 4 mg/kg per body 
weight administered BID
VOR oral: 
Day 1b: 300 mg BID
Day 2-84c: 200 mg BID
a Most subjects begin IV study drug and then step down/transition to oral study drug. If clinically indicated, 
some subjects may begin study drug with oral therapy instead of IV therapy.
b Day 1 refers to the first day of subject taking either IV or Oral therapy.  Subjects will only take one 
formulation, either IV or oral at a time
c The planned duration of study therapy is 12 weeks (84 days) with a maximum allowable duration of up to 
98 days.
IV=intravenous; POS=posaconazole; VOR=voriconazole
The dosing regimens will be as follows:
Arm 1 POS:
POS IV loading dose, 300 mg IV BID on Day 1; followed by 300 mg POS IV QD 
beginning on Day 2; followed by POS tablet 300 mg QD to begin following transition 
from POS IV.  Transition to oral therapy may occur when the subject is considered 
clinically stable and able to take oral medication.  Most subjects will initiate IV 
therapy, and then transition to oral; however, some subject may initiate via the oral 
route if clinical indicated.  Subjects taking oral therapy on Day 1 will receive POS 
tablet 300 mg BID as a loading dose; followed by POS tablet 300 mg QD.  
Subjects randomized to Arm 1 POS will receive a placebo infusion of 5% dextrose in 
water once a day to make the total number of infusions per day (2) similar for both 
treatment arms.  Subjects will also receive double-dummy capsules with appearance 
consistent with VOR capsules when transition to oral therapy.
Arm 2 VOR:
VOR IV loading dose, 6 mg/kg IV BID on Day 1; followed by 4 mg/kg VOR IV BID
maintenance dose, beginning on Day 2; followed by oral VOR capsule 200 mg BID 
to begin following transition from VOR IV.   Transition to oral therapy may occur 
when the subject is considered clinically stable and able to take oral medication.  
Most subjects will initiate IV therapy, and then transition to oral; however, some 
subject may initiate via the oral route if clinical indicated.  Subjects taking oral 
therapy on Day 1 will receive VOR capsule 300 mg BID as a loading dose; followed 
by VOR capsule 200 mg BID.  
 
 
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Subjects randomized to Arm 2 VOR will also receive double-dummy tablets with 
appearance consistent with POS tablets when transition to oral therapy.
7.4.1.2
Method of Treatment Assignment, Randomization, and/or 
Stratification
Subjects will be stratified prior to treatment assignment by risk status for mortality 
and poor outcome.  Randomized treatment assignment will be stratified as follows:  
High Risk: Any one of the following are present at Baseline or in the patient’s 
medical history:

Allogeneic hematopoietic stem cell transplant (HSCT).

Relapsed leukemia, undergoing salvage chemotherapy.

Liver transplant recipients [12].
Not High Risk: Any other eligible subject (none of the high-risk criteria are present at 
Baseline or in the subject’s medical history)
Within each stratum, subjects will be randomly assigned (in a 1:1 ratio) to receive 
either POS or VOR according to a computer-generated randomization schedule 
using the interactive voice response system (IVRS).
7.4.1.3
Selection and Timing of Dose for Each Subject
Selecting the Dose for Each Subject
The rationale for the selection of doses to be used in this trial is presented in Section 
5.3.  Dosing for all of the subjects will be based on Table 3.  The VOR IV dose will 
be calculated based on the screening weight of the subject.  Details of the 
calculations can be found in the Pharmacy Manual.
Most subjects will begin antifungal azole (VOR or POS) therapy via the IV route.  
Azole therapy will be switched from IV route to the oral route when the subject is 
considered clinically stable and able to take oral medication.  If during the course of 
the study, the subject can no longer tolerate oral medication, the subject may be 
switched back to IV therapy.  Subjects with worsening clinical symptoms may also 
be switched back to IV therapy as clinically indicated. Based upon product labeling, 
similar study drug exposures for a 300 mg dose have been noted for POS IV and 
POS tablet, while 4 mg/kg IV VOR dosing achieves exposures similar to a 300 mg 
oral maintenance dose of VOR.  Please refer to VOR EU product circular for full 
details [32].   
If clinically indicated, some subjects may initiate study therapy via the oral route: Day 
1 dosing of oral therapy is: POS 300 mg BID or VOR 300 mg BID.
 
 
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For subjects with mild to moderate hepatic cirrhosis (Child-Pugh score of A or B), the 
standard loading dose will be used, but the maintenance dose will be reduced.  See 
Appendix 4 for Child-Pugh Classification.  Appropriate dosing modifications will be 
included in the trial design in a blinded fashion.  
Determining the Timing of Dose Administration for Each Subject
7.4.1.3.2.1
Posaconazole
Table 4 provides what subjects randomized to the POS arm will receive when on IV 
therapy.
Table 4 Summary of POS IV Therapy
Day 1 Dose
Day 2-84 Dose
Day 2-84 Dose for subjects 
with hepatic impairment
Drug
POS 300 mg
twice a day
POS 300 mg first dose, 
placebo infusion second dose
POS 300 mg first dose, placebo 
infusion second dose
Volume
200 mL
150 mL
150 mL
Infusion rate
100 mL/hr
100 mL/hr
100 mL/hr
Infusion Duration
2 hr
1.5 hr
1.5 hr
Table 5 provides what subjects randomized to the POS arm will receive when on 
oral therapy.
Table 5 Summary of POS Tablet Therapy
Daily Oral Dose
300mg QDa
Daily Oral Dose for subjects with 
hepatic impairment
300mg QD
First Dose
2 orange VOR capsule placebos
3 yellow POS tablets
1 orange VOR capsule placebos
3 yellow POS tablets
Second Dose
2 orange VOR capsule placebos
1 orange VOR capsule placebos
a    If the subject starts on Day 1 with POS Tablet, they will receive 300 mg BID.  The first dose should 
be: 3 orange VOR capsule placebos, and 3 yellow POS tablets.  The second dose should be: 3 orange 
VOR capsule placebos, and 3 yellow POS tablets.
7.4.1.3.2.1.1 POS IV Solution
Subjects will have their IV infusions begun at the same time each day and are not to 
be administered until after the collection of the specified blood samples 
(Section 7.6). 
POS IV will be given every 12 hours on the first day, with infusions being not less 
than 10 hours or no more than 14 hours apart.  The subsequent POS IV infusions 
will be administered once daily 24 hours (± 2 hours) apart, in order to control one 
 
 
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source of variability in drug levels.  Subjects who are randomized to POS will also 
receive a placebo infusion of 5% dextrose in water to make the number of infusions 
per day (2) similar for both treatment arms.  Subjects will receive an IV infusion 
(POS or placebo) every 12 hours.
If the dosing of study medication is delayed, the dose should be administered as 
soon as possible.  If it is more than 6 hours since the missed dose, the missed dose 
should be skipped, and the next dose should be administered at the regularly 
scheduled time.  Any missed doses should be properly documented in the subject's 
eCRF and source documentation.  The infusions will be administered via a 
programmable pump.  On Day 1 the infusions will run for approximately 2 hours.  
The infusions on the subsequent days will run for approximately 1.5 hours.  If 
necessary, the IV infusions may be prepared up to 24 hours prior to administration 
and stored at 2°C to 8°C refrigerated.  The IV infusions should return to room 
temperature prior to administration.
IV infusions should be administered via a peripherally inserted central catheter, or a 
dedicated lumen of a central venous catheter.  No infusions of study drug should be 
given via a peripherally inserted peripheral catheter as the duration of infusion 
mandated in the study for IV study therapy differs for peripheral catheter 
administration as compared to central catheter administration.  Dosing duration is 90 
minutes.  The dosing of study drug via peripheral venous administration may not 
occur due to the potential occurrence of thrombophlebitis when IV study drug is 
given via peripheral route.  POS IV infusions will be prepared in 5% dextrose in 
water.  
Subjects will receive the IV infusions at a hospital or clinic.  No IV doses should be 
missed.
See the Unblinded Pharmacy Binder and Administrative Binder for detailed POS IV 
Solution preparation and administration procedures.
7.4.1.3.2.1.2 Posaconazole Tablet
POS tablet will be started on the day after completion of the IV therapy (within 12 
hours of the placebo infusion matching VOR IV) and continue up to Week 12 post 
randomization.  POS tablet will be administered as a 300 mg dose QD (three 100 
mg tablets, once a day).  Every attempt should be made to ensure that the subject 
takes study medication at approximately the same time every day.  If the dosing of 
study medication is delayed, the dose should be taken as soon as possible.  Any 
missed doses should be properly documented in the subject's eCRF and source 
documentation.  
If clinically indicated, some subjects may initiate study therapy via the oral route.  For 
these subjects POS tablet will be administered on Day 1 as a 300 mg dose BID 
(three 100 mg tablets, twice a day at approximately 12-hour intervals).  After Day 1, 
the dose will be 300 mg QD (three 100 mg tablets, once a day).
 
 
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If a subject vomits within 15 minutes of POS tablet administration, the dosing should 
be repeated as soon as possible, following appropriate antiemetic treatment.  The 
adverse event, supportive treatments, and ability to subsequently dose study 
medication should be appropriately recorded in the subject's eCRF.  If repeated 
vomiting occurs, the subject should switch to POS IV therapy.
Details of the patient’s food intake surrounding each dose of POS tablet or dummy 
placebo tablet should be recorded relative to each dose of POS tablet. Specifically, 
food intake data to be recorded should include whether the subject had no food, a 
light meal, a moderate meal or a full meal within 2 hours before or within 1 hour after 
taking study drug. 
The exact time of POS study drug taken prior to collection of the population PK
sample, as well as the exact time the Population PK sample blood draw occurs will
be recorded in the appropriate eCRF.
7.4.1.3.2.2
Voriconazole
Table 6 provides what subjects randomized to the VOR arm will receive when on IV 
therapy.
Table 6 Summary of VOR IV Therapy
Day 1 Dose
Day 2-84 Dose
Day 2-84 Dose for subjects 
with hepatic impairmenta
Drug
VOR 6 mg/kg 
twice a day
VOR 4 mg/kg
twice a day
VOR 2 mg/kg
twice a day
Volume
200 mL
150 mL
150 mL
Infusion rate
100 mL/hr
100 mL/hr
100 mL/hr
Infusion Duration
2 hr
1.5 hr
1.5 hr
a The maintenance dose of VOR should be reduced for subjects with mild to moderate hepatic impairment 
(Child-Pugh Class A and B).
 
 
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Table 7 provides what subjects randomized to the VOR arm will receive when on 
oral therapy.
Table 7
Summary of VOR Capsule Therapy
Daily Oral Dose
200mg BIDa
Daily Oral Dose for subjects with hepatic 
impairmentb
100mg BID
First 
Dose
2 orange VOR capsules
3 yellow POS tablet placebos
1 orange VOR capsules
3 yellow POS tablet placebos
Second 
Dose
2 orange VOR capsules
1 orange VOR capsules
a    If the subject starts on Day 1 with VOR Solid Oral, they will receive 300 mg BID.  The first dose 
should be: 3 orange VOR capsules, and 3 yellow POS tablet placebos.  The second dose should be: 
3 orange VOR capsules, and 3 yellow POS tablet placebos.
b  The maintenance dose of VOR should be reduced for subjects with mild to moderate hepatic 
impairment (Child-Pugh Class A and B).
7.4.1.3.2.2.1 Voriconazole IV
Subjects will have their IV infusions begun at the same time each day and are not to 
be administered until after the collection of the specified blood samples 
(Section 7.6). 
VOR IV infusions must be given every 12 hours with no dose given less than 10 
hours or no more than 14 hours apart.  If the dosing of study medication is delayed, 
the dose should be administered as soon as possible.  If it is more than 6 hours 
since the missed dose, the missed dose should be skipped, and the next dose 
should be administered at the regularly scheduled time.  Any missed doses should 
be properly documented in the subject's eCRF and source documentation.  The 
infusions will be administered via a programmable pump.  On Day 1 the infusions 
will run for approximately 2 hours.  The infusions on the subsequent days will run for 
approximately 1.5 hours.  If necessary, the IV infusions may be prepared up to 24
hours prior to administration and stored at 2°C to 8°C refrigerated.  The IV infusions 
should return to room temperature prior to administration.
IV infusions should be administered via a peripherally inserted central catheter, or a 
dedicated lumen of a central venous catheter.  VOR IV infusions will be prepared in 
5% dextrose in water.
Subjects will receive the IV infusions at a hospital or clinic.  No IV doses should be 
missed.
See the Unblinded Pharmacy Binder and Administrative Binder for detailed VOR IV 
preparation and administration procedures.
 
 
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7.4.1.3.2.2.2 Voriconazole Capsule
VOR oral capsule will be started on the day after completion of the IV therapy (within 
12 hours of the last dose of IV VOR) and continued up to Week 12 post 
randomization.  VOR will be administered as a 200-mg dose BID (two 100-mg 
capsules, twice a day at approximately 12-hour intervals). VOR oral capsules 
SHOULD NOT BE TAKEN WITH A MEAL and should be taken at least one hour 
before or one hour following a meal.  If the dosing of study medication is delayed, 
the dose should be taken as soon as possible at least one hour before or one hour 
following a meal.  Any missed doses should be properly documented in the subject's 
eCRF and source documentation. 
If clinically indicated, some subjects may initiate study therapy via the oral route.  For 
these subjects VOR oral capsule will be administered on Day 1 as a 300-mg dose 
BID (three 100 mg capsules, twice a day at approximately 12-hour intervals).  After 
Day 1, the dose will be 200 mg BID (two 100-mg capsules, twice a day at 
approximately 12-hour intervals).
If a subject vomits within 15 minutes of VOR capsule administration, the dosing 
should be repeated as soon as possible, following appropriate antiemetic treatment.  
The adverse event, supportive treatments, and ability to subsequently dose study 
medication should be appropriately recorded in the subject's eCRF.  If repeated 
vomiting occurs, the subject should switch to VOR IV therapy.
7.4.1.4
Blinding Trial Treatments
Double-Blind, Double-Dummy (for Oral Administration)
Only the investigational pharmacists or qualified medical personnel responsible for 
preparing the study drug will have knowledge of the treatment identity and will 
prepare study medications according to the protocol guidelines; all other study 
personnel will be blinded to study treatment.  The unblinded pharmacists will not be 
involved in any post-treatment assessments for the subjects enrolled in this trial.  
Subjects will receive the blinded IV study therapy from the unblinded pharmacist.  In 
order to maintain the blind, preparation of the intravenous study drugs must be 
performed by someone other than the persons who will evaluate the subject for 
clinical response and presence of adverse experiences.
IV infusions will be masked to blind the appearance of the IV study drugs.  Matching 
placebo infusions of 5% dextrose will be used for the additional daily doses to make 
the number of infusions per day (2) similar in both treatment arms.  Subjects in both 
treatment arms will receive the same number of infusions per day with equivalent 
infusion rates and volumes.  This is not dependent on the treatment arm. 
POS tablets and VOR capsules will be administered using a double-dummy, double-
blind method to blind study personnel and subjects as to the assigned treatment 
arm.  Oral VOR will be given as over-encapsulated tablets with each capsule 
 
 
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containing 100 mg of VOR or a placebo to VOR. The POS oral tablet will also be 
blinded by use of a dummy tablet with each tablet containing 100 mg of POS or a 
placebo to POS.  Subjects in both treatment arms will receive the same number of 
tablets and capsules per day when on oral therapy.  This is not dependent on the 
treatment arm.
As VOR labeling recommends, dosage adjustment based upon hepatic insufficiency 
will be made.  The maintenance dose of VOR will be reduced in subjects with mild to 
moderate hepatic impairment (Child-Pugh Class A and B).  Subjects on VOR IV will 
receive 2 mg/kg maintenance dose BID.  Subjects on VOR capsules will receive 100 
mg BID.  Appropriate dosing modifications will be included in the trial design in a 
blinded fashion.  There is no planned dose reduction or dose adjustment of POS IV 
or POS tablet or POS dummy tablet.
This study will be conducted using in-house blinding procedures.  See 
Section 7.7.2.6.4 for a description of the method of unblinding a subject during the 
trial, should such action be warranted.
7.4.1.5
Investigational Medicinal Products 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, handling, storage, distribution, 
and usage of these materials in accordance with the protocol and any applicable 
laws and regulations.
Identity of Investigational Medicinal Products
The following study medications will be used in the trial:
Posaconazole 100 mg IV, 18mg/mL, 5.6mL fill
Posaconazole 200 mg IV, 18mg/mL, 11.2mL fill
Posaconazole 300 mg IV; 18mg/mL, 16.7mL fill (When available, may replace 
100/200 mg vials)
Voriconazole 200 mg IV 
Posaconazole 100 mg tablets
Posaconazole Placebo tablets
Voriconazole 100 mg capsules
Voriconazole Placebo capsules
Source
All products listed in Section 7.4.1.5.1 will be provided by the sponsor.
 
 
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Labeling
Labeling for POS IV and VOR IV vials and cartons should include but not limited to 
the following information and will comply with the regulatory requirements for the 
clinical site: Space for Randomization #, component ID and the following statement 
"For Intravenous Use Only".  
In addition, the POS IV cartons will include the following: Contents: One 100 mg and 
one 200-mg POS vial.
Labeling for POS active/placebo tablet bottles should include but not limited to the 
following information and will comply with the regulatory requirements for the clinical 
site: Space for Randomization #, component ID and the following statement: Oral 
Use.
Labeling for VOR active/placebo capsule bottles should include but not limited to the 
following information and will comply with the regulatory requirements for the clinical 
site: Space for Randomization #, component ID, the following statements: Oral Use 
and should be taken at least one hour before or after a meal.
The labeling of the POS active/ placebo tablets bottle and VOR active/placebo 
capsules bottle will maintain the double-blind double-dummy design of the trial. The 
labeling of the POS IV and VOR IV will be open label.
Packaging
POS IV will be supplied as a carton with one 100 mg and one 200 mg POS IV vials.  
A rollout of POS IV 300 mg vials will also occur during the study.
VOR IV will be supplied as a carton with one 200 mg VOR vial.
POS active and placebo will be supplied as bottles of 30 tablets each.
VOR active and placebo will be supplied as bottles of 40 capsules each.
The packaging of the POS active/placebo tablets bottle and VOR active/placebo 
capsules bottle will maintain the double-blind double-dummy design of the trial.  The 
packaging of the POS IV and VOR IV will be open label.
Storage
Trial treatment supplies must be stored in a secure, limited-access location under 
the storage conditions specified on the supply label and pharmacy manual.  Site 
storage conditions should be monitored by the site personnel for adherence to label 
and pharmacy manual specifications and reviewed during site visits.
 
 
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Dispensing
The investigator or qualified designee(s) will dispense trial treatments at the 
designated site(s) to subjects who have provided written informed consent and have 
met the entry criteria.  Clinical supplies may not be used for any purpose other than 
that which is stated in this protocol.
See the Trial Flow Chart in Section 2.2 for a schedule of when clinical supplies are 
to be dispensed to the subjects.
Replacement of Investigational Product
Refer to the Unblinded Pharmacy Binder and Administrative Binder for details 
regarding replacement of clinical supplies.
Investigational Medicinal Product Accountability
Accurate and current accounting of the dispensing and return of investigational 
products will be maintained on an ongoing basis by a member of the trial site staff:
•
Investigational medicinal products dispensed to each site will be recorded in the 
trial-specific Site Investigational Medicinal Product (IMP) Accountability Log (or 
equivalent document approved by the sponsor);
Investigational medicinal products dispensed to each subject will be recorded.  
In this study, as part of the routine recording of the amount of study treatment taken 
by each patient, at each site, the volume of infusion administered, and the number of 
tablets/capsules dispensed and returned will be counted, reviewed, and recorded at 
regular intervals at the local level. Pharmacy records of dispensing and return of 
study medication will be recorded using local documentation records and will be 
monitored and reviewed by un-blinded study monitors throughout the study period. 
Pharmacy records will be retained at the local pharmacy and available for Sponsor 
review.  Site records will be used to ensure and document study medication 
compliance.  Study medication dosing will be recorded in the electronic case report 
for each study medication component (IV or oral, placebo or active drug) based 
upon local documentation records.
After use by the subject, the following test articles may be collected and destroyed
according to the hospital’s hazardous/medical waste policies, as applicable:

IV bags and solution set 

Used POS and VOR IV vials
In the event the investigational products destruction is arranged by the site, copies of 
the destruction records should be returned to the sponsor.
 
 
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The sponsor’s trial monitor will instruct the site on the return of all investigational 
products supplies.  A final inventory of the total amount of investigational products 
received at each trial site against the amount used and returned must be recorded in 
the Site IMP Accountability Log.  Inventory records must be readily available for 
inspection by the trial monitor and/or auditor, and open to government inspection at 
any time.
7.4.2
Non-Trial Treatments
7.4.2.1
Prior and Concomitant Medications
Medications, Supplements, and Other Substances Prohibited Prior to 
Randomization and During the Trial
A record of all prior medication (prescription or over the counter) taken by the 
subject within 7 days before starting the study and all concomitant therapy taken by 
the subject during the study is to be obtained and recorded in the subject's eCRF.  
Parenteral nutrition products will also be documented as concomitant therapy.  A 
record of chemotherapeutic agents used for any chemotherapy regimen within 30
days of Enrollment is to be obtained.  A record of all prior immunosuppressive 
therapies and antifungal therapy should be recorded for 30 days prior to Baseline 
through Day 1.  The identity of the therapy, route, and regimen, the dates started 
and stopped (or notation of “continuing” if that is the case), and the reason for use 
are to be included in the record.
Nasal sprays of amphotericin B (AMB) and aerosolized AMB are prohibited during 
the Treatment Phase.  If subjects are on such treatment before study entry, such 
drugs must be discontinued at the time of Enrollment.  Investigational drugs 
(i.e., other drugs not yet approved for marketing by the FDA or local health 
authorities) are also prohibited during the Treatment Phase.
Topical nonabsorbable antifungals may be used for the treatment of oropharyngeal 
candidiasis, vaginal candidiasis, or cutaneous fungal infection.  These include: oral 
AMB, miconazole (oral or topical), nystatin (oral or topical), oral or topical 
clotrimazole.  All other topical, nonabsorbable antifungal therapies must be approved 
by the sponsor prior to use.  No other topical or oral antifungal agents may be used 
as prophylactic treatments (e.g., clotrimazole as prophylaxis in patients with 
mucositis).
The medications, supplements, and other substances prohibited prior to and after 
randomization are listed in Table 2 in Section 7.3.2 with the subject exclusion 
criteria.  
The washout period for study medication after discontinuation is approximately 7
days.  Subjects should be monitored for untoward reactions if any of the prohibited 
medications are administered during the washout period (7 days post treatment) and 
AEs related to potential drug interactions should be recorded in the subject's eCRF.
 
 
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Refer to Section 7.4.2.1.2 for information regarding coadministration of POS with 
CYP3A4 substrates.  Tables are also included regarding coadministration of VOR 
with other drugs.
Concomitant Medications, Supplements, and Other Substances 
Allowed During the Trial
POS is a potent inhibitor of CYP3A4.  Coadminstration of POS with CYP3A4 
substrates may result in large increases in exposure of CYP3A4 substrates.  Caution 
is advised during coadministration of POS with CYP3A4 substrates and the dose of 
the CYP3A4 substrate may need to be reduced.  Plasma concentrations of the 
CYP3A4 substrate and/or AEs should be closely monitored and the dose adjusted 
as needed.
VOR is metabolized by CYP2C19, CYP2C9, and CYP3A4.  Inhibitors or inducers of 
these enzymes may increase or decrease VOR exposure, respectively.
Note that the use of any concomitant medication must relate to the documented 
medical history, prophylaxis, or an adverse event of the subject.
The following medications, supplements, and other substances are allowed during 
the trial; however, caution is advised during coadministration (See Table 8). 
Table 8 Medications, Supplements, and Other Substances Allowed During the Trial
Drug/Drug Class 
Recommendations for Drug Dosage 
Adjustment/Comments
Cyclosporine
Tacrolimus
When initiating therapy with study drug follow with monitoring of 
blood levels of these drugs.  When study drug is discontinued, 
concentrations must be frequently monitored, and the dose 
increased as necessary.
Methadone 
Monitoring for adverse events and toxicity related to methadone 
is recommended during coadministration. Dose reduction of 
methadone may be needed.
Fentanyl 
Alfentanil
Oxycodone
Reduction in the dose of fentanyl and other long-acting opiates 
metabolized by CYP3A4 should be considered when 
coadministered with study drug. Extended and monitoring for 
opiate associated adverse events may be necessary.
NSAIDs including. ibuprofen and 
diclofenac 
Monitoring for adverse events and toxicity related to NSAIDs. 
Dose reduction of NSAIDs may be needed. 
Oral Contraceptives containing ethinyl 
estradiol and norethindrone 
Monitoring for adverse events related to oral contraceptives is 
recommended during coadministration.  If oral contraceptives 
are used, an additional form of contraception should be used.
Warfarin
Monitor PT or other suitable anticoagulation tests. Adjustment 
of warfarin dosage may be needed.
Omeprazole
Monitoring for adverse events is recommended during 
coadministation.
Other HIV Protease Inhibitors
Monitoring for adverse events and toxicity related to other HIV 
protease inhibitors
 
 
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Drug/Drug Class 
Recommendations for Drug Dosage 
Adjustment/Comments
Other NNRTIsa
Monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines
Monitoring for adverse events and toxicity (i.e., prolonged 
sedation) related to benzodiazepines metabolized by CYP3A4 
(e.g., midazolam, triazolam, alprazolam). Adjustment of 
benzodiazepine dosage may be needed.
Dihydropyridine Calcium Channel 
Blockers
Monitoring for adverse events and toxicity related to calcium 
channel blockers. Adjustment of calcium channel blocker 
dosage may be needed.
Sulfonylurea Oral Hypoglycemics
Monitoring of blood glucose and for signs and symptoms of 
hypoglycemia. Adjustment of oral hypoglycemic drug dosage 
may be needed.
a
Non-Nucleoside Reverse Transcriptase Inhibitors
7.4.2.2
Other Treatments
Clinical and/or QTc monitoring is recommended when the study drug is 
coadministered with one of the following drugs that have reported a potential risk of 
torsades de pointes:  amiodarone, chlorpromazine, clarithromycin, domperidone, 
droperidol, levomethadyl, mesoridazine, methadone, erythromycin, sparfloxacin, and 
thioridazine.
In addition to the medications in Table 8, the drugs listed below are permitted, 
although their efficacy and safety should be clinically monitored and/or serum levels 
followed with appropriate dosage adjustments as necessary at the initiation of study 
drug, periodically during treatment, and after discontinuation of study drug:

Oral hypoglycemic agents

Digoxin

Coumadin-type anticoagulants

Calcium channel blockers

Theophylline

Antiretroviral therapy (e.g., atazanavir, or tenofovir).
POS interferes with the hepatic clearance of triazolam and midazolam, and thus, 
may enhance the sedative effects of these agents.  Therefore, these agents are not 
allowed unless monitoring is provided for excessive sedation.
Please refer to POS and VOR product circulars for the most up to date details 
regarding the drugs and any updates in contraindications.
 
 
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7.4.3
Procedures for Monitoring Subject Compliance With Administration of 
Trial Treatments
At all protocol-specified visits, the investigator or qualified designee is to record 
whether treatment had been taken per protocol in the preceding interval.  If not, the 
date(s) and reason for each dosing noncompliance must be recorded in the subject's 
eCRF.
7.5
Trial Schedule
The visit-by-visit schedule of trial activities is provided in the Trial Flow Chart in 
Section 2.2.
The timing of each visit is relative to Day 1, which is defined as administration of the 
first dose of trial medication (Section 7.4.1.1).
All visits should be performed within the windows specified in Section 2.2, the Trial 
Flow Chart.  Every attempt should be made to have each subject attend each visit 
as scheduled.  However, if a subject is unable to attend a visit within the specified 
windows, the visit should be scheduled as closely as possible to these windows.  A 
subject should not miss a protocol-specified visit due to scheduling difficulties.
7.6
Trial Procedures
The Trial Flow Chart in Section 2.2 summarizes the trial procedures to be performed 
at each visit.  Individual trial procedures are described below.
In order to minimize variability of evaluations, it is preferred that the same individuals 
perform the same types of evaluations for all subjects at each trial site.
Screening and randomization visits may occur on the same day to help 
accommodate the initiation of treatment in ill patients.
1.
Explain Trial and Obtain Written Informed Consent

Study Informed Consent
The investigator or qualified designee will explain the trial to the subject, answer 
all of his/her questions, and obtain written informed consent before performing 
any trial-related procedure.  A copy of the informed consent will be given to the 
subject (see Section 9.1.2 for further description of the Informed Consent). 

Assent
For a subject under the age of consent, a legal representative must provide 
written informed consent on his/her behalf, and assent will be obtained from the 
minor.
 
 
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
Pharmacogenetic Informed Consent (Optional)
The investigator or qualified designee will explain the Pharmacogenetic (PGt) 
testing to the subject, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to PGt testing.  A copy of the 
informed consent will be given to the subject.
2.
Review Inclusion/Exclusion Criteria
The inclusion and exclusion criteria will be reviewed by the investigator or 
qualified designee to ensure that the subject qualifies for the trial.
3.
Issue or Collect Subject Identification Card
The investigator or qualified designee will provide the subject with a Subject 
Identification Card after the subject provides written informed consent.  The 
investigator or qualified designee will retrieve the card from the subject at the last 
in-person contact (see Section 9.1.3 for further description of the Subject 
Identification Card).
4.
Obtain Medical / Disease History
A complete medical history will be obtained by the investigator or qualified 
designee and recorded in the eCRF.  The medical history should include details 
regarding underlying conditions that may qualify the subject for possible, 
probable, or proven IA according to modified 2008 EORTC/MSG criteria.  The 
medical history should include details regarding any ongoing or prior cancer 
diagnoses, immunosuppressive conditions (including HIV), and transplant 
procedures (BMT and solid organ).  The history should also include details 
regarding recent or ongoing bacterial infectious episodes, and any prior histories 
of invasive fungal infection as well as details regarding the current episode of IA.  
The history should also include any details of prior or ongoing visual disturbances 
(including, but not limited to: abnormal vision, blurred vision, photopsia, visual 
hallucination, decreased acuity, hallucination).  Any history of hepatitis should 
also be recorded.
 
 
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5.
Pharmacogenetic (PGt) Samples (Optional)
Informed consent specific for PGt sampling, must be obtained prior to collection. 
To obtain sufficient DNA for pharmacogenetic studies, a single 8.5-mL blood 
sample will be drawn indicated in Section 2.2, Study Flow Chart, into the 
appropriate tubes provided by the sponsor (see Laboratory Manual for 
information on PG sample management, and see Appendix 5 for a summary of 
procedures for PGt.).
6.
Stratification and Randomization by IVRS 
IVRS will be utilized to assign a Screening Number, Subject Number, 
randomization, and log of treatment status (either completed treatment or 
discontinued treatment).  Drug will be allocated and dispensed at Day 1.  
Subjects will be randomized to either POS or VOR.  Since randomization is 
performed at Baseline (Day 1), it must be determined that the subject has met all 
eligibility criteria prior to randomization.  IVRS will be utilized for drug allocation 
and dispensing at scheduled study visits.  
7.
Problem Focused Physical Examination
A problem focused physical examination will be performed and all abnormal 
findings are to be recorded in the eCRF.
8.
Body Weight
Body weight will be recorded at screening.  Actual body weight is to be recorded 
at screening for all subjects in the eCRF
9.
Vital Signs
Vital signs, including temperature, pulse, and blood pressure, will be taken.  Vital 
signs will be recorded daily for hospitalized subjects and on scheduled days if 
outpatient.  While subjects are on IV treatment, vital signs should be collected 
daily.  Temperature recorded should be highest temperature (maximum 
temperature) for each day.  For the screening period, vital signs including daily 
maximum temperature, pulse, and blood pressure should be recorded beginning 
on the first day of screening immediately following signing of informed consent 
and daily thereafter.
10. Review Prior Medications
Review of appropriate prior medications, including the necessary washout times, 
with the subject.  Prior medications to be recorded include all antifungal drugs 
taken within 30 days before starting the trial.  A record of all chemotherapy 
agents and immunosuppressive agents used within 30 days before starting the 
trial is to be obtained.  All prior medication taken by the subject within 7 days 
before starting the trial is to be obtained.
 
 
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11. Clinical Signs and Symptoms of IA
Details regarding all clinical signs and symptoms that may be related to fungal or 
bacterial infections should be evaluated and recorded.  Any clinical sign and 
symptom that may be possibly, probably, or related to a fungal infection should 
be identified.  All subjects will be evaluated for the presence of IA based on 
modified 2008 EORTC/MSG definitions at all visits (Appendix 2).
12. Electrocardiogram (ECG)
An ECG must be performed at Screening (Visit 1) for purposes of protocol 
eligibility.
The Day 1 ECG should be performed prior to initiation of study treatment.
Prior to study enrollment or study drug administration, all ECGs should be 
reviewed to determine study eligibility.
For subjects on IV therapy an ECG will be performed at the Week 1 study visit 
(Day 4-8) following the completion of the 90-minute infusion. 
Subjects who are receiving oral study therapy at the week 1 study visit may have 
the ECG performed without regard to the timing of study therapy.
A standard 12-lead ECG, reporting ventricular rate, PR, QRS, QT, and QTc 
intervals, will be performed using equipment provided by the sponsor for this 
purpose.  Any clinically significant abnormality must be followed until stabilization 
or return to Baseline.
During the Treatment Phase, if a QTc interval is found to be abnormal (greater 
than 500 msec) an assessment is to be done 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 
magnesium, calcium, and potassium levels).
ECGs performed will be transferred to a blinded third-party for an evaluation of 
the QT, QTc (Fridericia 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.
Procedures for printing, archiving, and review of ECGs will be specified by the 
central laboratory vendor.
 
 
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Note:  When the collection of vital signs, ECGs, and PK samples coincide, the 
blood samples for PK determination (so that the PK samples are collected on 
time) should be collected first, then 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.
13. Safety Laboratory Test (Hematology and Chemistry) 
Safety laboratory tests (Table 9 and Table 10) will be tested centrally.  At 
baseline, clinical laboratory tests can be done locally if central laboratory results 
are not available to determine eligibility.  
On Day 1, clinical laboratory tests should be drawn prior to initiation of study 
treatment.  If clinically indicated, safety laboratory tests may be repeated more 
often to evaluate clinical symptoms of AEs and must be followed until 
stabilization or return to Baseline.  Clinical laboratory tests may be performed at 
the local certified laboratory and if abnormal and clinically significant will be 
repeated at the investigator’s discretion.   The results of the any local laboratory 
tests should be recorded in the subject's eCRF and source documentation.  
Blood specimens may be drawn either peripherally or via a central venous 
catheter.  A Study Laboratory Manual will be provided for sample acquisition, 
shipping and labeling instructions.
Table 9 Laboratory Tests- Hematologic Studies
Red blood cell count (RBC)
Hematocrit
Hemoglobin
Platelet count
Total white blood cell count (WBC) 
Differential (total neutrophils [granulocytes] or segmented neutrophils plus bands, lymphocytes, monocytes, 
eosinophils and basophils).
Absolute Neutrophil Count (ANC)
Table 10
Laboratory Tests- Serum Chemistries
Total protein
Total Bilirubin
Albumin
Alkaline Phosphatase (ALK-P)
Calcium
Lactate Dehydrogenase (LDH)
Glucose
Uric Acid
Serum Glutamic Oxaloacetic Transaminase 
(SGOT)/Aspartate Serum Transaminase (AST)
Serum Creatinine
Serum Glutamine Pyruvic Transaminase 
(SGPT)/Alanine Serum Transaminase (ALT)
Blood Urea Nitrogen (BUN or Urea)
Electrolytes (sodium, potassium, magnesium, 
and chloride)
 
 
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If an unscheduled ECG is performed, a full set of electrolytes, including a 
determination of serum potassium (K), calcium (Ca), and magnesium (Mg), 
should be drawn on the same days as the ECGs are performed.  The results 
must be documented in the eCRF, as well as in the subject's source 
documentation, and any electrolyte abnormalities corrected.
If any central laboratory result is outside the reference range and is Grade 2 or 
higher, the test should be repeated locally at appropriate time intervals until it 
returns to Baseline or becomes a clinically insignificant finding, and appropriate 
standard of care should be instituted.
14. hCG Pregnancy Test 
A serum human chorionic gonadotropic (hCG) determination will be required for 
all female subjects of childbearing potential and must be performed at Baseline 
or within 72 hours before the start of the study drug.  Negative serum results 
must be available to the investigator before the subject can begin taking the 
study drug.
15. Aspergillus Galactomannan EIA 
Serum will be collected for Aspergillus Galactomannan enzyme immunoassay 
(EIA) at Screening, Baseline, all scheduled Treatment Visits, and the 30-day 
Posttherapy Visit.  At Baseline, serum drawn for Aspergillus Galactomannan EIA 
should be split into two aliquots and tested.  Broncho-alveolar lavage (BAL) fluid 
can also be collected for testing as necessary.  Results from any previous 
Aspergillus Galactomannan tests will also be recorded in the subject's eCRF.  
The quantitative value and time of collection of the galactomannan sample 
should be documented for all galactomannan tests performed on patients. The 
results of all galactomannan samples taken during the period from screening to 
the 1 month follow up visit should be provided. Galactomannan EIA serological 
test results may not be used to confirm a probable diagnosis of Invasive 
Aspergillosis if subjects have taken piperacillin/tazobactam within 72 hours of 
serum sampling.  

Serum:  a positive result is defined as two consecutive results with a cut-off 
index ≥0.5., or a single value of ≥1.0.   

Broncho-alveolar lavage fluid: a positive result is defined as a cut-off index 
≥1.0 based on testing of a single BAL fluid sample.
16. Beta-D-Glucan
Serum will be collected for Beta-D-Glucan assay at Screening, Baseline, all 
scheduled Treatment Visits, and the 30-day Posttherapy Visit.  
 
 
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17. Mycology Testing
Mycology testing includes standard fungal cultures from all sites of suspected 
Aspergillus infection, as clinically appropriate.  Unless clinically inappropriate or 
not warranted due to the patient’s health, condition or disease progression/ 
regression, mycology testing should occur at the following visits: screening/ 
baseline, Week 6 and Week 12.  Additional mycology testing will be done as 
clinically indicated and should correlate with potential disease regression/ 
progression.  All fungal culture results (positive or negative) are to be recorded.  
All fungal isolates clinically relevant to infection should be stored locally for 
possible shipment to central laboratory.  Identification to species level and 
minimum inhibitory concentration (MIC) testing will be done by a central 
laboratory on subcultures provided by site.
18. Bacterial Testing
Results of all bacteriologic culture results (positive and negative) regarding 
bacterial conditions evaluated during the screening, treatment, or follow-up 
period are to be recorded in the subject's eCRF.  Bacteriologic cultures will be 
performed locally.
19. CYP2C19 Genotyping
Blood for DNA will be obtained at baseline to determine CYP2C19 genotype in 
patients enrolled in the study. 2C19 genotype results will be studied to determine 
any genetic associations with safety and response to VOR and POS.  To obtain 
sufficient DNA for this mandatory main study DNA analysis, a single 6-mL blood 
sample will be drawn indicated in Section 2.2, Study Flow Chart, into the 
appropriate tubes
20. Diagnostic Imaging
Diagnostic imaging is required for all attributable infected sites of disease at 
Screening/Baseline, Week 6, and Week 12/EOT.  The type of imaging used (e.g.,
CT or MRI) will depend on the site of infection.  For all pulmonary sites of 
infection, digital high-resolution CT scanning is required.  Each site of infection 
identified during screening should be followed throughout the study by repeating 
the same type of scan and the same imaging modality.  All imaging that is 
performed will be transferred to a central imaging laboratory and will be made 
available to a blinded third-party for evaluation of infection.  The central imaging 
laboratory will be responsible for quantification of images.  Please refer to the 
Imaging Operations Manual for requirements and instructions.  Assessments 
made by the central imaging vendor will not be used for clinical management.  
See Appendix 6 for a summary of the imaging charter that will be used by the 
central imaging laboratory.
 
 
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21. Drug Dosing  
The date and time of administration of each dose of study drug should be 
recorded in the subject's eCRF.  While hospitalized, the timing of dosing will be
recorded in the dosing record at the time of dosing.  If study drug is administered 
as an outpatient, then the subject will maintain a dosing card and bring it to each 
scheduled visit.  Refer to Section 7.4.1.1 for POS and VOR treatment 
administration.  While subjects are receiving IV treatment, infusion site 
examination will be performed prior to dosing and at the end of infusion.  Vital 
signs should be recorded daily for subjects on IV treatment. Food intake 
information associated with POS tablet or dummy placebo tablet will be recorded.
22. Concomitant Treatments
A record of medications and therapeutic procedures during the trial is to be 
obtained and recorded in the subject's eCRF.
23. Assess Global Clinical Response
The investigator will assess global clinical response at 6 weeks and 12 weeks of 
therapy.  In the event of early therapy discontinuation, global clinical response 
will be assessed at that time.
In addition, an independent CAC will assess global clinical response based upon 
EORTC/MSG criteria and will be blinded as to the assigned treatment arm.  All 
data collected related to the evaluation of global clinical response will be 
collected including clinical signs and symptoms, imaging, serologic testing, and 
fungal culture and histology.  The assessment of global clinical response 
performed by the CAC will not be used for clinical management.
24. Plasma Pharmacokinetic Assessment
Blood trough samples for determination of POS and VOR concentrations in 
plasma will be collected on Baseline, Day 7, Week, 2, Week 4, Week 6, and 
Week 12.  Blood samples will be collected pre-dose as near to the morning dose 
as possible and the actual time of blood sample collection should be documented 
in the subject's eCRF.  If a subject discontinues early, a trough level sample 
should be taken as feasible. The recommended timing of this blood sample 
would be at least 8 hours and no more than 24 hours after the last dose of study 
drug.  However, if this timing is not feasible, a blood sample should be taken and 
the date and time of the last prior POS dose as well as the date and time of the 
blood sample should be noted.
 
 
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For adolescent subjects on IV therapy, plasma samples will be collected at the 
time of completion of their 90-minute infusion at Day 7, Week 2, Week 4, Week 6 
and Week 12 (EOT). These PK samples should be collected via peripheral 
venipuncture and not be drawn from the central catheter.  For adult subjects on 
IV therapy at the Week 1 study visit an additional Cmax PK sample should be 
collected at the time of the completion of the 90-minute infusion.  This PK sample 
should be collected via peripheral venipuncture and not be drawn from the 
central catheter.
25. Collect Unused Medications
Unused medications will be collected at each site visit.
26. Dosing Compliance Assessment
Dosing compliance will be assessed using the dosing card completed by each 
subject.
27. Drug Accountability Inventory
Drug accountability will be performed at the times indicated in the Flow Chart.  
The investigator or qualified designee will be responsible for accounting for all 
drug supplies dispensed to and returned by the subjects and will complete all 
drug accountability documentation.
28. Record (Serious) Adverse Events 
See Section 7.7.2.4 for instructions on the assessment and reporting of (Serious) 
Adverse Events and Section 7.7.2.5 for instructions on the reporting of (Serious) 
Adverse Events to the sponsor.  All adverse events related to the Tier 1 safety 
events should be captured at all scheduled visits.  The Tier 1 events include: 
hepatic safety, CNS and visual safety, dermatologic reactions, and adrenal 
steroidogenesis.  See Section 7.7.2.1 for a list of the safety events.
29. Final Survival / IFI Assessment 
For each subject, a survival assessment, if the subject is alive or dead, will be 
performed. If the subject dies, the date of death will be recorded in the eCRF.  It 
should be recorded if the subject has a recurrent or relapse of IA infection or on 
long-term antifungal prophylaxis following completion of study treatment.
 
 
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7.7
Assessments
7.7.1
Efficacy Assessments
7.7.1.1
Primary Endpoint
The Primary Endpoint is related to the Primary Trial Objective.  The Primary 
Endpoint for the trial is the all-cause mortality through Day 42 post-randomization in 
the ITT population.
7.7.1.2
Secondary Endpoints
The secondary endpoints are: all-cause mortality through Day 42 and through Day
84 post-randomization in the FAS population, global clinical response for POS vs. 
VOR at Week 6 and Week 12 post-randomization in the FAS population, all-cause 
mortality through Day84 post-randomization in the ITT population time to death (all 
causes) in the FAS population and Mortality due to IA through Day 42 and Day 84 in 
the FAS population.
See Table 11 for the definitions for global clinical response from the 2008 
MSG/EORTC guidelines [9].
Table 11
Global Clinical Response Definitions from the 2008 MSG/EORTC Guidelines
Outcome, Response
Criteria
Success
Complete response
Survival within the prespecified period of observation, resolution of 
all attributable symptoms and signs of disease, resolution of 
radiological lesion(s), and documented clearance of infected sites 
that are accessible to repeated sampling.
Partial response
Survival within the prespecified period of observation, improvement 
in attributable symptoms and signs of disease, improvement of 
radiological lesion(s)a, and evidence of clearance of infected sites 
that are accessible to repeated sampling.
In the case of radiological stabilizationb, resolution of all attributable 
symptoms and signs of fungal disease; or where biopsy of an 
infected site shows no evidence of hyphae; or where culture is 
negative.
Failure
Stable response
Survival within the prespecified period of observation and minor or 
no improvement in fungal disease; or persistent isolation of 
Aspergillus spp or histological present in infected sites.
Progression of fungal disease
Worsening of clinical symptoms and signs of disease plus new sites 
of disease or radiological worsening; or persistent isolation of 
Aspergillus spp from infected sites.
Death
Death during the prespecified period of evaluation, regardless of 
attribution.
a  improvement of radiological lesions is defined as at least 25% reduction in diameter of radiological lesion.
b  radiological stabilization is defined as 0%-25% reduction in the diameter of the lesion.
 
 
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Imaging data should be performed at the timepoints designated and if not able to be 
performed, the analysis closest to the designated timepoint will be used.  For the 
global clinical response endpoint (6 weeks) the assessment would be ± 2 weeks.  At 
the 12-week time point, it could be ± 4 weeks. 
7.7.2
Safety Monitoring and Assessments
7.7.2.1
Safety Endpoints

The incidence of serious adverse events (SAEs), incidence of treatment-
emergent and treatment-related AEs (overall, treatment-related, and selected 
AEs of interest) as well as other safety endpoints will be summarized by 
treatment groups.

The analysis of safety results will follow a tiered approach.  The tiers differ 
with respect to the analyses that will be performed.  The following four 
categories are Tier 1 events:

Hepatic safety:  Elevated AST or ALT lab value that is 3 x the upper limit 
of normal (ULN) and an elevated total bilirubin lab value that is 2 x ULN 
and, at the same time, an alkaline phosphatase lab value that <2 ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing;

CNS and visual safety:  Treatment-emergent adverse events (TEAEs) 
related to visual and CNS disturbances.  See Section 8.5.2 for a list of 
terms;

Dermatologic reactions:  TEAEs including rash and photosensitivity rash;

Adrenal steroidogenesis:  TEAEs indicating adrenal insufficiency or 
temporally associated TEAEs of hypotension.

The following are Tier 2 events based on specific AE categories:  (1) 
proportion of subjects with at least one adverse experience; (2) proportion of 
subjects with at least one drug related adverse experience; (3) proportion of 
subjects with at least one serious adverse experience; (4) proportion of 
subjects with at least one serious and drug related adverse experience; (5) 
proportion of subjects who discontinued study therapy due to an adverse 
experience.  95% confidence intervals (Tier 2) will be provided for between-
treatment differences in the percentage of subjects with events; these 
analyses will be performed using the Miettinen and Nurminen method, an 
unconditional, asymptotic method.
The APaT population will be used to assess safety in this study.  All patients who 
received at least one dose of study treatment will be included in the APaT 
population.
 
 
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7.7.2.2
Definition of Terms
Adverse Event
Per the International Conference on Harmonization (ICH), an adverse event (AE) 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 AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to this medicinal product.
Serious Adverse Event
Serious Adverse Event (SAE) is any untoward medical occurrence or effect that at 
any dose:
1.
Results in death;
2.
Is life-threatening; 
3.
Requires hospitalization or prolongation of existing inpatients’ hospitalization;
4.
Results in persistent or significant disability or incapacity; and/or
5.
Is a congenital anomaly or birth defect;
6.
Is a cancer;
7.
Is associated with an overdose;
8.
Is an ‘Other Important Medical Event’.
Life-threatening in the definition of a serious adverse event refers to an event in 
which the subject was at risk of death at the time of event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.
Medical judgment should be exercised in deciding whether an adverse 
event/reaction is serious in other situations.  Important adverse events/ reactions 
that are not immediately life-threatening or do not result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, should also be considered serious.  
These are considered “Other Important Medical Events”.
Events of Clinical Interest
An "Event of Clinical Interest" is a non-serious adverse event or occurrence that is 
designated to be of special interest and must be reported to the sponsor as though it 
were a serious adverse event – as described in Section 7.7.2.5.1.
 
 
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The following events are considered events of clinical interest for this trial:
1.
An overdose of Sponsor's product, as defined in Section 7.7.2.2.4, Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results is to 
be reported as a non-serious ECI, using the terminology "accidental or intentional 
overdose without adverse effect."
2.
An elevated AST or ALT lab value that is 3 x the upper limit of normal (ULN) 
and an elevated total bilirubin lab value that is 2 x ULN and, at the same time, 
an alkaline phosphatase lab value that <2 x ULN, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing is to be 
reported as a non-serious ECI.
Overdose
An overdose is a significant variation above the recommended/scheduled dosage for 
a product.  In this current trial an overdose of POS IV Solution, POS tablet, VOR IV, 
and VOR capsule is any dose higher than 2-times the scheduled dose specified in 
Section 7.4.1.1 of this protocol.
Clinical Supply Complaint
A clinical supply complaint is defined as any communication concerning 
manufacturing, packaging, labeling or distribution (including adverse storage at 
depots) of a clinical supply that describes a potential defect related to its identity, 
strength, quality or purity after it is released and left the control of a Merck-approved 
packaging facility for distribution.  A clinical supply GCP inquiry is defined as any 
communication of an event taking place at a trial site after the product was 
satisfactorily received at the trial site, which puts product disposition in question.  
Examples include adverse storage of product at the trial site and dosing past 
expiration.  Alleged Counterfeit, Diversion and Tampering (CDT), adverse events 
and trial site errors/issues which do not put product disposition in question should 
not be reported.
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.  This responsibility includes reporting of all clinical 
supply complaints and/or clinical supply GCP inquiries to the Sponsor.
Clinical supplies complaints and GCP inquiries, as defined above, must be reported 
to the Sponsor within 1 business day of first becoming aware of the issue.   Sponsor 
Contact information and related reporting details can be found in the Investigator 
Trial File Binder
 
 
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Planned Hospitalization
A hospitalization planned by the subject prior to signing the ICF is considered a 
therapeutic intervention and not the result of a new SAE and should be recorded as 
medical history.  If the planned hospitalization or procedure is executed as planned, 
the record in the subject’s medical history is considered complete.  However, if the 
event/condition worsens during the trial, it must be reported as an AE.
7.7.2.3
Monitoring
Monitoring Adverse Events
Each subject will be monitored for the occurrence of AEs immediately after the 
subject has signed informed consent.  Each subject will be followed for serious 
adverse events for up to and including 30 days after the last treatment visit 
described in Section 7.2.  Of note, all subjects are to be followed for mortality for the 
entire study period (i.e., until the final study visit at 16 weeks) regardless of the 
duration of study treatment.
Subjects will be questioned and/or examined by the investigator or a qualified 
designee for evidence of AEs.  The questioning of subjects with regard to the 
possible occurrence of adverse events will be generalized such as, "How have you 
been feeling since your last visit?”  The presence or absence of specific AEs should 
not be elicited from subjects.
Subjects having AEs will be monitored with relevant clinical assessments and 
laboratory tests, as determined by the investigator.
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the 
electronic Case Report Forms (eCRF; Section 9.2), as well as in the subject's source 
documentation.  Follow-up laboratory results should be filed with the subject's 
source documentation.
For all AEs that require the subject to be discontinued from the trial and SAEs, 
relevant clinical assessments and laboratory tests will be repeated as clinically 
appropriate, until final resolution or stabilization of the event(s).  The frequency and 
duration of the event(s) should be recorded
Adverse event reporting will be conducted as follows:
•
Laboratory Abnormalities
Laboratory abnormalities which have clinical manifestations, or which require an 
intervention should be recorded on the AE screen; use a clinical term if 
applicable.
 
 
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•
Minor or Routine Surgical Procedures
All minor surgical procedures (unless pre-planned as part of routine care, 
e.g., Hickman catheter placement) and the reason for the procedure are AEs.  
(For example, removal of a Hickman catheter for thrombosis after study drug has 
been given would be reported as an AE, i.e., incision and drainage of abscess 
requiring admission to the hospital would be indicated as an SAE with outcomes 
of hospitalization and additional therapy.)
Adrenal Insufficiency
Evaluation of electrolytes should be conducted.  If adrenal insufficiency is present 
without associated electrolyte disturbances, the study drug may be continued.  If the 
subject experiences adrenal insufficiency with associated electrolyte disturbances 
and related blood pressure grading, then the subject will be discontinued from 
treatment.
Grade 4 Adverse Events
The following guidelines will be used regarding continuation of treatment:
•
If considered probably related to study drug, subject will be discontinued from 
treatment.
•
If considered possibly related to study drug:  the subject will be discontinued from 
treatment, except in the case of AEs for which a relationship to the primary 
disease and/or other concomitant drugs is equally likely.  In these cases, a 
decision to discontinue study drug or interrupt study drug will be made by the 
investigator.  If the AE again worsens to Grade 4 after study drug has been 
reintroduced, the subject must be discontinued from treatment.
•
If considered unlikely to be related to study drug: study drug may be continued at 
the discretion of the investigator.
Grade 3 Adverse Events
Outcomes for Grade 3 AEs include the following:
•
If a subject experiences a Grade 3 AE (other than CNS/visual) considered at 
least possibly or probably related to study drug, a decision to continue, interrupt 
or discontinue study drug will be made by the investigator, taking into account the 
event severity, clinical significance, treatment options, and likelihood of 
relationship to study drug versus underlying disease and/or other concomitant 
drugs.  
 
 
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•
If a subject experiences a Grade 3 AE considered unlikely to be related to study 
drug, study drug may be continued.
Less Severe Adverse Events
Interruption or discontinuation of study drug may be appropriate in some cases for 
less severe AEs, which are medically significant.  In such cases, the investigator 
should consult with the project physician or designee to decide the most appropriate 
course of action with regard to dosing.
Monitoring Laboratory Assessments
All laboratory assessments will be performed either centrally at a certified laboratory 
selected by the sponsor, or at the investigators local lab.  The clinical laboratory 
values will be reported to the investigator by the laboratory and he/she will review 
them for significance and consideration as an AE.  Clinical laboratory test may be 
performed at the local certified laboratory.  All results of tests done in the local 
laboratory must be recorded in the eCRF, as well as in the subject's source 
documentation.
7.7.2.4
Assessment of Adverse Events
Assessment of Severity
Where the determination of adverse event severity rests on medical judgment, the 
determination of severity must be made with the appropriate involvement of a 
medically-qualified investigator.
The National Cancer Institute's Common Terminology Criteria for Adverse Events 
v4.0 or the most current version (NCI CTCAE) will be used for grading severity of 
AEs (see http://ctep.cancer.gov/reporting/ctc.html).  For AEs not covered by this 
grading system, the following definitions will be used:
The severity of AEs will be graded according to the following definitions:
Mild:
awareness of sign, symptom, or event, but easily tolerated;
Moderate:
discomfort enough to cause interference with usual activity and 
may warrant intervention;
Severe:
incapacitating with inability to do normal daily living activities or 
significantly affects clinical status, and warrants intervention;
 
 
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Assessment of Causality
A medically-qualified investigator must assess the relationship of any AE (including 
SAEs) to the use of the investigational product using the guidelines listed below:
•
Yes, there is reasonable possibility of drug relationship.  There is evidence of 
exposure to test drug.  The temporal sequence of the AE onset relative to the 
administration of the test drug is reasonable.  The AE is more likely explained by 
the test drug than by another cause.
•
No, there is not a reasonable possibility of drug relationship.  Subject did not 
receive the test drug OR temporal sequence of the AE onset relative to 
administration of the test drug is not reasonable OR there is another obvious 
cause of the AE.  (Also entered for a subject with overdose without an associated 
AE.)
Reference Safety Information (RSI) for the Assessment of 
Expectedness of Adverse Events
Refer to the Investigator’s Brochure (IB) for detailed background information on POS 
(MK-5592 [SCH 56592]).
Refer to the recent Summary of Product Characteristics (SmPC) for detailed 
background information on VOR IV and tablets.
Known Potential Toxicities of Investigational Products
The following observations are the most common known potential toxicities of the 
investigational product POS: 
1.
gastrointestinal events (diarrhea, nausea, vomiting),
2.
fever
3.
headache, and
4.
cough.
The following observations are the most common known potential toxicities of the 
investigational product VOR: 
1.
visual disturbances (abnormal vision, color vision changes, and photophobia). 
2.
fever, 
3.
nausea, and
4.
rash.
 
 
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Refer to the Investigator’s Brochure or approved labeling for additional information 
on AEs related to toxicities observed to date.
Known Adverse Events Relating to the Underlying Clinical Condition
Any adverse event which is worse than expected with the primary disease or its 
treatment (i.e., greater severity or more prolonged in duration) should be reported as 
an AE.
7.7.2.5
Reporting Safety Observations by the Investigator to the Sponsor
Expedited Reporting of Safety Observations by the Investigator to 
the Sponsor
Any occurrence of the following events or outcomes in a subject in the trial must be 
reported expeditiously by the investigator or qualified designee to the sponsor’s 
Global Safety representative or designee by entering all information relevant to the 
event in the appropriate eCRFs within 24 hours of learning of the event.  The 
Safety Data Reporting form 1727 – or a sponsored-approved equivalent form –
should be used in the event that the EDC system is not functioning.
1.
SAE (including SAEs associated with overdose, pregnancy, exposure during 
pregnancy or lactation 
2.
Death;
3.
Planned hospitalizations (not previously reported in the medical history);
4.
Events of clinical interest;
5.
Cancer.
Any occurrence of pregnancy or exposures during pregnancy or lactation NOT 
associated with an SAE in a subject in the trial must be reported expeditiously by the 
investigator or qualified designee to the sponsor or designee by entering all 
information relevant to the event in the appropriate eCRFs within 24 hours of 
learning of the event.  The Safety Data Reporting form 1727 – or a sponsored-
approved equivalent form - should be used in the event that the EDC system is not 
functioning.
If the investigator is unsure about when to report an observation from the lists above, 
the event or outcome should be reported to the sponsor or designee by entering all 
information relevant to the event in the appropriate eCRFs within 24 hours of 
learning of the event.  The Safety Data Reporting form 1727 – or a sponsor-
approved equivalent form – should be used in the event that the EDC system is not 
functioning.
 
 
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Any observation reported to the sponsor or designee that is also an AE, is to be 
recorded in the eCRF (Section 9.2), as well as in the subject's source 
documentation, along with any actions taken as a result of AE and follow-up results.
If an autopsy is performed, available results should be entered into the EDC
screens.
The investigator must assess causality of the event as relative to the investigational 
product administered in the trial as described in Section 7.7.2.4.2.  The EDC uses 2 
categories of causality as described in Section 7.7.2.4.2.  The Safety Data Reporting 
form 1727 uses 3 categories of causality.  If the Safety Data Reporting form 1727 
must be used to report an event because the EDC system is not available, the 
investigator is to record causality according to the guidance for the form using the 3 
categories.  The 3 categories from the form will be mapped to the 2 categories for 
evaluation by the sponsor according to the guidance in Table 12).
Table 12
Mapping Causality for SAE from EDC to Safety Data Reporting form 1727
Protocol No. MK-5592-069-00 (also known as P06200)
Record the following
Use the following criteria as guidance
On the eCRFs
On the 1727 
Form
No
Unlikely Related
No temporal association, or the cause of the event has been 
identified, or the drug, biological, or device cannot be implicated 
based on available information
Yes
Possibly Related
Temporal association, but other etiologies are likely to be the 
cause; however, involvement of the drug, biological, or device 
cannot be excluded based on available information
Probably Related
Temporal association, other etiologies are possible, but unlikely 
based on available information
Expedited Reporting by the Sponsor to a Regulatory Health Authority
Global Safety will monitor data for safety.  The Sponsor will manage the expedited 
reporting of relevant safety information to concerned health authorities, competent 
authorities, and IRBs/IECs in accordance with local laws and regulations.
Protocol-Specific Exceptions to (Serious) Adverse Event Reporting 
to Global Safety and Other Points to Consider
The following will not be considered SAEs:

In all subjects, surgical procedures that are required for treatment of the 
underlying disease.  Surgical procedures should not be reported as SAEs 
unless they are required due to medical conditions other than aspergillosis 
(in such case the medical condition itself, rather than the surgical 
procedure, will be reported as an SAE).
 
 
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7.7.2.6
Discontinuation, Treatment Interruption, and Unblinding of Blinded 
Treatment Due to Safety Observations
Discontinuation
See Section 7.3.3 for the criteria by which a subject must be discontinued.  Should a 
subject be discontinued from the trial, complete the visit activities as specified for 
discontinuation in the Trial Flow Chart in Section 2.2.
Temporary Interruption of Treatment for a Subject
Subjects who become temporarily unable to tolerate oral drug will be temporarily 
discontinued from the oral study medication and the IV medication should be 
substituted as provided in Section 7.4.1.3.2.  Additionally, if the subject cannot have 
IV therapy administered, the subject can take oral study therapy.
When the subject is again able to tolerate oral medication, the oral study drug should 
be administered.
Low dose cyclophosphamide use is allowed during the treatment period with a 
temporary interruption of study therapy on the day of cyclophosphamide dosing.
Temporary interruption may be required due to adverse events as described in 
Section 7.7.2.3.1.  A temporary interruption of no more than 3 sequential days 
without study medication will be allowed with resumption of treatment.  
Modification of Dose and/or Administration of Investigational 
Product for a Subject
For subjects with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) may 
be enrolled in the study; however, the dose of VOR IV and capsules will need to be 
adjusted.  The dose on Day 1 will be as described, but the dose thereafter will be 
reduced.  Appropriate dosing modifications will be included in the trial design in a 
blinded fashion.  There is no planned dose reduction or dose adjustment of POS IV 
or POS oral tablet or POS dummy tablet.
Unblinding Treatment for a Subject During the Trial
To assess an occurrence of a safety observation, Global Safety may unblind the 
treatment of any subject for whom a safety observation was reported investigator to 
the sponsor as described in Section 7.7.2.5.1.
Unblinding by the request of the investigator should occur only in the event of 
adverse event for which it is necessary to know the trial treatment to determine an 
appropriate course of therapy for the subject.  
When the investigator or sub-investigator needs to identify the drug used by a 
subject and the dosage administered in case of emergency e.g., the occurrence of 
 
 
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serious adverse experiences, he/she will contact the emergency unblinding call 
center by telephone and make a request for emergency unblinding.  As requested by 
the investigator or sub-investigator the emergency unblinding call center will provide 
the information to him/her promptly and report unblinding to the sponsor.  The 
emergency unblinding call-center will make a record promptly however, the 
investigator or sub-investigator must enter the intensity of the adverse experiences 
observed, their relation to study drug, the reason thereof, etc., in the medical chart 
etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind 
in the IVRS system to update drug disposition.  In the event that the emergency 
unblinding call center is not available for a given site in this trial, IVRS/IWRS should 
be used for emergency unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding 
(e.g., date and reason) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.  Only the principal investigator or delegate and 
the respective subject’s code should be unblinded.  Trial site personnel and Sponsor 
personnel directly associated with the conduct of the trial should not be unblinded
7.7.3
Pharmacogenetics
7.7.3.1
Pharmacogenetics Endpoints
Exploratory pharmacogenetics (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.  
Pharmacogenetic studies will be conducted with Biostatistics design and analysis 
and compared to PK/PD results or clinical outcomes.
CYP2C19 exhibits genetic polymorphism, which can cause large differences in the 
pharmacokinetics of VOR.  Individuals are classified as either extensive 
metabolizers or poor metabolizers of this enzyme, and the distribution of these 
genotypes varies greatly across different populations.  Exploratory analysis genetic 
testing of the CYP2C19 polymorphisms and PK/PD, safety and efficacy relationships 
may be conducted as the data allow.
7.7.3.2
PD/PGt, PK/PGt and Safety/PGt Analysis
Pharmacogenetic interrelationships may be explored.
7.7.4
Other Endpoints
Sparse pharmacokinetic (steady state trough) sampling will be performed on all 
subjects throughout the treatment period.  Food intake data at the time of POS tablet 
administration will be collected to evaluate the effect of food intake on POS steady 
state pharmacokinetic profile.  For adolescents on IV therapy, plasma samples will
be collected at the time of completion of their 90-minute infusion at Day 7, Week 2, 
 
 
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Week 4, Week 6 and Week 12 (EOT). These PK samples should be collected via 
peripheral venipuncture and not be drawn from the central catheter. PK/PD 
correlation tests assessing achievable serum drug levels of POS and VOR vs.
minimum inhibitory concentrations for Aspergillus isolates and global clinical 
response will be conducted on all randomized subjects with available data.  
Exposure/response assessments will be conducted including an exploration of the 
relationship between PK/PD indices with efficacy and safety timepoints as available 
data allow.
7.8
Criteria for Early Termination of the Trial
The clinical trial may be stopped if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the trial population as a 
whole is unacceptable.  The external Data Monitoring Committee will evaluate the 
results and safety assessments and can make recommendation for stopping the trial 
early.
In addition, further recruitment in the trial or at (a) particular site(s) may be stopped 
due to insufficient compliance with the protocol, GCP and/or other applicable 
regulatory requirements, procedure-related problems, or the number of 
discontinuations for administrative reasons is too high.
8.0 STATISTICAL AND ANALYTICAL PLAN
This section outlines the statistical analysis strategy and procedures for the study.  
If, after the study has begun, but prior to any unblinding, changes are made to 
primary and/or 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.
8.1
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility 
of the Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding 
procedures.  The official, final database will not be unblinded until medical/scientific 
review has been performed, protocol violators have been identified, and data have 
been declared final and complete.
The Clinical Biostatistics department will generate the randomized allocation 
schedule(s) for study treatment assignment.  Randomization will be implemented in 
an interactive voice response system (IVRS).
 
 
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8.2
Hypotheses/Estimation
8.2.1
Primary
Objective:  To compare the all-cause mortality for posaconazole (POS) compared to 
voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) through
Day 42 in all randomized subjects who received at least one dose of study treatment
(in the ITT [Intention to Treat] population). (see Section 8.4.1).
Hypothesis:  The all-cause mortality rate through Day 42 in the POS IV/oral 300-mg 
QD treatment group is non-inferior to that in the VOR IV 4 mg/kg BID/oral 200- mg 
BID treatment group.
8.2.2
Secondary
Objective:  To evaluate the all-cause mortality for POS vs. VOR through Day 42 in 
the FAS population.
Objective:  To evaluate the all-cause mortality for POS vs. VOR through Day 84 in 
the ITT population.
Objective:  To evaluate the all-cause mortality for POS vs. VOR through Day 84 in 
the FAS population
Objective:  To evaluate the adjudicated global clinical response for POS vs. VOR at 
Week 12 in the FAS population.
Objective:  To evaluate the adjudicated global clinical response for POS vs. VOR at 
Week 6 in the FAS population.
Other secondary objectives are:

To evaluate time to death (all causes) in subjects with proven or probable IA 
receiving POS versus VOR.

To evaluate the mortality due to IA through Day 42 and Day 84 in subjects 
receiving POS vs. VOR.

To evaluate the safety and tolerability of POS and VOR by analyzing Tier 1 
Safety and all adverse events.

To evaluate the safety of POS compared to VOR therapy in the All-Patients-as-
Treated (APaT) population.
 
 
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
To evaluate, in the subset of subjects that have pharmacokinetic data and food 
intake records, the pharmacokinetic profile of POS and VOR, including an 
evaluation of the effect of food intake on the POS tablet steady state 
pharmacokinetic profile, and to evaluate the exposure-response (efficacy and 
safety endpoints) relationships of POS and VOR in a subset of subjects with 
available data.
8.2.3
Exploratory 
•
To explore the effects of CYP2C19 polymorphisms and predicted metabolic 
enzyme activity on POS and VOR plasma concentration.
•
To explore pharmacogenetic endpoints and their association with key efficacy 
and safety parameters.
•
To explore the effect of treatment on serological biomarkers (e.g.,
galactomannan EIA, beta-D-glucan).
Please note the analyses to test the above three exploratory objectives may be 
conducted at a later date, as data allow.
8.3
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-
treatment differences are listed below, followed by the descriptions of the derivations 
of selected endpoints.
8.3.1
Efficacy/Pharmacokinetics Endpoints
A description of efficacy measures is provided in Section 7.7.1.
8.3.2
Safety Endpoints
An initial description of safety measures is provided in Section 7.7.2.  
The analysis of safety results will follow a tiered approach.  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse 
experiences of special interest that are identified a priori constitute “Tier 1” safety 
endpoints that will be subject to inferential testing for statistical significance with p-
values and 95% confidence intervals provided for between-group comparisons.  
Other safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters 
(requires that at least 4 patients in any treatment group exhibit the event) will be 
assessed via point estimates with 95% confidence intervals provided for between-
group comparisons; only point estimates by treatment group are provided for Tier 3 
safety parameters.  
 
 
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The following four categories are Tier 1 events†:

Hepatic safety: Elevated AST or ALT lab value that is ≥3 x the upper limit of 
normal (ULN) and an elevated total bilirubin lab value that is ≥2 x ULN and, at 
the same time, an alkaline phosphatase lab value that <2 ULN, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory 
testing;

CNS and visual safety: Treatment-emergent adverse events (TEAEs) related 
to visual and CNS disturbances.  See Section 8.5.2 for a list of terms 

Dermatologic reactions: TEAEs including rash and photosensitivity rash;

Adrenal steroidogenesis: TEAEs indicating adrenal insufficiency or temporally 
associated TEAEs of hypotension.
† The team has listed specific terms, see section 8.5.2, that they believe fall under these broader 
categories, however these categories may include additional related terms when full data reporting for 
the study is complete.
The following are Tier 2 events based on specific AE categories:  (1) at least one 
adverse experience; (2) drug related adverse experience; (3) serious adverse 
experience; (4) serious and drug related adverse experience; (5) discontinued study 
therapy due to an adverse experience.
8.4
Analysis Populations
This study will investigate two extended spectrum azoles (POS and VOR) in 
subjects with proven or probable IA based on modified 2008 EORTC/MSG 
definitions.  Subjects with possible IA may also be enrolled into the study with further 
evaluation of proven or probable IA.
8.4.1
Efficacy Analysis Populations
The Intention to Treat (ITT) population will serve as the primary population for the 
analysis of all-cause mortality through Day 42 in this study. The ITT population 
consists of all randomized subjects who received at least one dose of study 
treatment.
The Full Analysis Set (FAS) population will serve as the secondary population for the 
analysis of efficacy data in this study.  The FAS population consists of all 
randomized subjects who have been classified as having proven or probable IA 
(based upon independent adjudication assessment using the modified 2008 
EORTC/MSG definitions), and receive at least one dose of study drug.  
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the ITT and FAS populations.  Details on the 
approach to handling missing data are provided in Section 8.5 Statistical Methods.
 
 
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8.4.2
Safety Analysis Populations
The All Patients as Treated (APaT) population will be used for the analysis of safety 
data in this study.  The APaT population consists of all randomized subjects who 
received at least one dose of study treatment.  Subjects will be included in the 
treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population.  For most subjects this will be the 
treatment group to which they are randomized.  Subjects who take incorrect study 
treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received. 
At least one laboratory or vital sign measurement obtained subsequent to at least 
one dose of study treatment is required for inclusion in the analysis of each specific 
parameter.  To assess change from baseline, a baseline measurement is also 
required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.5 Statistical Methods.
8.5
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 8.5.2. 
Efficacy results that will be considered to be statistically significant after 
consideration of the strategy for controlling the Type I error are described in 
Section 8.6, Multiplicity.  Nominal p-values may be computed for other efficacy 
analyses as a measure of strength of association between the endpoint and the 
treatment effect rather than formal tests of hypotheses.  For both the efficacy and 
safety analyses, unless otherwise specified, all statistical tests will be conducted at 
α=0.05 level (two-sided).  
8.5.1
Statistical Methods for Efficacy Analyses
All-Cause Mortality
The primary endpoint, corresponding to the primary trial objective, is all-cause 
mortality through Day 42 in subjects in the ITT population.    
The primary analysis is to compare the POS arm to the VOR arm. The difference in 
mortality rate between arms (POS minus VOR) and the associated 95% confidence 
interval (CI) on the difference will be calculated using Miettinen and Nurminen’s 
method [13] stratified by risk for mortality/poor outcome (high risk, not high risk).  If 
the upper limit of that CI is less than 10% (the non-inferiority margin), then non-
inferiority of POS will be declared.  If non-inferiority is declared, it can be further 
concluded that POS is superior to VOR if the lower limit of the CI exceeds zero.  Due 
to the principle of closed testing, no adjustment for multiplicity is required since non-
inferiority can always be concluded whenever the data also supports superiority.  
Summary statistics and a tabulated treatment comparison will be provided.
 
 
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Other secondary endpoints include all-cause mortality through Day 42 and Day 84
for the FAS population and will be evaluated using similar methodology as will be 
used for the primary endpoint in the ITT population.  
Mortality will be evaluated through Day 42 and through Day 84 with no time window 
applied either before or after the target day.
Survival will also be assessed using Kaplan-Meier methodology and compared 
between the two arms using the Log-Rank test stratified by risk for mortality/poor 
outcome (high risk, not high risk).
Proportion Of Subjects Achieving Global Clinical Response
A secondary endpoint is global clinical response (partial or complete response 
defined by the 2008 MSG/EORTC criteria) at 6 weeks post-randomization in the 
FAS population.
The analysis is to compare the POS arm to the VOR arm. The difference in 
proportions between arms (POS minus VOR) and the associated 95% confidence 
interval (CI) on the difference will be calculated using Miettinen and Nurminen’s 
method [13] stratified by risk for mortality/poor outcome (high risk, not high risk). For 
the analysis, missing or unable to determine responses will be considered as 
failures.  
An assessment between the two treatment arms will be performed on ITT subjects 
that are excluded from the FAS, looking at potentially key baseline prognostic 
factors, such as the stratification variable of risk status for mortality/poor outcome.
As one of the secondary endpoints, the global clinical response at Week 12 in the 
FAS population will be analyzed in a similar manner. 
Global clinical response at Week 6 and Week 12 will be evaluated to include the 
completion of the response components within the visit windows, ±2 weeks for Week 
6 and ±4 weeks for Week 12. 
See Appendix 7 for detailed analysis methods and modeling procedures.
Table 13 summarizes the key efficacy analyses.
 
 
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Table 13
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
All-cause mortality through
Day 42
P
95% CIb to test for 
non-inferiority and  if 
established, test for 
superiority
ITT
M=Fc
Secondary Endpoints
Proportion of subjects 
achieving global clinical 
response at Week 6 and 
12
P
95% CIb
FAS
M=Fc
All-cause mortality through
Day 42 and Day 84
P
95% CIb
FAS
M=Fc
All-cause mortality through
Day 84
P
95% CIb
ITT
M=Fc
Time to all-cause mortality
S
Kaplan-Meier product-
limit estimates; 
stratified Log-rank 
test
FAS
Right Censoring
Mortality due to IA through
Day 42 and Day 84
S
95% CIb
FAS
DAO
a
P=Primary approach; S=Secondary approach.
b
Miettinen and Nurminen's method [13] with stratification by risk status for mortality/poor outcome (high/not 
high).
c
Missing or ‘unable to determine’ responses will be considered as failures.
d
M=F:  Missing = failure; DAO=Data as observed.
The strategy to address multiplicity issues with regard to multiple treatment 
comparisons, multiple [efficacy] endpoints, multiple timepoints, and/or interim 
analyses is described in Section 8.6, Multiplicity and Section 8.9, Interim Analyses.
8.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters 
including adverse experiences (AEs), laboratory tests, vital signs, and ECG 
measurements.
The analysis of safety results will follow a tiered approach (Table 14).  The tiers 
differ with respect to the analyses that will be performed.  Safety parameters or 
adverse experiences of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance 
with p-values and 95% confidence intervals provided for between-group 
 
 
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comparisons.  Other safety parameters will be considered Tier 2 or Tier 3.  Tier 2 
parameters will be assessed via point estimates with 95% confidence intervals 
provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and 
predefined limits of change in laboratory, vital signs, and ECG parameters that are 
not pre-specified as Tier-1 endpoints prior to database lock will be classified as 
belonging to "Tier 2" or "Tier 3", based on the number of events observed.  
Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit 
the event; all other adverse experiences and predefined limits of change will belong 
to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval 
for the between-group difference in percent incidence will always include zero when 
treatment groups of equal size each have less than 4 events and thus would add 
little to the interpretation of potentially meaningful differences.  Because many 95% 
confidence intervals may be provided without adjustment for multiplicity, the 
confidence intervals should be regarded as a helpful descriptive measure to be used 
in review, not a formal method for assessing the statistical significance of the 
between-group differences in adverse experiences and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and 
ECG parameters that are not pre-specified as Tier-1 endpoints will be considered 
Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, and 
change from baseline values will be provided by treatment group in table format.  In 
addition, summary statistics for the difference between treatment groups will also be 
provided, along with nominal p-values for between-group differences.  Mean change 
from baseline over time will be plotted with the corresponding standard errors.  
The following four categories are Tier 1 events:

Hepatic safety: Elevated AST or ALT lab value that is ≥3 x the upper limit of 
normal (ULN) and an elevated total bilirubin lab value that is ≥2 x ULN and, at 
the same time, an alkaline phosphatase lab value that <2 ULN, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory 
testing;

CNS and visual safety: Treatment-emergent adverse events (TEAEs) of 
visual abnormalities (including terms related to visual hallucination, diplopia, 
nystagmus, photophobia, photopsia, dyschromatopsia, scotoma, hemianopia, 
optic neuritis, uveitis, optic disc disorder, visual impairment, vision blurred, 
visual acuity reduced, blindness, optic atrophy, papilledema, and optic 
neuropathy); confusion, hallucination, altered mental status, cognitive 
disturbance, dizziness, altered level of consciousness, depressed level of 
consciousness, asterixis, tremor, seizures, or encephalopathy. 
 
 
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
Dermatologic reactions: TEAEs of rash (including: MedDRA Terms of 
dermatitis exfoliative, dermatitis bullous, dermatitis allergic, dermatitis allergic, 
drug eruption, photosensitivity rash, phototoxic skin eruption, rash, rash 
erythematous, rash macular, rash maculo-papular, rash popular, rash pruritic, 
rash vesicular, toxic skin eruption, and urticarial);

Adrenal steroidogenesis: TEAEs indicating adrenal insufficiency or temporally 
associated TEAEs of hypotension.
CNS and visual AEs are of particular interest in subjects taking VOR.  Each of these 
AEs tends to occur with higher VOR plasma concentration so that they will be 
analyzed as Tier 1 events.  Additionally, severity of these events will be summarized 
and the time to first occurrence of these events will be analyzed using time-to-event 
methodology.  Association between plasma concentration in both groups may be 
also explored. 
Tier 2 analysis of treatment difference and 95% CI will be provided for the following 
events based on specific AE categories: (1) at least one adverse experience; (2) 
drug related adverse experience; (3) serious adverse experience; (4) serious and 
drug related adverse experience; (5) discontinued study therapy due to an adverse 
experience. Other AE categories such as SOCs (System Organ Class) or PDLC
(Pre-Defined Limit of Change) in which there are more than 4 events in both groups, 
Tier 2 analysis of treatment difference and 95% CI will also be provided. 
Table 14
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Hepatic Safety
CNS and visual safety
Dermatologic reactions
Adrenal steroidogenesis
X
X
X
Tier 2
Proportion of subjects:
(1)with at least one AE
(2)with a drug related AE
(3)with a serious AE
(4)with serious and drug related 
AE
(5)discontinued study therapy due 
to an adverse experience
Specific AEs, SOCs, or PDLCs 
(incidence ≥4 of subjects in one 
of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs 
(incidence <4 of subjects in all 
of the treatment groups)
Change from baseline in laboratory 
measurements
X
a
Adverse Experience references refer to both Clinical and Laboratory AEs.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; a listing of subjects and their values 
falling outside the PDLC will also be provided; X = results will be provided; AE = Adverse Experience
 
 
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8.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be 
assessed by the use of tables and/or graphs.  No statistical hypothesis tests will be 
performed on these characteristics.  The number and percentage of subjects 
screened, randomized, the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed.  Demographic variables (e.g., age, 
gender, race, etc.), baseline characteristics, primary and secondary diagnoses, and 
prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
8.6
Multiplicity
Efficacy
No multiplicity adjustment is necessary as there is only one primary efficacy 
hypothesis based on a single efficacy endpoint at a single timepoint.  Statistical 
significance in this setting is equivalent to nominal significance and will be based on 
a one-sided alpha level of 0.025.
If non-inferiority is declared, it can be further concluded that POS is superior to VOR 
if the lower limit of the CI exceeds zero.  Due to the principle of closed testing, no 
adjustment for multiplicity is required since non-inferiority can always be concluded 
whenever the data also supports superiority.  
Safety
No multiplicity adjustment will be used for the safety analysis.
8.7
Sample Size and Power Calculations
8.7.1
Justification of Non-inferiority Margin for Response Rate
Since both VOR, the current standard of care for IA, and POS are both triazole anti-
fungal agents, a non-inferiority design was selected, hypothesizing that POS has at 
least a similar effect on overall all-cause mortality through Day 42 compared to VOR.  
In terms of safety, POS may have a better overall profile compared to VOR, notably 
in terms of hepatic safety, central nervous system and visual side effects.  Thus, the 
intent was to establish POS as an alternative to VOR that was equally efficacious 
but with improved tolerability.
In terms of assessing non-inferiority, the upper bound of the 95% CI on the 
difference (POS-VOR) in the all-cause mortality rates will be compared to 10%, the 
pre-specified non-inferiority margin, as described in Section 8.5.1.  A summary of the 
 
 
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statistical power under various assumptions of true clinical mortality rates assuming 
this margin is presented in Section 8.7.2.  
It is noted that the selected margin needs to be relevant in terms of what percentage 
of the effect VOR above placebo is retained with POS.  If the margin for determining 
the non-inferiority of POS relative to VOR is too large, the possibility exists that POS
could be found to be non-inferior to VOR and simultaneously be no better than 
placebo.  Therefore, the size of the non-inferiority margin must be small enough to 
ensure this does not happen.  For example, a NI margin in which more than 50% of 
the benefit of VOR could be lost would be considered unacceptable.  Thus, the 
rationale for the NI margin of 10% is presented below and based on the preservation 
of the majority of the effect size (>50%) of VOR compared to placebo under a 
number of scenarios.  Since there are no direct studies of VOR versus placebo in 
the treatment of IA, the approach consists of linking data from a variety of studies of 
VOR and the assumed mortality in placebo/untreated patients being treated for 
acute IA.
8.7.1.1
Summary of Historical Response Data for VOR in IA
The first step in determining a non-inferiority margin is determining that the control 
treatment had a consistent effect in past studies, i.e., "Historical evidence of 
sensitivity to drug effects" (HESDE).
A literature search was performed using combinations of search terms such as the 
following: invasive aspergillosis (IA), VOR, controlled clinical trial.  There were no 
placebo-controlled studies for the treatment of IA, only studies that were active-
controlled.  Overall, three articles were identified that best described the relevant IA 
patient population and which contained information about all-cause mortality of VOR 
versus active control and had sufficient data to assess clinical outcomes on 
individual patients after a period of observation following completion of  antifungal 
drug treatment [2, 16, 27].
Based on the above data and additional information found in registration documents 
for VOR [17, 18], we identified 3 clinical trials and used a meta-analyses of the 
available data to estimate the VOR all-cause mortality rate, which will be used later 
to determine what percentage of the benefit in efficacy that VOR has over Placebo
that would be retained by a 10% NI margin in this study comparing POS to VOR.  
The first of the studies included in the meta-analysis below consists of two phase 3 
studies 150-307 and 150-602, which enrolled 392 subjects in 1997 through 2000, 
using identical protocols worldwide (Study 307: Europe, Israel, and Australia; Study 
602: US, Canada, Mexico, Brazil, and India), and evaluated VOR versus 
Amphotericin B (AmB) for the primary treatment of acute IA.  Although these are 
separate studies using identical protocols, the original data analysis plan indicated 
that these study results were to be combined and as such, the published all-cause 
mortality rate is combined across both studies [2].  In these combined studies, the 
all-cause mortality of VOR was 18.8% (27/144, 95% CI 12.7, 26.1) compared to 
 
 
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34.6% (46/133) for patients receiving AmB in the primary treatment of acute IA.  The 
majority of study patients had underlying hematologic malignancies, including bone 
marrow transplantation.  The study also included patients with solid organ 
transplantation, solid tumors, and AIDS.  The patients were mainly treated for 
definite or probable IA of the lungs.  In these 2 studies, VOR was administered with 
2 loading doses of 6 mg/kg IV q 12 h followed by 4 mg/kg q 12 h for at least 7 days 
followed by oral VOR 200 mg BID up to a total of 12 weeks.
In addition to these two combined studies, the meta-analysis was conducted 
including two additional studies: a study of VOR + Anidulafungin published by Marr 
et al (2015) [16, 26], and a recent study of ISA versus VOR published by Maertens 
[27].
The results presented by [26] were based on a prospective, randomized, double-
blind clinical trial in allogeneic hematopoietic stem cell transplant (allo-HSCT) 
recipients and patients with hematological malignancies with proven or probable IA 
according to the European Organization for Research and Treatment of Cancer 
(EORTC) and the Mycoses Study Group consensus criteria. Subjects were 
randomized to receive either VOR monotherapy or VOR in combination with 
anidulafungin.  All subjects received open-label VOR (6 mg/kg IV every 12 hours on 
Day 1) followed by 4 mg/kg IV every12 hours); combination therapy was 
administered for 2-4 weeks and the investigator could switch to VOR monotherapy 
after 2 weeks, to complete at least 6 weeks of AF therapy.  In this study, the analysis 
population was defined as those subjects with proven or probably IA confirmed.  
Through Day 42 all-cause mortality for the VOR monotherapy patients was 27.5% 
(39/142, 95% CI 20.3, 35.6).  
The results published by Maertens et al (2015) [27] were based on a Phase 3, 
double-blind, global multi-center non-inferiority trial, where patients with suspected 
invasive mold disease were randomized 1:1 to receive either ISA (equivalent to 200 
mg ISA intravenously 3 times a day on Days 1 and 2 then either intravenously or 
orally once daily) or VOR (6 mg/kg intravenously twice daily on Day 1, 4 mg/kg 
intravenously twice daily on Day 2, then intravenously 4 mg/kg twice daily or orally 
200 mg twice daily from Day 3 onwards). The all-cause mortality rate at Day 42 for 
ITT patients who received VOR was 20.2% (52/258, 95% CI 15.4, 25.6).  
Based on these 3 studies, a random effects meta-analysis gave an overall estimate 
for all-cause mortality of 23.0% with a 95% asymptotic CI of (16.4, 29.6) [19].  The 
test for heterogeneity was found to be not significant (p=0.1443) based on the
Cochran-Mantel-Haenszel (CMH) test.
 
 
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Table 15
Meta-Analysis (3 studies)
Study
Patient 
Population
N
All-cause Mortality 
through Day 42(%) and 
(95% CI)
307/602
mITT
144
18.8% (27/144)
(12.7, 26.1)
Marr et al 
(2015)
mITT
142
27.5% (39/142)
(20.3, 35.6)
Maertens 
et al (2015)
ITT
258
20.2% (52/258)
(15.4, 25.6)
Pooled (raw)
544
21.7% (118/544)
(18.3, 25.4)
Pooled (meta-analysis)
544
23.0%
(16.4, 29.6)
8.7.1.2
Percentage Effect Size Retained with Selected Margin
The percentage retained by POS in terms of mortality may be better understood as 1 
minus the percentage of the effect size that one may be willing to lose given a 
selected NI margin, i.e. where effect size loss "allowed" is simply the selected NI 
margin as a percentage of the estimated effect of the active control VOR over 
placebo (Pbo) with respect to all-cause mortality.
Two different statistical approaches were used and differ as to which estimate of the 
effect of VOR over Pbo is used in the calculations.  In both approaches, the 95% CI 
lower bound of the Pbo mortality is assumed.  We first consider the "point estimate" 
approach, which takes the point estimate of the VOR mortality and subtracts the 
assumed Pbo mortality to determine the VOR effect size.  The second, more 
conservative "fixed margin" approach, uses the 95% upper bound of the VOR 
mortality and subtracts the 95% lower bound of the Pbo mortality to determine the 
VOR effect size.  The second approach is often referred to as the "95-95" method 
since the NI margin itself represents a 95% lower bound [20].  As a frame of 
reference, the minimal Pbo mortality that would have to be assumed to preserve at 
most 50% of the VOR effect is also calculated.
Since there were no Pbo-controlled studies for the treatment of IA, we assumed an 
all-cause mortality rate for Pbo of 75%.  This is based on an internal meta-analysis 
of historical data from 1952 to 2006 cited in Maertens et al. [27].  That analysis 
reported the all-cause mortality rate in untreated patients of 84.8% with a 95% CI of 
(75.1, 94.5).  Maertens et al. further indicate that this mortality rate is supported by a 
rate of 100% in untreated patients reported Denning (1996) [22].
In the first approach, the point estimate of the historical VOR effect is used (23.0%
point estimate from the meta-analysis).  Thus, the effect size for all-cause mortality 
of VOR over Pbo is estimated to be 52 percentage points (75% Pbo mortality minus 
23% VOR mortality), and thus a NI margin of 10% represents approximately 20% of 
 
 
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this effect size (0.10/0.52).  Therefore, ~80% of the effect size of VOR over Pbo is 
retained with a NI margin of 10%.  
A more conservative approach instead uses the upper 95% CI limit for the historical 
VOR effect, here 29.6%.  In this instance, then, the effect size for all-cause mortality 
of VOR over Pbo is estimated to be 45.4 percentage points (75% Pbo mortality 
minus 29.6% VOR mortality).  A NI margin of 10% would then represent 
approximately 22% of the VOR effect size over Pbo (0.10/0.454) and ~78% of the 
effect size is retained.
Under both sets of assumptions, a large majority of the effect size of VOR over Pbo 
is preserved with a 10% non-inferiority margin.  This is summarized in Table 16
below.  
Finally, Table 16 also presents the minimal Pbo mortality rate that would have to be 
assumed in order for a 10% NI margin to preserve exactly 50% of the VOR over Pbo 
effect size.  Using the most conservative estimate for VOR mortality of 29.6%, the 
minimal Pbo mortality would have to be 49.6%, which is substantially lower than any 
published mortality rate associated with Pbo found in the literature [25, 26, 19, 27].
Table 16
Percentage (%) of Effect Size  Retained with 10% Margin
Method
VOR 
Mortality
Pbo 
Mortality
Effect Size
(Pbo – VOR)
Percent of Effect Size 
Preserved with 10% NI 
Margin
(1-0.10/Effect Size)
VOR Point Estimate
23.0%
75%
0.52
80.8%
VOR Upper CI Limit
29.6%
75%
0.454
78.0%
VOR Upper CI Limit, 
Minimal Pbo Mortality to 
Preserve 50% of VOR 
Effect
29.6%
49.6%
0.20
50%
The above calculations present a variety of scenarios and data assumptions 
supporting a 10% NI margin in this study.  All relevant historical data on IA and VOR 
was reviewed in this assessment.  If relevant new data on VOR becomes available 
in this patient population, the margin justification may be re-assessed. 
One strength in establishing 'comparability' of the historical data is the active control 
treatment in study PN069 is nearly identical to the ones administered in Studies 
307/602 studies, i.e., subjects in PN069 start with a VOR IV loading dose of 6 mg/kg 
IV BID on Day 1 followed by 4 mg/kg VOR IV BID maintenance dose, beginning on 
Day 2.  Subject, if considered clinically stable, can then transition to oral VOR (200 
mg BID), for a total of 12 weeks.  Although some subjects in PN069, if clinically 
indicated, will be able to start oral VOR therapy on Day 1 (300 mg BID) followed by 
200 mg BID, this difference is believed not to have an impact on the true effect of 
VOR on all-cause mortality. 
 
 
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The meta-analysis conducted gives credibility to the constancy of the treatment 
effect of VOR, i.e., a reasonably consistent estimate of the effect was observed.  It is 
apparent that VOR itself is quite active and in the pivotal studies used for registration 
(Studies 307/602), VOR was not only shown to be non-inferior to AmB, but also 
superior, as the lower bound of 95% CI of the treatment difference excluded 0. 
In summary, two different approaches were used to assess the % of the efficacy 
retained and included a conservative assessment (95%-95% method) which still 
resulted in a substantial % of efficacy retained (>50%) under realistic scenarios.
8.7.2
Sample Size and Power for Efficacy Analyses
Approximately 600 subjects in the ITT population (randomized and treated) will be 
enrolled in this study and randomly assigned to receive either POS monotherapy or 
VOR monotherapy in a 1:1 ratio.  This study (with approximately 300 ITT population 
in each azole monotherapy arm) will have ~> 80% power (with 1-sided alpha=0.025) 
to show non-inferiority of POS monotherapy compared to VOR monotherapy using a 
10% margin and assuming a mortality rate through Day 42 of 23% for VOR treated 
subjects (based on the estimated historical VOR all-cause mortality rate through Day 
42 shown in Table 17 [25, 27].  
Table 17 summarizes the study power for assumed VOR mortality rates ranging 
between 18% and 28%, for different number of subjects in each arm, with the POS 
mortality rate ranging from -2% to +2% from the VOR rate.  

For example, if the VOR mortality is assumed to be 18% and the POS 
mortality is assumed to be 19% with 600 subjects (300/arm) in ITT population, 
then this study design has 80.4% power to demonstrate non-inferiority with a 
10% margin.

Alternatively, if the VOR mortality is assumed to be 22% and the POS 
mortality is assumed to be 21% with 540 subjects (270/arm), then this study 
design has 87.2% power to demonstrate non-inferiority with a 10% margin.  
 
 
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Table 17
Power (%) Under Various Assumptions of All-cause Mortality Through 42 days (10% Non-
inferiority Margin)
Underlying All-
cause Mortality 
Through 42 days
for VOR (%)
Underlying Difference in Mortality (%)
(POS minus VOR)
-2.0
-1.0
0.0
1.0
2.0
600 subjects (300/arm) 
18%
97.2%
94.0%
88.5%
80.4%
69.9%
19%
96.7%
93.1%
87.3%
79.0%
68.4%
20%
96.1%
92.2%
86.1%
77.5%
66.9%
21%
95.5%
91.3%
84.9%
76.2%
65.5%
22%
94.8%
90.4%
83.8%
74.9%
64.2%
23%
94.2%
89.5%
82.7%
73.7%
63.0%
24%
93.6%
88.6%
81.6%
72.5%
61.8%
570 subjects (285/arm) 
18%
96.5%
92.8%
86.9%
78.4%
67.7%
19%
95.9%
91.9%
85.6%
76.9%
66.2%
20%
95.2%
90.8%
84.3%
75.4%
64.6%
21%
94.5%
89.9%
83.1%
74.1%
63.3%
22%
93.8%
88.9%
81.9%
72.7%
61.9%
23%
93.1%
88.0%
80.8%
71.5%
60.8%
24%
92.4%
87.0%
79.6%
70.3%
59.6%
540 subjects (270/arm) 
18%
95.6%
91.5%
85.0%
76.2%
65.3%
19%
94.9%
90.4%
83.7%
74.7%
63.8%
20%
94.1%
89.3%
82.3%
73.1%
62.3%
21%
93.4%
88.3%
81.0%
71.8%
61.0%
22%
92.6%
87.2%
79.8%
70.4%
59.6%
23%
91.8%
86.2%
78.6%
69.2%
58.5%
24%
91.0%
85.2%
77.4%
68.0%
57.3%
Note:  The power is calculated based on a non-inferiority margin of 10%
and =0.025 (one-sided).
In terms of observed mortality rates that would meet the non-inferiority criteria, if an 
all-cause mortality rate of 23% is observed in the 300 VOR patients (23%=69/300), 
the largest observed all-cause mortality rate that could be observed among POS 
patients and still meet the non-inferiority criterion would be 26% (78/300).  In this 
instance, the observed difference in mortality rates would be 3.0 percentage points 
(POS minus VOR) with a 95% CI of (-3.9, 9.9).
 
 
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If an all-cause mortality rate of 23% is observed in 270 VOR patients (23%=62/270), 
the largest observed all-cause mortality rate that could be observed among POS 
patients and still meet the non-inferiority criterion would be 26% (69/270). In this 
instance, the observed difference in mortality rates would be again 3.0 percentage 
points (POS minus VOR) with a 95% CI of (-4.7, 9.8).  
If the criteria for non-inferiority are met, then a superiority analysis of POS arm will 
be assessed.
8.7.3
Sample Size and Power for Safety Analyses
The safety hypotheses will be assessed by review of the accumulated safety data. 
Table 18 gives the difference in percentage points (POS minus VOR) that can be 
ruled out with different power levels and 95% confidence when there are 300 or 285 
or 270 randomized subjects in each treatment group. The true frequency of subjects 
experiencing an AE on POS arm is assumed the same as that in the VOR arm. For 
a reasonably common adverse experience which occurs in 20% of subjects 
receiving either POS or VOR, the study with 300 randomized subjects in each arm 
has 90% power to declare, with 95% confidence that the true difference between 
group proportions is no more than 12.7 percentage points. 
If a particular AE is not observed from the 300 randomized subjects receiving POS, 
it can be ruled with 2-sided 95% confidence interval that the upper limit of the true 
occurrence of this AE is no more than 1.8 percentage points.
Table 18
Difference in AE Proportions (POS minus VOR)† That Can Be Ruled Out With Different 
Number of Randomized Subjects in Each Group. 
Difference in Percentage Points that can be Ruled Out
with Target Power when True AE Occurrence is
Target Power
10%
20%
30%
40%
50%
600 subjects (300/arm)
80%
8.8
11.0
12.1
12.5
12.5
85%
9.4
11.7
12.9
13.3
13.2
90%
10.3
12.7
13.9
14.3
14.2
95%
11.5
14.1
15.3
15.8
15.6
570 subjects (285/arm)
80%
9.1
11.3
12.4
12.9
12.8
85%
9.7
12.0
13.2
13.7
13.6
90%
10.6
13.0
14.2
14.7
14.6
95%
11.9
14.4
15.7
16.2
16.0
540 subjects (270/arm)
80%
9.4
11.6
12.8
13.2
13.1
85%
10.1
12.4
13.6
14.0
13.9
90%
10.9
13.4
14.6
15.1
14.9
95%
12.2
14.8
16.2
16.6
16.4
†The upper bound of the two-sided 95% confidence interval [21] for the difference in AE 
incidences (POS minus VOR) assuming the incidences are the same.
 
 
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8.8
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, 
the estimate of the between-group treatment effect (with a nominal 95% CI) for the 
primary endpoint will be estimated and plotted within each category of the following 
classification variables: 
•
Region (US, Ex-US)
•
Sex (female, male)
•
Age among adults (≥18 years to ≤median of adults, >median of adults)
•
Ethnic Origin (Black, White, Other) and (Hispanic, Non-Hispanic)
•
Risk status for mortality/poor outcome (high risk, not high risk).
•
Patients population: (1) proven vs. probable IA; (2) site of IA infection (lung, 
sinus, multiple sites, etc.); (3) underlying disease; (4) neutropenic status at 
baseline (ANC <500 vs. >500)
The consistency of the treatment effect will be assessed descriptively via summary 
statistics by category for the classification variables listed above.
8.9
Interim Analyses
There is no formal interim analysis planned for this study.  
A formal independent external Data Monitoring Committee (eDMC) will be 
assembled at the onset of the study and will examine data for safety.  The eDMC will 
monitor safety and provide recommendations to the executive committee of the 
SPONSOR.  The executive committee, composed of the SPONSOR Senior 
Management, will provide the overall scientific direction for the trial, and will receive 
and decide on any recommendations made by the eDMC regarding interrupting 
enrollment due to safety issues or early stopping of the study.  Details regarding the 
eDMC will be described in External Data Monitoring Committee Charter.
8.10
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study treatment taken 
by each patient, at each site, the volume of infusion administered, and the number of 
tablets/capsules dispensed and returned will be counted, reviewed, and recorded at 
regular intervals at the local level. Pharmacy records of dispensing and return of 
study medication will be recorded using local documentation records and will be 
monitored and reviewed by un-blinded study monitors throughout the study period. 
Pharmacy records will be retained at the local pharmacy and available for Sponsor 
 
 
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review.  Site records will be used to ensure and document study medication 
compliance.  Study medication daily dosing will be recorded in the electronic case 
report for each study medication component (IV or oral, placebo or active drug) 
based upon local documentation records.  
For IV study therapy, on each day, each patient should take a certain 
infusions/injections dosage encompassing both the assigned treatment and any 
matching placebo (sham infusions).  A day within the study will be considered an 
“On-therapy” day if the patient receives at least one infusion. 
For oral therapy, on each day, each patient should take a certain number of tablets 
and capsules encompassing both the assigned treatment and any dummy placebo 
tablets or capsules. A day within the study will be considered an “On-Therapy” day if 
the patient takes one capsules/tablet.  
For a patient who is followed for the entire study period, the “Number of Days Should 
be on Therapy” is the total number of days from randomization to the last scheduled 
day for treatment administration for that patient.  The compliance rate for each 
patient will be computed as follows:
Summary statistics will be provided on percent compliance by treatment group.
8.11
Extent of Exposure
In addition, the Extent of Exposure to study treatment will be evaluated by summary 
statistics (N, mean, median, standard deviation) and frequencies for the “Number of 
Days on Therapy” by treatment group.
8.12
Data Monitoring Committee
The accruing data from patients in this trial will be monitored by an external Data 
Monitoring Committee (eDMC) on an ongoing basis. The composition, activities, and 
responsibilities of the eDMC are described in the eDMC Charter that will be provided 
to the eDMC are described in Section 8.9.
9.0 ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
The trial must be conducted in accordance with Good Clinical Practice (GCP) as 
outlined in the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, 
E6 Good Clinical Practice:  Consolidated Guidance and other applicable laws and 
regulations.  In addition, the trial must be conducted in accordance with:  (i) the USA 
Code of Federal Regulations (CFR) if the trial is conducted under a USA IND, 
 
 
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regardless of the country involved; (ii) the European Union (EU) Clinical Trial 
Directive (CTD) and local regulations if the trial is conducted in the EU; and (iii) any 
specific local regulations if the trial is conducted elsewhere.
9.1
Ethical Conduct of the Trial
9.1.1
Independent Ethics Committee or Institutional Review Board
Prior to initiation of the trial at any site, the trial, including the protocol, informed 
consent, and other trial documents must be approved by an appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).  The IRB/IEC must be 
constituted according to applicable regulatory requirements.  As appropriate, 
amendments to the protocol must also be approved by the IRBs/IECs before 
implementation at the sites, unless warranted to eliminate an immediate hazard.  
The IRB/IEC approval should be obtained in writing, clearly identifying the trial, the 
documents reviewed (including informed consent), and the date of the review.  The 
trial as described in the protocol (or amendment), informed consent, and other trial 
documentation may be implemented only after all the necessary approvals have 
been obtained and the sponsor has confirmed that it is acceptable for the 
investigator to do so.
In the event that the IRB/IEC requires changes in the protocol, the sponsor shall be 
advised and must approve the changes prior to implementation.  The investigator 
shall not modify the trial described in the protocol once finalized and after approval 
by the IRB/IEC without the prior written approval of sponsor.
In countries where the investigator submits the trial protocol and statement of 
informed consent to the IRB/IEC, the investigator or qualified designee will forward 
the approvals to the sponsor.
9.1.2
Subject Information and Consent
The details of the protocol must be provided in written format and discussed with 
each potential subject and written informed consent must be obtained for all subjects 
before any trial-related procedure is performed.  In obtaining informed consent, the 
information must be provided in language and terms understandable to the subject.  
The subject, or the subject's legal representative, must give their written consent to 
participate in the trial.  The signed and dated consent form itself must be retained by 
the investigator as part of the trial records.  A copy of the signed and dated consent 
form must be given to the subject.  The consent form must include all of the required 
elements of informed consent in accordance with ICH Guidelines E6 and local laws.  
In addition, the sponsor specifically requests that the consent form identify it as the 
sponsor and state that use of the investigational product(s) is experimental and the 
side effects of the investigational product(s) are not completely known.  The consent 
form must be approved by the appropriate IRB/IEC and sponsor before trial initiation 
at a trial site.  Any subsequent changes to the approved informed consent form must 
 
 
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be reviewed and approved by the appropriate IRB/IEC and sponsor before 
implementation.
9.1.3
Subject Identification Card
A Subject Identification Card is provided to each subject to carry on his or her 
person (e.g., in a wallet) at all times while the subject is participating in the trial.  The 
Subject Identification Card must be provided to the subject no later than when IMP is 
dispensed.  The card is to be shown to caregivers in the event of an emergency.
At a minimum, the card must contain the following information:
1.
Protocol number;
2.
The subject’s protocol identification number;
3.
A statement identifying the card-carrier as a participant in a clinical trial (e.g., 
“This person is participating in a clinical research trial.”);
4.
A statement indicating the person might be taking an investigational drug 
(e.g., “This person is taking an experimental drug which could have interactions 
with other medications, or placebo”); and
5.
Contact information in the event of an emergency or hospitalization.  The contact 
information on the card is to be the investigator or a designated site contact, 
rather a contact from within the sponsor.
The cards may also include other trial-specific information to assist with treatment 
decisions in the event of an emergency, such as types of concomitant therapies that 
may, or may not be, permitted as part of emergency treatment.  As with any other 
information provided to subjects, the Subject Identification Card must be approved 
by the IRB/IEC.  Monitors will request that Investigators provide Subject 
Identification Cards to each subject.  Investigators will be asked to request that 
subjects carry the cards with them while they are participating in the trial.
The Investigator/site should collect the cards at the end of the trial and retain them 
with other clinical trial documents.
9.1.4
Registration of the Trial
The trial will be registered by the sponsor on a publicly accessible database.  The 
results will be disclosed by the sponsor on a publicly accessible database.
9.1.5
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient 
and diligent manner and in conformance with this protocol; generally accepted 
 
 
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standards of Good Clinical Practice; and all applicable federal, state, and local laws, 
rules and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the 
ethical and scientific conduct of clinical investigations sponsored by Merck & Co., 
Inc., is attached.
The investigator also agrees to allow monitoring, audits, Institutional Review 
Board/Independent Ethics Committee review, and regulatory agency inspection of 
trial-related documents and procedures and provide for direct access to all study-
related source data and documents.
The investigator agrees not to seek reimbursement from subjects/patients, their 
insurance providers, or from government programs for procedures included as part 
of the study reimbursed to the investigator by the SPONSOR.
The Investigator shall prepare and maintain complete and accurate study 
documentation in compliance with Good Clinical Practice standards and applicable 
federal, state, and local laws, rules and regulations; and, for each subject/patient 
participating in the study, provide all data, and upon completion or termination of the 
clinical study submit any other reports to the SPONSOR as required by this protocol 
or as otherwise required pursuant to any agreement with the SPONSOR.
Study documentation will be promptly and fully disclosed to the SPONSOR by the 
investigator upon request and also shall be made available at the investigator’s site 
upon request for inspection, copying, review, and audit at reasonable times by 
representatives of the SPONSOR or any regulatory agencies.  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 study documentation and 
worksheets/case report forms.
International Conference of Harmonization 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 agency 
inspection conducted for this study.
Persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on this SPONSOR’s 
studies.  The investigator will immediately disclose in writing to the SPONSOR if any 
person who is involved in conducting the study is debarred, or if any proceeding for 
debarment is pending or, to the best of the investigator’s knowledge, threatened.
In the event the SPONSOR prematurely terminates a particular trial site, the 
SPONSOR will promptly notify that site’s IRB/IEC.
 
 
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9.1.6
Quality Control and Quality Assurance
By signing this protocol, the SPONSOR agrees to be responsible for implementing 
and maintaining quality control and quality assurance systems with written 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 study.
9.2
Reporting Trial Data to the Sponsor
9.2.1
Data Collection Forms
The Sponsor will provide the site with data collection forms, be they Case Report 
Forms (CRF), either in paper format or electronic Case Report Forms (eCRF); 
diaries; Electronic Data Capture (EDC) screens; or other appropriate data collection 
forms as the trial requires.  The investigator is to provide subject data according to 
the Sponsor’s instructions, in the designated data collection form, compliant with 
GCP practices.  The Sponsor will also provide the site with instructions for assisting 
other parties - such as a central laboratory - to collect data.  As instructed by the 
Sponsor, a designated central laboratory may collect data in a database and provide 
the completed database to sponsor.  All data collection forms and the databases 
from the trial are the exclusive property of sponsor.
The investigator must maintain records and data during the trial in compliance with 
all applicable legal and regulatory requirements.  Each data point must be supported 
by a source document at the trial site.  Any records or documents used as the 
source of information (called the “subject source data”) are to be retained for review 
by authorized representatives of the sponsor or a regulatory agency.
The investigator will ensure that there are sufficient time, staff, and facilities available 
for the duration of the trial to conduct and record the trial as described in the protocol 
and according to all applicable guidances, laws, and regulations.
All data collection forms (e.g., CRFs, diaries; EDC screens), electronic database 
entries, etc., should be completed within 3 business days after the evaluation has 
occurred.  All dates appearing on the sponsor's subject data collection forms for 
laboratory tests, cultures, and other data collected, must be the dates on which the 
specimens were obtained, or the procedures performed.
9.2.2
Preparing Case Report Forms for All Subjects
A CRF must be completed for all subjects who have given informed consent.  The 
Sponsor must not collect subject names, initials, or other personal information that is 
beyond the scope of the trial from any subject.  Subjects are not to be identified by 
name or initials on the CRF or any trial documents.  The only acceptable 
identification for a subject who may appear on a CRF or trial document is the unique 
 
 
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subject identification number.  The investigator must maintain contact information for 
each participant so that all can be quickly contacted by the investigator, if necessary.
All entries into CRFs are the responsibility of the investigator and must be completed 
by the investigator or a qualified designee.  The investigator will attest in writing at 
the beginning of the trial that his/her electronic signature is the legally binding 
equivalent of a written signature and will acknowledge by entering his/her electronic 
signature that he/she has verified the accuracy of the recorded data.
9.2.3
Preparing Case Report Forms for Subjects Who Fail Screening
Data are to be collected from the time the informed consent form is signed until the 
subject is determined to have failed screening.  A CRF with a minimum of the 
following information must be completed for subjects who fail screening:  
(1) demographics, (2) subject status, (3) reason for screen failure, and (4) serious 
adverse events.
9.3
Publications and Other Rights
9.3.1
Rights to Publish by the Investigator
The investigator has the right to publish or publicly present the results of the trial in 
accordance with this Section 9.3 of the protocol.  In the event that the protocol is a 
part of a multi-site trial, it is understood that it is the intent of the sponsor and the 
investigator to initially only publish or present the trial results together with the other 
sites, unless specific written permission is obtained in advance from the sponsor to 
publish separate results.  The sponsor shall advise as to the implications of timing of 
any publication in the event clinical trials are still in progress at sites other than the 
investigator's site.
The investigator agrees not to publish or publicly present any interim results of the 
trial without the prior written consent of the sponsor.  The investigator further agrees 
to provide to the sponsor 45 days prior to submission for publication or presentation, 
review copies of abstracts or manuscripts for publication (including, without 
limitation, slides and text of oral or other public presentations and text of any 
transmission through any electronic media, e.g., any computer access system such 
as the Internet, World Wide Web, etc.) that report any results of the trial.  The 
sponsor shall have the right to review and comment with respect to publications, 
abstracts, slides, and manuscripts and the right to review and comment on the data 
analysis and presentation with regard to the following concerns:
1.
Proprietary information that is protected by the provisions contained in 
Section 9.3.2;
2.
The accuracy of the information contained in the publication; and
3.
To ensure that the presentation is fairly balanced and in compliance with FDA 
regulations.
 
 
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If the parties disagree concerning the appropriateness of the data analysis and 
presentation, and/or confidentiality of the sponsor's confidential information, 
investigator agrees to meet with the sponsor's representatives at the clinical trial site 
or as otherwise agreed, prior to submission for publication, for the purpose of 
making good faith efforts to discuss and resolve any such issues or disagreement.
9.3.2
Use of Proprietary or Confidential Information in a Publication
No publication or manuscript shall contain any trade secret information of the 
sponsor or any proprietary or confidential information of the sponsor and shall be 
confined to new discoveries and interpretations of scientific fact.  If the sponsor 
believes there is patentable subject matter contained in any publication or 
manuscript submitted for review, the sponsor shall promptly identify such subject 
matter to investigator.  If sponsor requests and at sponsor’s expense, investigator 
shall use its best efforts to assist sponsor to file a patent application covering such 
subject matter with the USA Patent and Trademark Office or through the Patent 
Cooperation Treaty prior to any publication.
9.3.3
Use of Trial Information in a Publication
Investigator is granted the right subject to the provisions of this protocol to use the 
results of all work provided by investigator under this protocol, including but not 
limited to, the results of tests and any raw data and statistical data generated for 
investigator's own teaching, research, and publication purposes only.  
Investigator/Institution agrees, on behalf of itself and its employees, officers, 
trustees, and agents, not to cause said results to be knowingly used for any 
commercial purpose whatsoever except as authorized by the sponsor in writing.
9.3.4
Authorship of Publications
Authors of publications must meet the International Committee of Medical Journal 
Editors (ICMJE) guidelines for authorship and must satisfy the 3 criteria that follow:
1.
Authors must make substantial contributions to the conception and design of the 
trial, acquisition of data, or analysis of data and interpretation of results;
2.
Authors must draft the publication or, during draft review, provide contributions 
(data analysis, interpretation, or other important intellectual content) leading to 
significant revision of the manuscript with agreement by the other authors;
3.
Authors must provide written approval of the final draft version of the publication 
prior to submission.
All contributors who do not meet the 3 criteria for authorship should be listed in an 
acknowledgments section within the publication, if allowed by the journal, per the 
ICMJE guidelines for acknowledgment.
 
 
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9.4
Trial Documents and Records Retention
During the trial and after termination of the trial – including after early termination of 
the trial – the investigator must maintain copies of all documents and records 
relating to the conduct of the trial.  This documentation includes, but is not limited to, 
protocols, CRFs and other data collection forms, advertising for subject participation, 
adverse event reports, subject source data, correspondence with health authorities 
and IRBs/IECs, consent forms, investigator’s curricula vitae/biosketch, monitor visit 
logs, laboratory reference ranges, and laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  Subject files and other source 
data must be kept for the maximum period of time permitted by the hospital, 
institution or private practice, or as specified below.  The sponsor must be consulted 
if the investigator wishes to assign the files to someone else, remove them to 
another location, or is unable to retain them for the specified period.
The investigator must retain trial records for the amount of time specified by 
applicable laws and regulations.  At a minimum, trial records must be retained for the 
amount of time specified by ICH Guidelines, the EU Good Clinical Practices 
Directive, or applicable local laws, whichever is longer:
1.
The ICH Guidelines specify that records must be retained for a minimum of 
2 years after a marketing application for the indication is approved (or not 
approved) or 2 years after notifying the appropriate regulatory agency that an 
investigation is discontinued.
2.
The European Union (EU) Commission Directive 2003/63/EC which requires that 
Essential Documents (including Case Report Forms) other than subjects’
medical files, are retained for at least fifteen (15) years after completion or 
discontinuation of the trial, as defined in the protocol.
All trial documents shall be made available if required by relevant health authorities.  
The investigator should consult with the sponsor prior to discarding trial and/or 
subject files.
Sponsor will retain all sponsor-required documentation pertaining to the trial for the 
lifetime of the investigational product.  Archived data may be held on microfiche or 
electronic record, provided that a back-up exists and that a paper copy can be 
obtained from it, if required.
 
 
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10.0INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
10.1
Sponsor
The sponsor of this trial is indicated in Section 1, Title Page.
10.2
Investigators
10.2.1
Selecting Investigators
Only investigators qualified by training and experience to perform a clinical 
investigation with POS and VOR are selected.  The sponsor will contact and select 
all investigators (i.e., the legally responsible party[ies] at each trial site), who, in turn, 
will select their staff.
10.2.2
Financial Disclosure Requirement
In connection with the clinical trial described in the protocol, the investigator certifies 
that, if asked, the investigator will read and answer the Certification/Disclosure Form 
or equivalent document truthfully and to the best of investigator's ability.  Investigator 
also certifies that, if asked, the investigator will have any other applicable party(ies) 
(e.g., subinvestigators) read and answer the Certification/Disclosure Form as a 
condition of their participation in the trial.
If the financial interests reported on the Certification/Disclosure Form change during 
the course of the trial or within 1 year after the last subject has completed the trial as 
specified in the protocol, the investigator and the other applicable party(ies) are 
obligated to inform the sponsor of such financial change.
10.2.3
Clinical Study Report Coordinator Investigator
A Clinical Study Report (CSR) will be prepared by the sponsor or its qualified 
designee to describe the results of the trial.  One of the investigators shall be 
selected by the sponsor to review the CSR and provide approval of the final CSR in 
writing.  The investigator chosen to review and approve the CSR is to be called the 
CSR Coordinating Investigator.  A second investigator shall be selected as the 
Alternate CSR Coordinating Investigator.  The Alternate CSR Coordinating 
Investigator is to review and approve the CSR should the first CSR Coordinating 
Investigator be unable to do so.  The sponsor is to select the CSR Coordinating 
Investigator and Alternate CSR Coordinating Investigator from the investigators 
using the following criteria:
1.
Must be the Principal Investigator at a trial site actively enrolling subjects and 
participating in the trial;
2.
Must be willing and capable of completing the necessary reviews and providing 
approval of the CSR in writing;
 
 
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3.
The sponsor will select the CSR Coordinating Investigator form the top three 
enrolling sites base on evaluable subjects.
10.3
Central Organizations
Central organizations to be used in the conduct, monitoring, and/or evaluation of this 
trial are provided on the Contact List.
10.3.1
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  
The SAC comprises both Sponsor and non-Sponsor scientific experts who provide 
input with respect to trial design, interpretation of trial results and subsequent peer-
reviewed scientific publications.
10.3.2
Clinical Adjudication Committee
A Clinical Adjudication Committee (CAC) will evaluate each subject's data to 
determine the baseline classification of the fungal infection as possible, probable, or 
proven IA. The CAC will also evaluate the following events for the purposes of 
confirming them according to the criteria in Section 8 “Statistical Analysis Plan,” as 
well as evaluating the presence of confounding factors. 
Six- and twelve-week global clinical response assessments will be performed by 
blinded clinicians based on the following information:
1.
Clinical data, including signs and symptoms of infection;
2.
Radiographic findings of infection;
3.
Serologic testing;
4.
Fungal culture and histology.
Once a sufficient number of subjects are classified as possible, probable, or proven 
IA the CAC can also be engaged to conduct a blinded sample size determination to 
see whether the number of FAS subjects (proven or probable IA) is on target with 
the current enrollment.
All personnel involved in the adjudication process will remain blinded to treatment 
allocation throughout the trial.  Specific details regarding endpoint definitions can be 
found in the Adjudication Charter.
10.3.3
Data Monitoring Committee
Specific details regarding responsibilities and governance, including the roles and 
responsibilities of the various members and the Sponsor protocol; meeting 
facilitation; the trial governance structure; and requirements for and proper 
 
 
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documentation of eDMC reports, minutes, and recommendations will be described in 
a separate charter that is reviewed and approved by the eDMC.  The eDMC will 
monitor the trial at an appropriate frequency, as described in the detailed eDMC 
charter.  
11.0REFERENCES
1. de Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. 
Revised definitions of invasive fungal disease from the European Organization 
for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative 
Group and the National Institute of Allergy and Infectious Diseases Mycoses 
Study Group (EORTC/MSG)  Consensus Group. Clin Infect Dis 2008;46:1813-
21.
2. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann 
JW, et al. Voriconazole versus amphotericin B for primary therapy of invasive 
apergillosis. N Engl J Med 2002;347(6):408-15.
3. Rudramurthy SM, Chakrabarti A, Geertsen E, Mouton JW, Meis JF. In vitro 
activity of isavuconazole against 208 Aspergillus flavus isolates in comparison 
with 7 other antifungal agents: assessment according to the methodology of the 
European Committee on Antimicrobial Susceptibility Testing. Diagn Microbiol 
Infect Dis 2011;71:370-7.
4. Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of the 
potential relationships between plasma voriconazole concentrations and visual 
adverse events or liver function test abnormalities. J Clin Pharmacol 
2006;46:235-43. 
5. Walsh TJ, Raad I, Patterson TF, Chandrasekar P, Donowitz GR, Graybill R, et al. 
Treatment of invasive aspergillosis with posaconazole in patients who are 
refractory to or intolerant of conventional therapy: An externally controlled trial. 
Clin Infect Dis 2007;44:2-12.
6. Investigator's Brochure: Posaconazole, A triazole antifungal compound for the 
treatment of serious fungal infections (Doc ID 5588029). Schering-Plough 
Research Institute, 24-Jun-2012.
7. Neofytos D, Lombardi LR, Shields RK, Ostrander D, Warren L, Nguyen MH, 
Thompson CB, and Marr KA.  Administration of Voriconazole in Patients With 
Renal Dysfunction.  Clin Infect Dis 2012; 54: 913-921. 
8. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, and Marchetti O.  Voriconazole 
therapeutic drug monitoring in patients with invasive mycoses improves efficacy 
and safety outcomes.  Clin Infect Dis 2008; 46: 201-211.
 
 
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9. Segal BH, Herbrecht R, Stevens DA, Ostrosky-Zeichner L, Sobel J, Viscoli C, et 
al. Defining responses to therapy and study outcomes in clinical trials of invasive 
fungal diseases: Mycoses study group and European organization for research 
and treatment of cancer consensus criteria. Clin Infect Dis 2008;47:674-83.
10.Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et 
al. Treatment of aspergillosis: Clinical practice guidelines of the infectious 
diseases society of America. Clin Infect Dis 2008;46:327-60.
11.Patterson TF, Kirkpatrick WR, White M, Hiemenz JW, Wingard JR, Dupont B, et 
al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. 
Medicine (Baltimore) 2000;79(4):250-60.
12.Singh N, Avery RK, Munoz P, Pruett TL, Alexander B, Jacobs R, et al. Trends in 
risk profiles for and mortality associated with invasive aspergillosis among liver 
transplant recipients. Clin Infect Dis 2003;36:46-52.
13.Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in 
Medicine 1985;4:213-226
14.Agarwal R, Singh N. Amphotericin B is still the drug of choice for invasive 
aspergillosis.  Am J Respir Crit Care Med 2012; 174: 102a-103.
15.Patterson TF, Baoucher HW, Herbrecht R, Denning DW, Lortholary O, Ribaud,P; 
Rubin,R.H.  Strategy of following Voriconazole versus Amphotericin B therapy 
with other licensed antifungal therapy for primary treatment of invasive 
aspergillosis: impact of other therapies on outcome.  Clin Infect Dise 2005; 41: 
1448-1452.
16.Marr KA, Schlamm H, Rottinghaus ST, Jagannatha S, Bow E J, Wingard JR, 
Pappas P.  A randomised, double-blind study of combination antifungal therapy 
with voriconazole and anidulafungin versus voriconazole monotherapy for 
primary treatment of invasive aspergillosis.  Poster presented at the 22nd 
European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 
London, UK, 31 March - 3 April 2012. 
17.Pfizer.  FDA - Antiviral Drugs Advisory Committee - 4-October-2001 - Briefing 
Document for Voriconazole - (Oral and Intravenous Formulations).  2001.
18.Pfizer.  Background Document for the Antiviral Drug Products Advisory 
Committee Meeting October 4, 2001 (voriconazole tablets) (voriconazole 
injection).  2001.
19.DerSimonian R, Laird N.  Meta-analysis in clinical trials.  Controlled Clinical Trials 
1986; 7: 177-188.
 
 
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20.FDA.  Guidance for Industry Non-Inferiority Clinical Trials.  U.S. Department of 
Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) Center for Biologics Evaluation and Research 
(CBER) March 2010 Clinical/Medical
21.Farrington CP, Manning G. Test statistics and sample size formulae for 
comparative binomial trials with null hypothesis of non-zero risk difference or 
non-unity relative risk. Statistics in Medicine 1990; 9: 1447-54.
22.Denning DW.  Therapeutic outcome in invasive aspergillosis.  Clin Infect Dis 
1996;23:608-615.
23.Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, Davies 
SF, Dismukes WE, Hage CA, Marr KA, Mody CH, Perfect JR, Stevens DA. 
Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients.  
American Journal of Respiratory Critical Care Medicine 2011; 183:96-128.
24.Voriconazole. American Society of Health Systems Pharmacists Drug 
Monograph. 2012; 1-9.
25.Astellas.  FDA - Antiviral Drugs Advisory Committee - 8-December-2014 -
Briefing Document for Isavuconazole - (Oral and Intravenous Formulations).  
2014.
26.Marr, et al. Combination Antifungal Therapy for Invasive Aspergillosis. Annals of 
Internal Medicine • Vol. 162 No. 2 • 20 January 2015;162:81-89.
27.Maertens et al. Isavuconazole versus voriconazole for primary treatment of 
invasive mould disease caused by Aspergillus and other filamentous fungi 
(SECURE): a phase 3, randomised-controlled, non-inferiority trial. The Lancet 
December 9, 2015
28.Conant et al. Use of posaconazole delayed-release tablets for treatment of 
invasive aspergillosis. Mycoses. Volume 58, Issue 5,  pages 313–314, May 2015
29.Cornely et al. Phase 3 pharmacokinetics and safety study of a posaconazole 
tablet formulation in patients at risk for invasive fungal disease. J Antimicrob 
Chemother, November 26, 2015 doi:10.1093/jac/dkv380
30.Maertens et al. Phase 1B Study of the Pharmacokinetics and Safety of 
Posaconazole Intravenous Solution in Patients at Risk for Invasive Fungal 
Disease. Antimicrobial Agents and Chemotherapy. July 2014, Vol 58, Number 5,
p. 3610–3617.
31.Duarte et al. Phase 1b Study of New Posaconazole Tablet for Prevention of 
Invasive Fungal Infections in High-Risk Patients with Neutropenia. Antimicrobial 
Agents and Chemotherapy. October 2014 Volume 58 Number 10 p. 5758–5765.
 
 
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32.E.U. Product Circular: Voriconazole 10 mg/ml solution, 50/200 mg film-coated 
tablets: 2015
 
 
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APPENDICES
 
 
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Appendix 1
Code of Conduct for Clinical Trials
 
 
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Appendix 2
Defining Opportunistic Invasive Fungal Infections 
(European Organization for Research and Treatment of 
Cancer/Invasive Fungal Infections Cooperative Group, 
National Institute of Allergy and Infectious Diseases 
Mycoses Study Group)
 
 
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Appendix 3
Criteria for Diagnosis of Invasive Aspergillosis
 
 
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In order to determine if a subject meets the modified 2008 EORTC/MSG consensus criteria for 
proven, probable, or possible invasive aspergillosis, use the criteria below.
A subject can be diagnosed as having…
if they have:
PROVEN Invasive Aspergillosis
One of the required criteria
PROBABLE Invasive Aspergillosis
One host factor   AND
One clinical criteria   AND
One mycological criteria
POSSIBLE Invasive Aspergillosis
One host factor   AND
One clinical criteria
Criteria for Proven Invasive Aspergillosis

Tissue histopathologic, cytopathologica, or direct microscopic examination of a needle aspiration 
or biopsy specimen showing hyphal forms with evidence of associated tissue damage (either 
microscopically or as an infiltrate or lesion by imaging)
OR

Recovery of Aspergillus species by culture from a sample obtained by a sterile procedure from a 
normally sterile and clinically or radiologically abnormal site consistent with an infectious disease 
process, excluding BAL, cranial sinus cavity, and urine.
a:  tissue and cells submitted for histopathology or cytopathology should be stained by Grocott-
Gomori methenamine silver stain or by periodic acid Schiff stain to facilitate inspection of fungal 
structures. Where possible, wet mounts of specimens from foci related to invasive fungal infectious 
disease should be stained with a fluorescent dye (e.g., calcofluor or Blankophor).
 
 
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Criteria for Probable and Possible Invasive Aspergillosis
Host Factorsa

Recent history of neutropenia (0.5 x 109 neutrophils/L [<500 neutrophils/mm3] for >10 daysb) 
temporally related to the onset of fungal disease

Receipt of an allogeneic HSCT

Treatment with other recognized T-cell immune suppressants, such as cyclosporine, TNF-α 
blockers, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the 
past 90 days.

Prolonged use corticosteroid (excluding among patients with allergic bronchopulmonary 
aspergillosis) at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for >3 weeks.

Inherited severe immunodeficiency (such as chronic granulomatous disease or several combined 
immunodeficiency)
a:  Host factors are not synonymous with risk factors and are characteristics by which individuals 
predisposed to invasive fungal diseases can be recognized. They are intended primarily to apply to 
patients given treatment for malignant disease and to recipients of allogeneic hematopoietic stem cell 
and solid-organ transplants. These host factors are also applicable to patients who receive 
corticosteroids and other T cell suppressants as well as to patients with primary immunodeficiencies.
b: Any duration of neutropenia is also acceptable for possible criteria in this study.
Criteria for Probable and Possible Invasive Aspergillosis
Clinical Criteriaa

Lower respiratory tract fungal diseaseb
o
The presence of 1 of the following 3 signs on CT:

Dense, well-circumscribed lesions(s) with or without a halo sign

Air-crescent sign

Cavity

Tracheobronchitis
o
Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on 
bronchoscopic analysis

Sinonasal infection
o
Imaging showing sinusitis plus at least 1 of the following 3 signs:

Acute localized pain (including pain radiating to the eye)

Nasal ulcer with black eschar

Extension from the paranasal sinus across bony barriers, including into the orbit

CNS infection1 of the following 2 signs:

Focal lesions on imaging

Meningeal enhancement on MRI or CT
a:  Must be consistent with the mycological findings, if any, and must be temporally related to current 
episode.
b:  Every reasonable attempt should be made to exclude an alternative etiology.
 
 
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Criteria for Probable Invasive Aspergillosis
Mycological Criteria

Direct test (cytology, direct microscopy, or culture)
o
Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, 
indicated by 1 of the following:

Presence of fungal elements indicating a mold

Recovery by culture of a mold (e.g., Aspergillus species)

Indirect tests (detection of antigen or cell-wall constituents)
o
Aspergillosis
Galactomannan antigen detected in serum or bronchoalveolar lavage (BAL) fluid
(a positive test result defined as a cut-off index ≥1.0 [single result from serum or BAL] or  ≥0.5 
[2 consecutive results from serum samples])
 
 
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Appendix 4
Child-Pugh Scoring and Classification
 
 
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Child-Pugh Scoring
Measure
1 point
2 points
3 points
Total bilirubin, µmol (mg/dl)
<34 (≤2)
34-50 (2-3)
>50 (>3)
Serum albumin, g/dl
>3.5
2.8-3.5
<2.8
PT prologation (INR)
<4 seconds 
(<1.7)
4-6 seconds 
(1.71-2.30)
>6 seconds 
(>2.30)
Ascites
None
Mild
Moderate to 
Severe
Hepatic encephalopathy
None
Grade I-II (or 
suppressed 
with 
medication)
Grade III-IV (or 
refractory)
Child-Pugh Interpretation
Points
Class
6
A
7-9
B
10-15
C
NOTE: Patients with IA will often have low albumin scores due to their underlying 
conditions or the fungal infection itself.  Hence, a patient who meets the criteria for 
Child-Pugh Class A or B based solely on a low albumin score without any other 
measure of hepatic insufficiency (i.e., albumin 2 or 3 points but no other hepatic 
measure above 1 point) should not be considered to have mild or moderate hepatic 
insufficiency, and, thus, such patients do not truly meet the mild or moderate hepatic 
insufficiency criterion to reduce the VOR dose.   
 
 
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Appendix 5
DNA Sampling and Pharmacogenetic Analysis Procedures
 
 
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1.
Definitions
a. Pharmacogenomics:  The investigation of variations of DNA and RNA 
characteristics as related to drug response.
b. Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is 
the influence of variations in DNA sequence on drug response.
c. Genomic Biomarkers:  A measurable DNA and/or RNA characteristic that is 
an indicator of normal biologic processes, pathogenic processes, and/or 
response to therapeutic or other interventions.
d. DNA:  Deoxyribonucleic acid.
e. RNA:  Ribonucleic acid.
2.
Summary of Procedures for Pharmacogenetics
f.
Subjects for Enrollment:  All subjects enrolled in the current clinical trials will 
be considered for enrollment.
g. Consent
Informed consent for biosamples (i.e., DNA, RNA, protein, etc.) will be 
obtained during screening for protocol enrollment from all subjects or legal 
guardians, at an outpatient visit, or during an inpatient stay by the investigator 
or his or her designate.
Subjects are not required to participate in the pharmacogenetic sub-study in 
order to participate in the main trial.
3.
Scope of Pharmacogenomic Study
The DNA and serum samples collected in the current trial will be used to study
various genetic causes for how subjects may respond to a drug.  The DNA 
samples will be stored to provide a resource for future studies conducted by 
Merck focused on the study of genes responsible for how a drug enters and is 
removed by the body, how a drug works, other pathways a drug may interact 
with, or other aspects of disease.  All samples will be used by Merck or 
designees and research will be monitored and reviewed by a committee of our 
scientists and clinicians.
4.
Techniques to Collect Samples
Blood samples will generally be obtained for all study participants.  Blood 
samples for both DNA and RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes.  
 
 
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5.
Confidential Subject Information for Pharmacogenomic Analysis
Samples will be collected and sent to the laboratory designated for the trial where 
they will be processed (i.e., DNA or RNA extraction, etc.) following the Merck 
approved policies and procedures for sample handling and preparation.
To maintain privacy of information collected from samples obtained for storage 
and future analysis, Merck has developed secure policies and procedures to 
maintain subject privacy.  At the clinical site, a unique Code will be placed on the 
blood sample for transfer to the storage facility.  The Code is a random number 
used only to identify the biosample of each subject.  No other personal identifiers 
will appear on the sample tube.  The first Code will be replaced with a Sample 
Code (e.g., Genetic Sample Code for DNA sample, Serum Sample code for 
serum sample) at the Central Laboratory or at the Merck designated facility.  This 
sample is now a single coded sample.  The Sample Code is stored separately 
from all previous sample identifiers.  A secure code, hereinafter referred to as a 
“first coding key”, will be utilized to match the Sample Code to the original blood 
code and subject number to allow clinical information collected during the course 
of the trial to be associated with the biosample.  This “first coding key” will be 
transferred by the central laboratory or Merck designated facility under secure 
procedures to the Merck group designated as the entrusted keyholder to 
maintain confidentiality of the biosamples.  The Sample Code will be logged into 
the primary biorepository database, 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 sample will be stored in a 
designated repository site with secure policies and procedures for sample 
storage and usage.
For DNA samples, a Storage Code will replace the Sample Code at the Merck
designated facility.  The DNA sample is now a double coded sample.  This 
storage code will be stored separately from all previous sample identifiers.  The 
second secure key referred to as a “second coding key” file will be transferred by 
the Merck designated facility under secure procedures to the Merck entrusted 
keyholder.  Samples with the second code are sometimes referred to as de-
identified samples. The use of the second code provides additional confidentiality 
and privacy protection for subjects over the use of a single code.  Access to both 
coding keys is needed to link any data or samples back to a subject identifier.
The “keys” could be utilized to reconstruct the link between genetic information 
and identifiable clinical information, at the time of analysis.  This linkage would 
not be possible for the investigator conducting the analysis, but may only be 
done by the Merck entrusted keyholder under strict security policies and 
procedures.  The Merck entrusted keyholder will link the information, conduct the 
analysis, then issue an anonymized data summary on the initially single or 
double coded samples to the investigator conducting the genetic analysis.  The 
only circumstance by which genetic information would be linked to clinical 
information would be those situations mandated by health authorities 
 
 
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(e.g., EMEA, FDA), whereby this information would be directly transferred to the 
health authority.  Once the link between subject’s identifiers and the unique 
codes is deleted, it is no longer possible to trace the data and samples back to 
individual subjects through the coding keys.  Anonymization is intended to 
prevent subject re-identification.
6.
Biorepository Sample Usage
Samples obtained for the Merck biorepository will be used for analyses using 
good scientific practices.  Exploratory analyses will not be conducted under 
highly validated conditions.  The scope of research performed on these samples 
is limited to the investigation of the variability in inherited biomarkers that may 
correlate with a clinical phenotype in subjects.
Genetic analysis utilizing the DNA samples may be performed by the sponsor, or 
an additional third party (e.g., a university investigator) designated by the 
sponsor.  The investigator conducting the analysis will be provided with a double 
(single) coded sample.  Reassociation of analysis results with corresponding 
clinical data will only be conducted by the Merck entrusted keyholder.  Any 
contracted third party genetic analysis will conform to the specific genetic 
analysis outlined in the clinical protocol.  DNA samples remaining with the third 
party vendor after genetic analysis will be returned to the sponsor or destroyed 
and documentation of destruction will be reported to Merck.
Consent form signed by the subject will be kept under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be 
traced to any samples, test results, or medical information once the specimens 
have been rendered de-identified.  Laboratory personnel performing the genetic 
testing will not have access to the informed consent document, nor will they be 
able to identify subjects from the double (single) coded specimens.  Specimens 
will be identified to the laboratory only by the Sample double (single) code.  
Subjects who decline to sign the informed consent document for the sub-study 
will not have the sample collected or stored, nor will they be discontinued from 
the main trial unless the pharmacogenetics sample is specifically required for trial
enrollment.
A template of each site’s informed consent will be stored in the Sponsor’s clinical 
document repository.  Each consent will be assessed for appropriate sample 
permissions.  The tracking number on this document will be used to assign 
sample permissions for each sample in the entrusted keyholder’s Sample 
Database.
 
 
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7.
Withdrawal From the Biorepository and Pharmacogenetic(-omic) Database
Subjects may withdraw their consent to store the blood sample or the DNA or 
RNA derived from it.  Subjects can also request that their sample be destroyed at 
any time.  If samples can be identified in any way (i.e., are not anonymized 
samples), subjects may withdraw consent for banking samples at any time by 
contacting the investigator responsible for administering their initial informed 
consent.  At that time, subject samples will be removed from the biorepository.  
Any DNA, RNA, or other biologic samples will be destroyed, destruction will be 
documented, and sample database information deleted.  However, any analyses 
performed or data obtained from the samples prior to the subject withdrawing 
consent will not be deleted.
8.
Retention of Data and Biosamples
It is anticipated that data generated from processed samples collected during the 
course this trial will be retained for an indefinite period. DNA specimens will be 
maintained for potential analysis for 20 years from the acquisition.  Samples will 
be destroyed according to Merck policies and procedures and this destruction will 
be documented in the repository database.
9.
Data Security
Pharmacogenetic and other research databases are accessible only to 
authorized sponsor and trial administrator research personnel and/or designated 
collaborators and are only stored and accessible as anonymized data.  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 key holder maintains 
control over access to all sample data.  These data are collected for 
pharmacogenetic research purposes only as specified in the clinical protocol and 
will not be used for any other purpose without explicit consent from the research 
subject.
10. Reporting of 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 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 of data, limitations of 
predictive capability of research data, concerns of misinterpretation of data, 
absence of good clinical practices standards in exploratory research.
 
 
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If any exploratory results are definitively associated with clinical significance for 
subjects while the Merck clinical trial is still ongoing, investigators will be 
contacted with information as to how to offer genetic testing (paid for by Merck) 
to subjects enrolled and will be advised that genetic counseling should be made 
available for all who choose to participate.
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 sites who participated in the Merck clinical 
trial, and post the 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 subjects may pursue genetic 
testing if they wish to do so.
11. 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 pharmacogenetic sampling.  When studies with samples 
are conducted and subjects identified to serve as controls, every effort will be 
made to group samples from subjects and controls to represent the ethnic and 
gender population representative of the disease under current investigation.
12. Risks Versus Benefits of Pharmacogenetic Testing
For pharmacogenetic testing, risks to the subject have been minimized.  Risks 
include those associated with venipuncture to obtain the whole blood sample.  
This sample will be obtained at the time of routine blood samples drawn for 
clinical reasons.
Data privacy concerns of the subject have been strictly protected against with 
Merck security, policies and procedures.  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 reassociated to double (single) coded samples 
at the time of data analysis.  These subject data will be kept in a separate, 
secure Merck database, and all samples will be stripped of subject identifiers.  
No information concerning results obtained from genotyping or biomarker studies 
conducted with samples from the biorepository will be entered into clinical 
records, nor will it be released to outside persons or agencies, in any way that 
could be tied to an individual subject.
 
 
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13. Self-Reported Ethnicity
Subjects who participate in pharmacogenetic study will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still 
participate in the pharmacogenetic study.
14. Questions
Any questions related to the genetic informed consent, genetic sampling, genetic 
sample handling, or genetic sample storage should be e-mailed directly to 
clinical.specimen.managment@merck.com.
 
 
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Appendix 6
Summary of Imaging Charter
 
 
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The imaging charter provides a comprehensive, detailed description of the imaging 
required as part of this protocol.  The following elements are part of the imaging 
charter that was developed in collaboration with the central imaging laboratory used 
for this study.  Please refer to the imaging charter and the Operations Manual for
details regarding the imaging requirements.
1.
Summary of Trial Design and Role of Imaging
2.
Imaging Acquisition Standards
a. Equipment standardization and operation
b. Imaging drug standardization
3.
Standards for Image Interpretation
c. Image transfer, receipt, and quality assessment
d. Image display and interpretation
4.
Charter Modification Process
5.
Imaging Data Transfer Process
6.
Archiving of Images and Image Interpretation
 
 
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Appendix 7
Additional Details on Statistical Methods
 
 
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Miettinen and Nurminen’s Asymptotic Confidence Interval
For the difference in the all-cause mortality rate of Posaconazole (POS) compared to 
Voriconazole (VOR), CIs will be calculated based on Miettinen and Nurminen’s 
method [13].  The method is described as follows:
The two-sided 95% CI for a difference between 2 proportions is given by the roots 
for 
of the following equation:
where

is the upper cut point of size α from the chi-square distribution with
one degree of freedom (
=3.84  for 95% confidence interval);

θ is the difference between two population proportions, i.e., 
;

, 
are the observed proportions (observed values of 
and 
, 
respectively) of POS and VOR groups, respectively;


n1 and n2 are the sample sizes for POS treatment group and VOR, respectively;

and 
are maximum likelihood estimates of 
and 
computed under the 
constraint 
, respectively.
However, since there are no explicit solutions for θ, a numerical algorithm will be 
used to obtain the two roots (confidence interval) for θ. Details of programming the 
numerical algorithm can be found in Miettinen and Nurminen [13].
2
1
P
P 


V
p
p
~
)
ˆ
ˆ
(
2
2
1
2





2


2


2
1
P
P 


1ˆp
2ˆp
1P
2P
)
1
(
)
(
)
~
1(
~
)
~
1(
~
~
2
1
2
1
2
2
2
1
1
1











n
n
n
n
n
p
p
n
p
p
V
1~p
2
~p
1P
2P



2
1
~
~
p
p
 
 
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Appendix 8
Terminology Criteria for Adverse Events (CTCAE) lab 
grading criteria -  Investigations System Organ Class.  
Please refer to the most recent complete CTCAE version 
and guidelines, if applicable.
 
 
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Appendix 9
Estimated blood volumes collected during the Study
 
 
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Estimated Blood Volumes
 
 
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INVESTIGATOR SIGNATURE PAGE
Title
A Phase 3 Randomized Study of the Efficacy and Safety of 
Posaconazole versus Voriconazole for the Treatment of Invasive 
Aspergillosis in Adults (Phase 3; Protocol No. MK-5592-069)
Sponsor
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Trial Physician/Director
, MD MSPH
Global Clinical Research, Infectious Diseases
Date of Finalization of This Current 
Version of the Protocol
07-FEB-2019 – PROTOCOL AMENDMENT#5
Previous Version(s) of the Protocol
01-AUG-2016– PROTOCOL AMENDMENT#4
08 JAN 2015 – Protocol Amendment#3
26 JUN 2013 – Protocol Amendment#2
12 DEC 2012 – Protocol Amendment #1
15 NOV 2012 – Initial Protocol
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR 
PRODUCT IS PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF THIS 
DRUG OR PRODUCT AND IS SUBJECT TO RECALL AT ANY TIME.  THE INFORMATION 
IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS 
REQUIRED BY APPLICABLE LAWS OR REGULATIONS.  SUBJECT TO THE 
FOREGOING, THIS INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS 
INVOLVED IN THE TRIAL WHO HAVE A NEED TO KNOW, WITH THE OBLIGATION NOT 
TO FURTHER DISSEMINATE THIS INFORMATION.  THESE RESTRICTIONS ON 
DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE ORAL OR WRITTEN
INFORMATION, SUPPLIED TO YOU BY THE SPONSOR OR ITS AFFILIATES OR 
REPRESENTATIVES THAT IS DESIGNATED AS "PRIVILEGED" OR "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.
Name and Degree of Sponsor Representative
dd MMM yyyy
Department of Sponsor Representative
I have read Protocol No. MK-5592-069-03 (also known as P06200) dated XX
including all appendices, and agree to conduct the trial in accordance with the 
protocol.  The protocol and trial documents must also be approved by the IRBs/IECs 
and regulatory authorities as appropriate, before implementation at the site.  I agree 
to implement the protocol and trial documents only after all necessary approvals 
have been obtained and the sponsor has confirmed that it is acceptable to do so.
Name, Degree, full mailing address of Investigator
Site Number
dd MMM yyyy
 
 
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