Clinical trial NCT03816176
Conditions: Invasive Mucormycosis Invasive Aspergillosis
Keywords: ASP9766 Cresemba BAL8557 isavuconazonium sulfate
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2019-08-22; Completion date: 2022-12-14
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the safety, tolerability, and efficacy of isavuconazonium sulfate in pediatric participants.

Detailed description:
Treatment began on Day 1 and then participants were followed for 60 days post-last dose for safety. Treatment was administered until the participant had a successful outcome or for a maximum duration of 84 days (IA) or 180 days (IM), whichever occured first.

Participants received a loading regimen of isavuconazonium sulfate (via intravenous or oral administration at the investigator's discretion), which consisted of a dose every 8 hours (± 2 hours) on Days 1 and 2 (for a total of 6 doses), followed by once daily maintenance dosing for up to 84 days (IA) or 180 days (IM) of dosing. The first maintenance dose started 12 to 24 hours after the administration of the last loading dose. Subsequent maintenance doses were administered once daily (24 hours ± 2 hours from the previous maintenance dose). The oral formulation could only be given to participants 6 years to \< 18 years of age and with a body weight of at least 12 kg. Participants who were discharged from the hospital with oral capsules for at-home administration had to return weekly for study drug accountability and to receive new oral dosing supplies. Participants who began oral administration were to complete the oral dosing acceptability assessment after ingesting their first oral dose.

Arms: arm 1: Participants received 10 milligrams/killograms (mg/kg) dose of isavuconazonium sulfate every 8 hours (± 2 hours) on days 1 and 2 for a total of 6 doses (via intravenous or oral administration at the investigator's discretion) followed by once-daily maintenance dose of 10 mg/kg for up to 84 days IA or 180 days IM or until the participant had a successful outcome as judged by the investigator, whichever occured first. The route of administration could have been changed per the investigator's discretion.
Interventions: intervention 1: Isavuconazonium sulfate intervention 2: Isavuconazonium sulfate
Intervention descriptions: intervention 1: Intravenous (IV) infusion intervention 2: Oral capsule

Protocol documents:
Prot_002.pdf: 
Sponsor: APGD
ISN/Protocol 9766-CL-0107
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A Phase 2, Open-Label, Non-Comparative, Multicenter Study 
to Evaluate the Safety and Tolerability, Efficacy and 
Pharmacokinetics of Isavuconazonium Sulfate for the 
Treatment of Invasive Aspergillosis (IA) or Invasive 
Mucormycosis (IM) in Pediatric Subjects
ISN/Protocol 9766-CL-0107
Version 4.0
Incorporating Substantial Amendment 3 [See Section 13]
05 Sep 2019
IND 72593
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [24Aug2018]
Version 1.1 [05Sep2018] Incorporating Non-substantial Amendment 1
Version 2.0 [12Feb2019] Incorporating Substantial Amendment 1
Version 3.0 [08May2019] Incorporating Substantial Amendment 2
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information, which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence. 


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Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································14
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································22
1
INTRODUCTION·················································································28
1.1
Background ····················································································28
1.2
Nonclinical and Clinical Data ·······························································29
1.3
Summary of Key Safety Information for Study Drugs ···································29
1.4
Risk Benefit Assessment ·····································································30
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS···································30
2.1
Study Objective(s) ············································································30
2.1.1
Safety Objective ·········································································30
2.1.2
Efficacy Objective·······································································30
2.1.3
Pharmacokinetic Objective·····························································30
2.2
Study Design and Dose Rationale···························································31
2.2.1
Study Design·············································································31
2.2.2
Dose Rationale···········································································33
2.3
Endpoints·······················································································36
2.3.1
Safety Endpoints·········································································36
2.3.2
Efficacy Endpoints ······································································36
2.3.3
Other Endpoints ·········································································37
3
STUDY POPULATION··········································································37
3.1
Selection of Study Population ·······························································37
3.2
Inclusion Criteria··············································································37
3.3
Exclusion Criteria ·············································································38
4
TREATMENT(S)··················································································39
4.1
Identification of Investigational Product(s) ················································39
4.1.1
Study Drug(s) ············································································39
4.1.2
Comparative Drug(s)····································································40
4.2
Packaging and Labeling ······································································40


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4.3
Study Drug Handling ·········································································40
4.4
Blinding ························································································41
4.5
Assignment and Allocation ··································································41
5
TREATMENTS AND EVALUATION························································41
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················41
5.1.1
Dose/Dose Regimen and Administration Period ····································41
5.1.2
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ··················································································43
5.1.3
Treatment Compliance··································································44
5.2
Demographics and Baseline Characteristics ···············································45
5.2.1
Demographics············································································45
5.2.2
Medical History··········································································45
5.2.2.1
Underlying Diseases or Conditions··············································45
5.2.2.2
Infectious Disease History························································45
5.3
Efficacy and Pharmacokinetic Assessments ···············································45
5.3.1
Efficacy Assessment ····································································45
5.3.2
Pharmacokinetic Assessment ··························································46
5.3.3
Oral Dosing Acceptability Assessment···············································47
5.4
Safety Assessment ············································································47
5.4.1
Vital Signs················································································47
5.4.2
Laboratory Assessments································································47
5.4.3
Physical Examination···································································48
5.4.4
Electrocardiogram·······································································49
5.4.5
Order of Assessments···································································49
5.5
Adverse Events and Other Safety Aspects ·················································49
5.5.1
Definition of Adverse Events ··························································49
5.5.1.1
Abnormal Laboratory Findings ··················································50
5.5.1.2
Potential Cases of Drug-Induced Liver Injury ·································50
5.5.1.3
Disease Progression and Study Endpoints······································50
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································51
5.5.2.1
Always Serious Adverse Events ·················································51
5.5.3
Criteria for Causal Relationship to Study Drug······································51
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························52
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································53


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5.5.6
Follow-up of Adverse Events··························································54
5.5.7
Monitoring of Common Serious Adverse Events ···································54
5.5.8
Special Situations········································································54
5.5.8.1
Pregnancy···········································································55
5.5.8.2
Medication Error, Overdose and “Off-label Use” ·····························56
5.5.8.3
Misuse/Abuse ······································································56
5.5.8.4
Occupational Exposure ···························································57
5.5.9
Supply of New Information Affecting the Conduct of the Study··················57
5.5.10
Urgent Safety Measures ································································57
5.5.11
Reporting Urgent Safety Measures····················································57
5.6
Test Drug Concentration ·····································································57
5.7
Other Measurements, Assessments or Methods ···········································58
5.8
Total Amount of Blood·······································································58
6
DISCONTINUATION············································································60
6.1
Discontinuation of Individual Subject(s) From Study Treatment ·······················60
6.1.1
Lost to Follow-up········································································60
6.2
Discontinuation of the Site···································································60
6.3
Discontinuation of the Study·································································61
7
STATISTICAL METHODOLOGY ···························································61
7.1
Sample Size····················································································61
7.2
Analysis Sets···················································································61
7.2.1
Full Analysis Set (FAS) ································································61
7.2.2
Modified Full Analysis Set (mFAS) ··················································61
7.2.3
Safety Analysis Set (SAF)······························································62
7.2.4
Pharmacokinetic Analysis Set (PKAS) ···············································62
7.3
Demographics and Baseline Characteristics ···············································62
7.3.1
Subject Disposition······································································62
7.3.2
Previous and Concomitant Medications ··············································62
7.3.3
Medical History··········································································62
7.4
Analysis of Efficacy ··········································································62
7.4.1
Analysis of Primary Efficacy Endpoint···············································63
7.4.1.1
Primary Efficacy Analysis························································63
7.4.1.2
Secondary Efficacy Analysis·····················································63
7.4.2
Analysis of Secondary Efficacy Endpoints···········································63


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7.4.2.1
Analysis of Key Secondary Endpoints··········································63
7.4.2.2
Analysis of Additional Secondary Endpoints ··································63
7.5
Analysis of Safety·············································································63
7.5.1
Adverse Events ··········································································63
7.5.2
Laboratory Assessments································································64
7.5.3
Vital Signs················································································64
7.5.4
Physical Examination···································································64
7.5.5
Routine 12-lead Electrocardiograms ··················································64
7.6
Analysis of Pharmacokinetics ·······························································64
7.6.1
Analytical Method·······································································64
7.6.2
Estimation of Pharmacokinetic Parameters ··········································64
7.7
Major Protocol Deviations and Other Analyses···········································65
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················65
7.9
Handling of Missing Data, Outliers, Visit Windows and Other Information ··········65
8
OPERATIONAL CONSIDERATIONS·······················································65
8.1
Data Collection················································································65
8.1.1
Specification of Source Documents···················································66
8.1.2
Clinical Study Monitoring······························································66
8.1.3
Direct Access to Source Data/Documents············································67
8.1.4
Data Management ·······································································67
8.2
Screen Failures ················································································67
8.3
Major Protocol Deviations ···································································67
9
END OF TRIAL ···················································································68
10
STUDY ORGANIZATION······································································68
10.1
Data and Safety Monitoring Board (DSMB) ··············································68
10.2
Adjudication Committee (AC) ······························································68
11
REFERENCES ····················································································69
12
APPENDICES ·····················································································71
12.1
Ethical, Regulatory and Study Oversight Considerations ································71
12.1.1
Ethical Conduct of the Study···························································71
12.1.2
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) ···················································71
12.1.3
Protocol Amendment and/or Revision················································71


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12.1.4
Financial Disclosure ····································································72
12.1.5
Informed Consent of Subjects ·························································72
12.1.5.1
Subject Information and Consent/Assent ·······································72
12.1.5.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························72
12.1.6
Source Documents ······································································73
12.1.7
Record Retention ········································································73
12.1.8
Subject Confidentiality and Privacy···················································73
12.1.9
Arrangement for Use of Information and Publication of the Clinical Study ·····74
12.1.10
Insurance of Subjects and Others······················································74
12.1.11
Signatory Investigator for Clinical Study Report····································74
12.2
Procedure for Clinical Study Quality Control ·············································76
12.2.1
Clinical Study Monitoring······························································76
12.2.2
Direct Access to Source Data/Documents············································76
12.2.3
Data Management ·······································································76
12.2.4
Quality Assurance·······································································76
12.3
Contraception Requirements·································································77
12.4
List of Excluded Concomitant Medications················································79
12.5
Liver Safety Monitoring and Assessment ··················································80
12.6
Common Serious Adverse Events···························································83
12.7
Oral Dosing Acceptability Assessment·····················································84
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 3 ··································86
14
COORDINATING INVESTIGATOR’S SIGNATURE·································· 109
15
SPONSOR SIGNATURES ···································································· 110


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I.
SIGNATURES
1.  SPONSOR’S SIGNATURES
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 15
Sponsor’s Signatures].


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2.  COORDINATING INVESTIGATOR’S SIGNATURE
The coordinating investigator’s signature can be found in [Section 14 Coordinating 
Investigator’s Signature]; located at the end of this document.


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3.  INVESTIGATOR’S SIGNATURE
A Phase 2, Open-Label, Non-Comparative, Multicenter Study to Evaluate the 
Safety and Tolerability, Efficacy and Pharmacokinetics of Isavuconazonium 
Sulfate for the Treatment of Invasive Aspergillosis (IA) or Invasive 
Mucormycosis (IM) in Pediatric Subjects
ISN/Protocol 9766-CL-0107
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05 Sep 2019
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice (GCP) guidelines and applicable local regulations. I will also ensure that subinvestigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH GCP 
guidelines to enable them to work in accordance with the provisions of these documents.
Principal Investigator:
Signature:
Date (DD Mmm YYYY)
Printed Name:
<Insert name and qualification of the Investigator>
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AC
Adjudication Committee
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
APGD
Astellas Pharma Global Development, Inc.
AST
aspartate aminotransferase
AT
Aminotransferases
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve at 24 hours
AUCSS
area under the concentration-time curve at steady state
AUST
Astellas US Technologies
BAL
bronchoalveolar lavage
CA
Competent Authorities
cEC
concerned Ethics Committee
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
Clearance
CRO
contract research organization
CV
coefficient of variation
CYP3A4
cytochrome P450
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eCRF
electronic case report form
EEA
European Economic Area
EORTC/MSG
European Organisation for Research and Treatment of Cancer/Mycoses Study 
Group
EOS
end of study
EOT
end of treatment
FAS
full analysis set
GCP
Good Clinical Practice
GI
Gastrointestinal
GM
Galactomannan
GMP
Good Manufacturing Practices
HSCT
hematopoietic stem cell transplant
IA
invasive aspergillosis
IB
investigator’s brochure
ICF
informed consent form
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use


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Abbreviations
Description of abbreviations
IEC
independent ethics committee
IFI
invasive fungal infection
IM
invasive mucormycosis
IMI
invasive mould infection
IND
investigational new drug
INR
international normalized ratio
IRB
institutional review board
IRR
Infusion-related reaction
IRT
interactive response technology
LA-CRF
liver abnormality case report form
LFT
liver function tests
LLOQ
lower limit of quantification
MedDRA
medical dictionary for regulatory activities
mFAS
modified full analysis set
PKAS
pharmacokinetic analysis set
(S)AE
serious adverse event or adverse event
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reactions
TBL
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
USM
urgent safety measure
Vd
volume of distribution


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Definition of Key Study Terms
Terms
Definition of terms
Baseline 
Assessments of subjects as they enter a trial before they receive any treatment. 
End of Study (EOS)
End of Study for each subject has occurred when the final protocol – defined 
assessment has been completed. In this study, the last protocol-defined 
assessment is approximately 60 days after last study drug dose.
End of Treatment 
(EOT)
The date the last dose of study drug was taken by the enrolled subject. In this 
study, the end of treatment is a maximum of 84 days for invasive aspergillosis
subjects or 180 days for invasive mucormycosis subjects.
Endpoint
Variable that pertains to the efficacy or safety evaluations of a trial.
Enroll
To register or enter a subject into a clinical trial. Note: Once a subject has 
received the study drug, the clinical trial protocol applies to the subject. 
Evaluable Subject
A subject who has received at least one dose of study drug.
Intervention
The drug, device, therapy or process under investigation in a clinical study that 
is believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety and pharmacoeconomics). 
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screening period
Period of time before entering the investigational period, usually from the time 
when a subject signs the consent until just before the test drug is given to a 
subject. 
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
05 Sep 2019 / Version 4.0
Sponsor:
Astellas Pharma Global Development Inc. (APGD)
Protocol Number:
9766-CL-0107
Name of Study Drug: 
Isavuconazonium sulfate
Phase of Development:
2
Title of Study:
A Phase 2, Open-Label, Non-Comparative, Multicenter Study to Evaluate the Safety and Tolerability, 
Efficacy and Pharmacokinetics of Isavuconazonium Sulfate for the Treatment of Invasive 
Aspergillosis (IA) or Invasive Mucormycosis (IM) in Pediatric Subjects
Planned Study Period:
From 1Q2019 to 1Q2021
Study Objective(s):
Safety Objective
To evaluate the safety and tolerability of isavuconazonium sulfate in pediatric subjects
Efficacy Objective
To assess the efficacy of isavuconazonium sulfate for the treatment of invasive aspergillosis (IA) or 
invasive mucormycosis (IM) in pediatric subjects
Pharmacokinetic Objective
To evaluate the pharmacokinetics of isavuconazole by monitoring the plasma concentrations in 
pediatric subjects during treatment with isavuconazonium sulfate
Planned Total Number of Study Centers and Location(s):
Approximately 30 investigative centers in the US and in Europe
Study Population:
Male and female subjects (1 to < 18 years of age) who have been diagnosed with proven, probable or 
possible IA or IM
Number of Subjects to be Enrolled/Randomized:
Approximately 30 subjects will be enrolled. 
Every effort will be made to achieve at least 5 evaluable subjects per age cohort: 1 to < 12 years of 
age and 12 to < 18 years of age. The sponsor reserves the right to stop enrollment if the cohort 
requirements are not achieved.
Study Design Overview:
This is a phase 2, open-label, non-comparative, multicenter study to assess the safety and tolerability, 
efficacy and pharmacokinetics of isavuconazonium sulfate in pediatric subjects for the treatment of 
IA or IM.
An approved informed consent form must be obtained from the subject’s parent or legal guardian, 
and, if required, pediatric assent prior to any study-related procedures being performed.
The subjects will enter into screening anytime between days -5 to day 1 (predose). All subjects will be 
assigned to open-label treatment via intravenous or oral treatment at the discretion of the investigator. 
The oral formulation can only be given to subjects 6 years to < 18 years of age and with a body 
weight of at least 12 kg. The route of administration may be changed per the investigator’s discretion 
as needed for treatment purposes as the resulting exposure from the 2 routes of administration is 
considered equivalent on a mg:mg basis. 


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Treatment will begin on day 1, and then subjects will be followed for 60 days post-last dose for 
safety.
Treatment will be administered until the subject has a successful outcome as judged by the 
investigator or for a maximum duration of 84 days (IA) or 180 days (IM), whichever occurs first. 
Investigator guidance of a successful outcome is provided in Table 4. 
Intravenous and Oral Dosing: Subjects will receive a loading regimen of isavuconazonium sulfate (via 
intravenous or oral administration at the investigator’s discretion), which consists of a 10 mg/kg dose 
every 8 hours (± 2 hours) on days 1 and 2 (for a total of 6 doses), followed by once daily maintenance 
10 mg/kg dosing for up to 84 days (IA) or 180 days (IM) of dosing. The first maintenance dose 
should start 12 to 24 hours after the administration of the last loading dose. Subsequent maintenance 
doses will be administered once daily (24 hours ± 2 hours from the previous maintenance dose). 
Subjects who are discharged from the hospital with oral capsules for at-home administration must 
return weekly for study drug accountability and to receive new oral dosing supplies. Subjects who 
begin oral administration are to complete the oral dosing acceptability assessment after ingesting their 
first oral dose. Isavuconazonium sulfate oral capsules can be administered with or without food.
Due to the similarity in exposure (AUC) between intravenous and oral in pediatric subjects, the 
investigator may change dosing between the 2 routes (intravenous oral) throughout the treatment as 
needed for treatment purposes. If the route of administration is changed after the 2-day loading 
regimen is completed, there is no need to repeat the loading dose for the new route of administration. 
The total doses for the loading period should not exceed 6 study drug administrations over the 2-day 
loading period, even if the route of administration is changed during the 2-day loading period.
Blood sampling for the analysis of isavuconazole trough levels will be obtained from all subjects. 
The samples should ideally be drawn immediately prior to the next dose of study drug, but must be 
taken no earlier than 1 hour prior to the next dose on days 7, 14, 21, 42 and 84 or end of treatment 
(EOT). 
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any one day between 
day 14 and day 42, while the subject is still receiving study drug, for subjects who consent to 
participation in the 24-hour pharmacokinetic assessment.
Subjects receiving intravenous administration:
The 24-hour pharmacokinetic samples will be obtained for intravenous dosing as follows:
1.
within 1 hour prior to the start of the intravenous isavuconazonium sulfate infusion (this sample 
will be the same as the trough sample prior to dose, if it coincides with scheduled days 14, 21 or 
42);
2.
immediately after the completion of the intravenous infusion (no more than 5 minutes after);
3.
within 4 to 10 hours after the start of the intravenous infusion; and 
4.
within 16 to 24 hours after the start of the intravenous infusion (must be obtained before the start 
of the next infusion).
Subjects receiving oral administration:
The 24-hour pharmacokinetic samples will be obtained for oral dosing as follows: 
1.
within 1 hour of next oral dose (this sample will be the same as the trough sample prior to dose, 
if it coincides with scheduled days 14, 21 or 42);
2.
1 hour post dose (± 10 minutes);
3.
3 hours post dose (± 10 minutes);
4.
4 hours post dose (± 10 minutes);
5.
within 6 to 8 hours (± 30 minutes) of study drug administration; and
6.
24 hours post dose (within 1 hour before next study drug administration) after study drug 
administration. 


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No additional samples will be taken from IM subjects after day 84.
Throughout the study, safety and tolerability will be assessed by the recording of adverse events 
(AEs), vital signs, electrocardiograms (ECGs) and safety laboratory evaluations. This includes 
assessments at 14 days, 28 days and 56 days. All subjects will complete 2 follow-up visits. At the 
discretion of the investigator, follow-up visits may be conducted via telephone with the subject, the 
subject’s parent or the subject’s legal guardian, 30 and 60 days after the subject’s day 84 (IA)/day 
180 (IM) or EOT visit.
If subject discontinues study drug prior to day 84 or day 180, all EOT procedures must be completed. 
If subject continues to allow consent, end of study (EOS) information will be collected 30 and 60 days 
after EOT.
Inclusion/Exclusion Criteria:
Inclusion:
1.
Institutional Review Board (IRB)-approved written informed consent and privacy language as 
required per national regulations (e.g., Health Insurance Portability and Accountability Act
authorization) must be obtained from the subject’s parent or legal guardian and, if required,
subject’s assent, prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable).
2.
Male or female subject 1 year to < 18 years of age diagnosed with IA or IM. A positive diagnosis 
is defined as follows:
●Proven, probable or possible invasive fungal infection (IFI) per the European Organisation for 
Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG], 2008 criteria
Note: Subjects with “possible” IFI will be eligible for enrollment; however, diagnostic tests 
to confirm the invasive fungal disease as “probable” or “proven” according to the 
EORTC/MSG criteria should be completed within 10 calendar days after the first dose of 
study drug
o Note: In addition to the criteria set for mycological criteria by the EORTC/MSG in 2008, 
and only for subjects with an underlying hematologic malignancy or recipients of 
hematopoietic stem cell transplant who also have clinical and radiologic features 
consistent with invasive fungal infection, the following are acceptable:
i.
Galactomannan (GM) levels (optical density index) meeting the below criteria are 
acceptable mycological evidence for enrollment or upgrading the diagnosis to 
probable IA:
1.
A single value for serum or bronchoalveolar lavage (BAL) fluid of 1.0 or
2.
Two serum GM values of 0.5 from 2 separate samples
3.
Subject has sufficient venous access to permit intravenous administration of study drug or the 
ability to swallow oral capsules.
4.
A female subject is eligible to participate if she is not pregnant and at least one of the following 
conditions applies:
a. Not a subject who is of childbearing potential as defined in [Appendix 12.3 Contraception 
Requirements].
OR
b. Subject who is of childbearing potential who agrees to follow the contraceptive guidance as 
defined in [Appendix 12.3 Contraception Requirements] throughout the treatment period and 
for at least 30 days after the final study drug administration.
5.
Female subject who is of childbearing potential must agree not to breastfeed starting at screening 
and throughout the study and for 30 days after the final study drug administration.


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6.
Female subject who is of childbearing potential must not donate ova starting at screening, 
throughout the study, and for 30 days after the final study drug administration.
7.
A male subject with female partner(s) of childbearing potential must agree to use contraception as 
detailed in [Appendix 12.3 Contraception Requirements] during the treatment period and for at 
least 30 days after the final study drug administration.
8.
Male subject must not donate sperm starting at screening and throughout the study and for 
30 days after the final study drug administration.
9.
Subject and subject’s parent(s) or legal guardian agree that the subject will not participate in 
another interventional study while on treatment with the exception of oncology trials.
Waivers to the inclusion criteria will NOT be allowed.
Exclusion:
1.
Subject has familial short QT syndrome, is receiving medications that are known to shorten the 
QT interval, or has a clinically significant abnormal ECG.
2.
Subject has evidence of hepatic dysfunction defined as any of the following:
Total bilirubin ≥ 3 times the upper limit of normal (ULN)
Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 5 times the ULN
Known cirrhosis or chronic hepatic failure
3.
Subject has used strong cytochrome P450 (CYP3A4) inhibitors or inducers such as ketoconazole, 
high dose ritonavir, rifampin/rifampicin, long acting barbiturates (e.g., phenytoin), carbamazepine 
and St. John’s Wort in the 5 days prior to the first dose of study drug.
4.
Subject has another IFI other than possible, probable or proven IA or IM.
5.
Subject has chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis.
6.
Subject has received mould active systemic antifungal therapy, effective against the primary 
invasive mould infection, for more than 4 days during the 7 days preceding the first dose.
Note: Prior use of prophylactic antifungal therapy is acceptable. In case of breakthrough IA while 
on prophylactic mould-active azole class drugs, additional documentation will be required to be 
submitted to the sponsor medical monitor or designee to approve subject enrollment.
7.
Subject has known history of allergy, hypersensitivity or any serious reaction to any of the azole 
class antifungals, or any components of the study drug formulation.
8.
Subject has any condition, which, in the investigator’s opinion, makes the subject unsuitable for 
study participation.
9.
Subject is unlikely to survive 30 days in the investigator’s opinion.
10. Subject has received investigational drug, with the exception of oncology drug trials or trials with 
investigational drugs treating graft versus host disease, within 28 days or 5 half-lives, whichever 
is longer, prior to screening.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product(s):
Isavuconazonium sulfate, 372 mg, lyophilized powder for injection (200 mg isavuconazole)
Isavuconazonium sulfate 74.5 mg capsules (40 mg isavuconazole)


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Dose(s): 
The investigator may determine the appropriate route of administration for each subject. The 
investigator can switch between the 2 routes of administration (intravenous oral) throughout the 
treatment period as needed. Changes to route of administration will be documented.
Intravenous
Subjects weighing ≤ 37 kg:

Loading regimen of 10.0 mg/kg isavuconazonium sulfate infusions every 8 hours (± 2) for 
6 doses (days 1 and 2)

Maintenance dose of 10.0 mg/kg isavuconazonium sulfate administered once daily starting 12 to 
24 hours after the last loading dose
Subjects weighing > 37 kg:

Loading regimen of 372 mg isavuconazonium sulfate infusions (1 vial) every 8 hours (± 2) for 
6 doses (days 1 and 2)

Maintenance dose of 372 mg isavuconazonium sulfate (1 vial) administered once daily starting 
12 to 24 hours after the last loading dose
The maximum loading and daily maintenance doses to be administered to any subject are 372 mg per 
individual dose.
Oral (only for subjects 6 to < 18 years of age and with a body weight of at least 12 kg)
Subjects will receive an oral loading regimen of isavuconazonium sulfate in a capsule form given 
every 8 hours (± 2 hours) on days 1 and 2 (a total of 6 doses), followed by once-daily oral 
maintenance dosing. Isavuconazonium sulfate oral capsules can be administered with or without 
food. The first maintenance dose should start 12 to 24 hours after the administration of the last 
loading dose, with subsequent maintenance doses to be administered once daily, 24 hours ± 2 hours 
from the previous maintenance dose. Subjects who are discharged from the hospital with oral 
capsules for at-home administration must return weekly to receive new oral dosing supplies. Subjects 
who begin oral administration are to complete the oral dosing acceptability assessment after ingesting 
their first oral dose.
The daily dose is based on body weight and is intended to deliver a dose approximately equal to 
10 mg/kg. The oral and intravenous formulations are equivalent on a mg:mg basis. The lower limit for 
oral dosing is 6 years of age and a body weight of at least 12 kg.
Body Weight 
(kg)
Loading (Days 1 and 2)/Total Daily 
Isavuconazonium Sulfate Dose (mg)
Maintenance (up to 84 days [IA] or 
180 days [IM])/Total Daily 
Isavuconazonium Sulfate Dose (mg)
12 to < 18
3 × 2 capsules/447 mg
1 × 2 capsules/149 mg
18 to < 25
3 × 3 capsules/670.5 mg
1 × 3 capsules/223.5 mg
25 to < 32
3 × 4 capsules /894 mg
1 × 4 capsules/298 mg
≥ 32
3 × 5 capsules/1117.5 mg
1 × 5 capsules/372.5 mg
Route of Administration:
Either intravenous or oral as shown below:
Intravenous: 1-hour (± 10 minutes) intravenous infusion of isavuconazonium sulfate through an 
in-line filter.
Oral: Isavuconazonium sulfate will be administered orally.


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Comparative Drug(s):
Not applicable.
Concomitant Medication Restrictions or Requirements:
Treatments with concomitant drugs that are strong inhibitors or inducers of CYP3A4 are prohibited, 
including ketoconazole, high dose ritonavir, rifampin/rifampicin, carbamazepine and St. John’s Wort 
or long acting barbiturates (e.g., phenytoin). Concomitant use of sirolimus, atorvastatin, cyclosporine, 
tacrolimus, midazolam, bupropion, mycophenolate mofetil and digoxin should be made with caution.
Treatments with concurrent drugs that are CYP3A4 substrates and have a narrow therapeutic range 
(e.g., vincristine) should be used with caution, and if clinically warranted, consider reduction of 
substrate dose. 
Use of other systemic antifungals is prohibited during study drug administration.
Duration of Treatment
Treatment will be administered until the subject has a successful outcome as judged by the 
investigator or for a maximum duration of 84 days (IA) or 180 days (IM), whichever occurs first.
Investigator guidance of a successful outcome is provided in Table 4.
Formal Stopping Rules
Individual subject(s) must be discontinued from treatment for any of the following:
Subject requests to stop treatment. 
Any clinical AE, laboratory abnormality or intercurrent illness, in the opinion of the investigator, 
indicates continued treatment is not in the best interest of the subject.
Parent(s) or legal guardian withdraws consent.
Subject experiences a systemic infusion-related reaction (IRR) such as hypotension, dyspnea, 
chills, dizziness, paresthesia and hypoesthesia attributable to study drug during or shortly after the 
intravenous administration; however, in case of an infusion-related reaction, the infusion must be 
stopped immediately and the subject must be discontinued from treatment. 
Note: If the IRR signs and symptoms are mild and self-limiting, the subject may continue in the 
study at the discretion of the investigator.
●Serious hypersensitivity or severe skin reactions, such as anaphylaxis or Stevens Johnson 
syndrome, have been reported during treatment with other azoles. If subject develops a severe 
hypersensitivity adverse reaction without alternative etiology, the subject must be discontinued 
from treatment. 
Investigator’s decision that further treatment is not in the best interest of the subject.
Female subject becomes pregnant.
Subject is lost to follow-up despite diligent efforts to contact.
Discontinuation of the subject from treatment should also be considered if a subject experiences an 
increase in liver enzymes as follows:
ALT or AST > 8 × ULN.
ALT or AST > 5 × ULN for more than 2 weeks.
ALT or AST > 3 × ULN and (TBL > 2 x or International Normalized Ratio [INR] > 1.5) (If INR 
testing is applicable/evaluated).
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%).


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Endpoints for Evaluation:
Safety Endpoints:
Safety outcomes will include AEs, vital signs, ECGs and laboratory parameters.
Efficacy Endpoints:
The primary efficacy endpoint will be all-cause mortality through day 42.
The key secondary efficacy endpoint will be all-cause mortality through day 84 and EOT.
Additional secondary efficacy endpoints will be overall, clinical, radiological and mycological 
response through day 42, day 84 and at EOT.
Other Endpoints:
Plasma trough (pre-dose) levels will be measured on days 7, 14, 21, 42 and 84 or EOT. 
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any one day between 
day 14 and day 42, while the subject is still receiving study drug.
After receiving their first dose of oral capsules, subjects will be asked to assess their initial 
experience with the new oral formulation (i.e., Acceptability Assessment).
Statistical Methods:
This study is not designed to make statistical inferences. Data will be summarized using appropriate 
summary statistics. Categorical data will be described using absolute and relative frequencies (n and 
%). Continuous data will be presented using descriptive statistics (n, mean, standard deviation, 
minimum, median and maximum).
All variables will be listed in individual subject listings.
Sample Size Justification
A formal statistical justification of the sample size is not made. The sample size of approximately 
30 subjects is planned. Every effort will be made to achieve at least 5 evaluable subjects per age 
cohort: 1 to < 12 years of age and 12 to < 18 years of age. The sponsor reserves the right to stop 
enrollment if the cohort requirements are not achieved.
Safety
All AEs will be listed by subject and by age cohort. The incidence of the following AEs will be 
summarized by system organ class and preferred term for overall subjects and by subjects in each age 
cohort: overall, serious, related to study drug and leading to the permanent discontinuation of study 
drug.
Vital signs will be listed and summarized. Laboratory test values will be presented in shift tables and 
by individual listings with flagging of values outside the normal reference ranges. ECG findings will 
be presented by listings and frequency tables, as appropriate.
The incidence of treatment emergent AEs will also be summarized by relationship to study drug and 
severity for all subjects and by subjects in each age cohort.
Efficacy
Per each diagnosis (IA or IM) accrued, the crude all-cause mortality rates will be calculated by 
dividing the number of deaths by the number of subjects in the full analysis set (FAS) (i.e., all 
enrolled subjects who received at least one dose of study drug), and a 2-sided exact 95% CI will be 
calculated. Each subject will be classified as either death or alive. Subjects who died on or before 
day 42/day 84/EOT, as well as subjects who are lost to follow-up before day 42/day 84/EOT will be 
counted as deaths.


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Efficacy (continued)
Crude success rates and 2-sided exact 95% CIs will be calculated for the overall, clinical, radiological
and mycological response at day 42, day 84 and EOT in the FAS.
For each efficacy endpoint, a summary will be presented for overall subjects and by subjects in each 
age cohort.
Pharmacokinetics
Observed plasma concentration data for isavuconazole will be presented in listings. 
In addition, pharmacokinetic plasma concentrations will be analyzed using population 
pharmacokinetic model. Details of the model and modeling procedure will be provided in separate 
modeling report.
Pharmacodynamics
Not applicable.
Interim Analyses
Not applicable.
Data and Safety Monitoring Board and Adjudication Committees
A Data and Safety Monitoring Board will be utilized to monitor subject safety throughout the study.
An Adjudication Committee will be utilized to confirm the diagnosis and overall, clinical, 
radiological and mycological response of IA or IM.




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Table 1
Schedule of Assessments (IA and IM Subjects) – Screening through Day 84 and IA Follow-up (30 and 60 Days Post-Day 84 or 
EOT [Last Dose of Study Drug])
Period Screening
Treatment
IA Follow-up2
Day
-5 to 1 
(predose)
1
2
3
7
14
21
28
35
42
49
56
63
70
77
84 or IA 
EOT1
110 
(30 Day) 
IA or EOS
Day 140 
(60 Day) 
IA or EOS
Visit window (days)
none
none
none
none
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 7
± 7
± 7
ASSESSMENTS
Informed consent/assent
X
Verify eligibility criteria
X
X
Demographics
X
Medical/surgical history
EORTC/MSG diagnosis3
Physical examination
X
X
Height and weight4
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Routine 12-lead ECG6
X
X
X
X
X
X
X
Serum or BAL galactomannan
X
Efficacy response assessment7
Pharmacokinetic trough sampling8
X
X
X
X
X
Pharmacokinetic 24-hour sampling9
X
Clinical laboratory tests (chemistry, 
INR, hematology)10
X
X
X
X
X
Hepatic panel11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test12
X
X
X
X
Prior and concomitant medications13
AE14
Isavuconazonium sulfate dosing15
q8h
q8h
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral dosing acceptability assessment
X16
Mortality Status17
X
X
AE: adverse event; BAL: bronchoalveolar lavage; ECG: electrocardiogram; EORTC/MSG: European Organisation for Research and Treatment of Cancer/Mycoses Study Group; EOS: 
end of study; EOT: end of treatment; IA: invasive aspergillosis; IM: invasive mucormycosis; INR: international normalized ratio; q8h: once every 8 hours.
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1.
If subject discontinues study drug prior to day 84 for IA subjects, all EOT procedures must be completed. If subject continues to allow consent, EOS information to be 
collected on follow-up.
2.
Follow-up is to be completed 30 (± 7) and 60 days (± 7) post-last dose from day 84 or EOT for IA subjects, and may be performed via telephone at the discretion of 
the investigator.
3.
Diagnosis must be completed within 10 days of first dose.
4.
Height is to be collected at baseline only. Weight is to be taken at baseline and day 84 or EOT.
5.
Vital signs are to be measured within 1 hour prior to and approximately 1 hour after the end of each infusion. No additional vital signs are needed on dosing days for oral 
administration.
6.
12-lead ECG will be performed prior to study drug administration on each scheduled day.
7.
Record assessments that are performed during the study to document response to antifungal therapy (e.g., serum galactomannan, radiology, mycological tests, changes 
in clinical signs and symptoms and any surgical procedure).
8.
Pharmacokinetic trough samples should ideally be drawn immediately prior to the next dose of study drug, but must be taken no earlier than 1 hour prior to the next dose 
on days 7, 14, 21, 42 and 84 or EOT. 
9.
For both intravenous and oral dosing: 24-hour pharmacokinetic samples will be obtained on any one day between day 14 and day 42, while the subject is still receiving study 
drug, for subjects who consent to participation in the 24-hour pharmacokinetic assessment. The intravenous pharmacokinetic samples will be collected as follows: within 1 
hour prior to the start of the intravenous isavuconazonium sulfate infusion. This sample will be the same as the trough sample prior to dose, if it coincides with scheduled days 
14, 21 or 42, and immediately after the completion of the intravenous infusion (no more than 5 minutes after); and within 4 to 10 hours after the start of the intravenous 
infusion and within 16 to 24 hours after the start of the intravenous infusion (must be obtained before the start of the next infusion). 
The oral pharmacokinetic samples will be collected as follows: within 1 hour of the next oral dose (this sample will be the same as the trough sample prior to dose, if it 
coincides with scheduled days 14, 21 or 42); 1 hour post dose (± 10 minutes); 3 hours post dose (± 10 minutes); 4 hours post dose (± 10 minutes); within 6 to 8 hours 
(± 30 minutes) of study drug administration; and 24 hours (within 1 hour before next study drug administration) after study drug administration.
10. Clinical (safety) laboratory samples will be assessed by the local laboratory.
11. Hepatic panels will be collected at baseline, day 3, day 7 and then weekly thereafter while subjects are receiving study drug.
12. Pregnancy testing not applicable for male subjects. Not necessary for female subjects who are of non-childbearing potential (e.g., premenarchal in the judgment of 
the investigator on day 1 and throughout the study treatment, or documented surgically sterile). Pregnancy testing may be urine or serum, dependent upon institutional 
standard of care.
13. Concomitant medications are to be captured during the study and only related to AE’s during the 30- and 60-day follow-up period.
14. All AEs must be monitored until symptom resolution or until the condition stabilizes.
15. For both intravenous and oral dosing: Loading doses on days 1 and 2 will be administered every 8 (± 2) hours. The first maintenance dose should start 12 to 24 hours after the 
administration of the last loading dose. Subsequent maintenance doses will be administered once daily (24 ± 2 hours from the previous maintenance dose). Subjects who are 
discharged from the hospital with oral capsules for at-home administration must return weekly to receive new oral dosing supplies. Return visits should coincide with days 
when study-related assessments are required. Oral dosing is allowed for subjects 6 to < 18 years of age and with a body weight of at least 12 kg.
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16. Subjects who begin oral administration are to complete the oral dosing acceptability assessment after ingesting their first oral dose.
17. All-cause Mortality will be assessed on days 42 and 84 or EOT.


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Table 2
Extended Schedule of Assessments (IM Subjects) – Day 85 through Day 180 and IM Follow-up (30 and 60 days Post-Day 180 
[Last Dose of Study Drug])
Period
Treatment
Follow-up2
Day
85
115
145
180/IM or EOT1
210 (30 Day) IM 
or EOS
240 (60 Day) IM 
or EOS
Visit window (days)
± 2
± 2
± 2
± 7
± 7
± 7
ASSESSMENTS
Physical examination
X
Weight
X
Vital signs3
X
X
X
X
Routine 12-lead ECG4
X
X
X
X
Efficacy response assessment5
Clinical laboratory tests (chemistry, hematology, hepatic panel, INR)6
X
X
X
Pregnancy test7
X
Prior and concomitant medications8
AE9
Isavuconazonium sulfate dosing10
X
X
X
X
Oral dosing acceptability assessment
X11
Mortality Status12
X
AE: adverse event; EOS: end of study (30 days post-last dose); EOT: end of treatment (60 days post-last dose); IA: invasive aspergillosis; IM: invasive mucormycosis; 
INR: international normalized ratio
1. If subject discontinues study drug prior to day 180 for IM subjects, all EOT procedures must be completed. If subject continues to allow consent, EOS information to be 
collected on Follow-up.
2. Follow-up is to be completed 30 days (± 7) and 60 days (± 7) post-last dose from day 180/EOT for IM subjects; may be performed via telephone at the discretion of the investigator.
3. Vital signs are to be measured within 1 hour prior to and approximately 1 hour after the end of each infusion. No additional vital signs are needed on dosing days for oral 
administration.
4. 12-lead ECG will be performed prior to study drug administration on each scheduled day.
5. Record assessments that are performed during the study to document response to antifungal therapy (e.g., serum galactomannan, radiology, mycological tests, changes in 
clinical signs and symptoms and any surgical procedures).
6. Clinical (safety) laboratory samples will be assessed by the local laboratory. Clinical laboratory tests (chemistry, hematology, hepatic panel and INR) to be drawn monthly.
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7. Pregnancy testing not applicable for male subjects. Not necessary for female subjects who are of non-childbearing potential (e.g., premenarchal in the judgment of the 
investigator on day 1 and throughout the study treatment, or documented surgically sterile).
8. Concomitant medications are to be captured during the study and only related to AE’s during the 30- and 60-day follow-up period.
9. All AEs must be monitored until symptom resolution or until the condition stabilizes. 
10.For both intravenous and oral dosing: Subsequent maintenance doses will be administered once daily (24 ± 2 hours from the previous maintenance dose). Subjects who are 
discharged from the hospital with oral capsules for at-home administration must return weekly to receive new oral dosing supplies. Return visits should coincide with days when
study-related assessments are required. Oral dosing is allowed for subjects 6 to < 18 years of age and with a body weight of at least 12 kg.
11.Subjects who begin oral administration are to complete the oral dosing acceptability assessment after ingesting their first oral dose.
12.All-cause Mortality will be assessed at day 180 or EOT.


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1
INTRODUCTION
Isavuconazonium sulfate is a new azole antifungal agent that was approved for use in adults for 
the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) in the US and in 
Europe for treatment of IA; and for the treatment of IM in subjects for whom amphotericin B 
is inappropriate. These same invasive fungal pathogens are also important hospital-acquired
pathogens in critically-ill pediatric subjects, especially those with underlyingconditions 
compromising the immune system and there are currently very limited approved treatment 
options for pediatric subjects.
Therefore, establishing an efficacious and safe dosage regimen for isavuconazole for use in
pediatric subjects will provide important information for physicians treating these subjects.
1.1
Background
As in adults, fungal infections remain an important cause of morbidity and mortality in 
pediatric subjects. In immunocompromised pediatric subjects, invasive mould infections 
(IMIs) are a leading cause of mortality [Georgiadou et al, 2012; Al-Rezqi et al, 2009; Burgos 
et al, 2008; Walsh et al, 2008; Sung & Johnston, 2007; Zaoutis et al, 2006]. In a large 
prospective multinational study to evaluate the epidemiology and spectrum of IMIs in 
children, which enrolled 131 pediatric subjects with proven or probable IMIs, the most 
common diagnosis was IA (75%), followed by other IMIs (17%) and IM (13%) [Wattier et 
al, 2015]. A large proportion of these subjects had some underlying immunosuppression. 
Overall mortality was 30% at 12 weeks [Wattier et al, 2015]. Another study identified 
48 pediatric subjects with proven or probable IMIs from a retrospective single-center in the 
US [Georgiadou et al, 2012] and found similar trends with Aspergillus species being the most 
common organism and the majority of subjects being immunocompromised with hematologic 
malignancy and/or neutropenia. Overall mortality in this study was 31% at 12 weeks; in all 
subjects, death was attributed to both IMI and the underlying disease.
Invasive Aspergillosis: Risk factors and underlying disease characteristics for IA are 
comparable between adults and children with the most common being malignancy, such as 
acute myeloid leukemia (AML) and allogeneic hematopoietic stem cell transplant (HSCT). 
Chronic granulomatous disease, which is typically diagnosed in children, is also a risk factor 
[Dornbusch et al, 2009]. The Infectious Diseases Society of America guidelines for the 
treatment of IA do not distinguish between the disease characteristics in adults and children 
[Walsh et al, 2008]. Therefore, aside from systemic dosing differences, the treatment 
guidelines for these 2 populations do not differ.
Invasive Mucormycosis: IM is extremely rare and can occur not only in subjects with a 
severely compromised immune system, but also occasionally in subjects with traumatic 
injuries or in subjects with uncontrolled diabetes mellitus. IM is one of the most life-
threatening mould infections in subjects with hematologic malignancies and in HSCT 
recipients [Skiada et al, 2011; Chamilos et al, 2008; Roden et al, 2005]. In a 10-year (1997 to 
2006) retrospective study in France, the incidence of IM annually increased with age, from
0.3 per million in children less than 9 years to 3.9 per million subjects > 89 years; overall the 


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annual incidence was 0.9 per million subjects [Bitar et al, 2009]. The incidence is reportedly 
1/10 of the incidence of IA on average [Abidi et al, 2014].
Presentation and pathogenesis of the disease are similar between children and adults. 
Therefore, diagnosis and treatment recommendations are the same in both populations at risk.
Given the similarity of the pathogenesis and features of invasive fungal infection (IFI) 
between adults and pediatric subjects for both IA and IM, this IA and IM treatment study in 
children is designed to assess the safety of the proposed clinical dosage regimen. The 
proposed clinical dosage regimen is supported by a prior clinical pharmacokinetic and safety 
study in children. The dosage regimen generates exposures in the pediatric population that 
are consistent with the exposures achieved in adults receiving the recommended clinical dose 
for adults. The current pediatric study is intended to evaluate the safety and tolerability of 
isavuconazonium sulfate in the pediatric population from 1 to < 18 years of age.
1.2
Nonclinical and Clinical Data
An overview of the nonclinical and adult clinical data of isavuconazole can be found in the 
latest version of the investigator’s brochure (IB).
Isavuconazole has been investigated in a phase 1 pharmacokinetic, safety and tolerability 
study in pediatric subjects following intravenous administration. In this study, a total of 
27 pediatric subjects received at least 1 dose of study drug (Protocol 9766-CL-0046). Nine 
subjects were between 1 and < 6 years of age, 8 subjects were between 6 and < 12 years of 
age and 10 subjects were between 12 and < 18 years of age. A majority of subjects were 
white and male. Most subjects had an underlying malignancy. Subjects weighing ≤40 kg 
received 10 mg/kg of isavuconazonium sulfate, and subjects > 40 kg received 372 of 
isavuconazonium sulfate intravenously daily, after a loading regimen. 
The vast majority of subjects experienced at least 1 adverse event (AE), and serious adverse 
events (SAEs) were experienced by about half of all subjects, which is expected given the 
medical history of the subjects enrolled. About a third of subjects experienced drug-related 
AEs. Important drug-related events included gastrointestinal (GI) disorders and infusion-
related reactions. Two subjects were withdrawn from the study due to an AE. The events 
leading to withdrawal were increased liver enzymes and QT prolongation, and both events 
were considered related to study drug. No differences were observed in the AE experience 
between the 3 age cohorts.
1.3
Summary of Key Safety Information for Study Drugs
In the isavuconazole juvenile toxicity study, the no-observed-adverse-effect-level in rats was
determined to be 10 mg/kg per day. In this study, no toxicities were observed in pediatric 
sensitive organs. A summary of the juvenile toxicity study, as well as anoverview of the key 
isavuconazole safety data collected in adult subjects during theclinical development program 
can be found in the latest version of the IB.


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In addition, isavuconazonium sulfate has been investigated in one pediatric clinical study 
[Study 9766- CL-0046]. In this small study, important adverse reactions were GI disorders, 
rash, increased liver enzymes and infusion-related reactions.
1.4
Risk Benefit Assessment
The safety of isavuconazonium sulfate in pediatric subjects has been investigated in a study 
with a total of 27 subjects. In this small study, isavuconazonium sulfate appeared to be 
generally well-tolerated with a safety profile similar to that observed in adults. The efficacy 
of isavuconazonium sulfate in pediatric subjects has not yet been studied. It is expected that 
the dosage regimen used in the study will result in efficacious exposures in pediatric subjects 
and therefore subjects will likely benefit from participating in this study.
Subjects enrolled in this study may experience AEs, including previously unknownAEs
related to study drug or may experience procedural complications (e.g., bruising fromblood 
draws and slight skin irritation from the adhesive on the electrocardiogram [ECG]electrodes). 
While the proposed dosage regimen was established to minimize the number of subjects 
reaching exposures associated with increased toxicity in adults, some pediatric subjects could 
reach exposures that resulted in central nervous system and GI-type adverse effects in adults. 
Subjects with familial short QT syndrome are excluded from participation in this study. 
Pediatric subjects enrolled in this study will be closely monitored for AEs, especially for liver 
toxicity. Overall, based on the target population selected for this study, the exclusion criteria 
and theproposed dosage regimen, which matches adult efficacious exposures, the benefit and
risk assessment associated with the participation of pediatric subjects in this clinical study is 
favorable.
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS
2.1
Study Objective(s)
2.1.1
Safety Objective
To evaluate the safety and tolerability of isavuconazonium sulfate in pediatric subjects.
2.1.2
Efficacy Objective
To assess the efficacy of isavuconazonium sulfate for the treatment of IA or IM in pediatric 
subjects.
2.1.3
Pharmacokinetic Objective
To evaluate the pharmacokinetics of isavuconazole by monitoring the plasma concentrations 
in pediatric subjects during treatment with isavuconazonium sulfate.


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2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a phase 2, open-label, non-comparative, multicenter study to assess the safety and 
tolerability, efficacy and pharmacokinetics of isavuconazonium sulfate in pediatric subjects 
for the treatment of IA or IM.
An approved informed consent form (ICF) must be obtained from the subject’s parent or legal 
guardian, and, if required, pediatric assent prior to any study-related procedures being performed.
Approximately 30 centers in the US and EU are planned to enroll approximately 30 subjects 
1 to < 18 years of age with at least 25 subjects evaluable. Every effort will be made to 
achieve at least 5 evaluable subjects per age cohort below:
●
Cohort 1: 1 to < 12 years of age
●
Cohort 2: 12 to < 18 years of age
The sponsor reserves the right to stop enrollment if the cohort requirements are not achieved.
The subjects will enter into screening anytime between days -5 to day 1 (predose). All 
subjects will be assigned to open-label treatment via intravenous or oral treatment at the 
discretion of the investigator. The oral formulation can only be given to subjects 6 years to 
< 18 years of age and with a body weight of at least 12 kg. The route of administration may 
be changed per the investigator’s discretion as needed for treatment purposes as the resulting 
exposure from the 2 routes of administration is considered equivalent on a mg:mg basis. 
Treatment will begin on day 1, and then subjects will be followed for 60 days post-last dose 
for safety. Treatment will be administered until the subject has a successful outcome as 
judged by the investigator or for a maximum duration of 84 days (IA) or 180 days (IM), 
whichever occurs first. Investigator guidance of a successful outcome is provided in Table 4. 
Intravenous and Oral Dosing: Subjects will receive a loading regimen of isavuconazonium 
sulfate (via intravenous or oral administration at the investigator’s discretion), which consists 
of a 10 mg/kg dose every 8 hours (± 2 hours) on days 1 and 2 (for a total of 6 doses), 
followed by once daily maintenance 10 mg/kg dose for up to 84 days (IA) or 180 days (IM) 
of dosing. The first maintenance dose should start 12 to 24 hours after the administration of 
the last loading dose. Subsequent maintenance doses will be administered once daily (24 
hours ± 2 hours from the previous maintenance dose). Subjects who are discharged from the 
hospital with oral capsules for at-home administration must return weekly for study drug 
accountability and to receive new oral dosing supplies. Return visits should coincide with
days when study-related assessments are required. Subjects who begin oral administration are 
to complete the oral dosing acceptability assessment after ingesting their first oral dose.
Due to the similarity in exposure (AUC) between intravenous and oral in pediatric subjects, 
the investigator may change dosing between the 2 routes (intravenous oral) throughout the 
treatment as needed for treatment purposes. If the route of administration is changed after the 
2-day loading regimen is completed, there is no need to repeat the loading dose for the new 
route of administration. The total doses for the loading period should not exceed 6 study drug 


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administrations over the 2-day loading period, even if the route of administration is changed 
during the 2-day loading period. 
Blood sampling for the analysis of isavuconazole trough levels will be obtained from all 
subjects. The samples should ideally be drawn immediately prior to the next dose of study 
drug, but must be taken no earlier than 1 hour prior to the next dose on days 7, 14, 21, 42 and 
84 or end of treatment (EOT).
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any one day 
between day 14 and day 42, while the subject is still receiving study drug, for subjects who
consent to participation in the 24-hour pharmacokinetic assessment.
Subjects receiving intravenous administration:
The 24-hour pharmacokinetic samples will be obtained for intravenous dosing as follows: 
1. within 1 hour prior to the start of the intravenous isavuconazonium sulfate infusion (this 
sample will be the same as the trough sample prior to dose, if it coincides with scheduled 
days 14, 21 or 42);
2. immediately after the completion of the intravenous infusion (no more than 5 minutes 
after);
3. within 4 to 10 hours after the start of the intravenous infusion; and
4. within 16 to 24 hours after the start of the intravenous infusion (must be obtained before 
the start of the next infusion).
Subjects receiving oral administration:
The 24-hour pharmacokinetic samples will be obtained for oral dosing as follows:
1. within 1 hour of next oral dose (this sample will be the same as the trough sample prior 
to dose, if it coincides with scheduled days 14, 21 or 42);
2. 1 hour post dose (± 10 minutes);
3. 3 hours post dose (± 10 minutes);
4. 4 hours post dose (± 10 minutes);
5. within 6 to 8 hours (± 30 minutes) of study drug administration; and
6. 24 hours post dose (within 1 hour before next study drug administration) after study drug 
administration.
No additional samples will be taken from IM subjects after day 84.
Throughout the study, safety and tolerability will be assessed by the recording of AEs, vital 
signs, ECGs and safety laboratory evaluations. This includes assessments at 14 days, 28 days 
and 56 days. All subjects will complete 2 follow-up visits. At the discretion of the 
investigator, follow-up visits may be conducted via telephone with the subject, the subject’s 
parent or the subject’s legal guardian, 30 and 60 days after the subject’s day 84 (IA)/day 180 
(IM) or EOT visit.
If subject discontinues study drug prior to day 84 or day 180, all EOT procedures must be 
completed. If subject continues to allow consent, end of study (EOS) information will be 
collected 30 and 60 days after EOT.


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2.2.2
Dose Rationale
The safety and efficacy of isavuconazonium sulfate in adults has been demonstrated for the 
treatment of IA and IM. The clinical dosage regimen used to establish the safety and efficacy 
was 372 mg isavuconazonium sulfate (equivalent to 200 mg isavuconazole) every 8 hours for 
the first 2 days followed by 372 mg once daily thereafter. While dosing is reflected as 
milligrams of the administered prodrug (isavuconazonium sulfate), exposure is represented as 
milligrams of the active moiety (isavuconazole), which is immediately present in the 
systemic circulation.
An exposure-response analysis was conducted using data from adult subjects receiving 
isavuconazonium sulfate for the treatment of IA in the phase 3 SECURE clinical study [Study 
9766-CL-0104] and the population pharmacokinetic model [Company Report 9766-PK-0005; 
Desai et al, 2017]. The objective was to determine if there was a threshold of exposure or 
plasma concentration that was optimal for successful outcome in the adult subjects receiving 
isavuconazonium sulfate for the treatment of IA. For this analysis, plasma concentrations at 
day 7 (C7), day 14(C14) and at steady-state (Css) and steady-state area under the concentration-
time curve at 24 hours (AUC24) estimates simulated from the population pharmacokinetic
model in adults were used. No specific exposure parameter or threshold of exposure or 
concentration showed a significant relationship with any measure of response (i.e., all-cause 
mortality through day 42, all-cause mortality through day 84, overall response at end of therapy 
and overall response at day 42) observed in subjects from [Study 9766-CL-0104].
These results suggested that the exposures achieved by the clinical dosage regimen were 
adequate to treat the infecting organisms in subjects treated in the study.
In addition, the probability of target attainment analysis, which assessed the ability of the 
clinical dosage regimen to achieve the pharmacodynamic target defined by the experimental 
IA model, suggested that the clinical dosage regimen was adequate to cover the wild-type 
population of Aspergillus species according to the defined epidemiological cutoff values for 
isavuconazole [Espinel-Ingroff et al, 2013].
The efficacy described for IM was established based on exposure to the same clinical dosing 
regimen in adults; therefore, the expectation would be that the exposure required(median
AUCss of 89.6 mg·h/L) for this disease in children would be similar.
In order to establish the upper exposure target for the proposed pediatric dosing regimen for 
the proposed pediatric study, the safety information from 2 clinical studies in which doses 
higher than the clinical adult dose of isavuconazonium sulfate were administered were 
reviewed:
●
[Study 9766-CL-0102]: dose-ranging study in adult subjects with AML receiving doses 
upto 744 mg isavuconazonium sulfate and
●
[Study 9766-CL-0017]: thorough QT study with healthy adult subjects receivingdoses up 
to 1116 mg isavuconazonium sulfate.


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The mean AUC24 for subjects in the 1116 mg isavuconazonium sulfate groupwas 353 mg*h/L, 
and the minimum AUC24 in this dose group was 233 mg*h/L [Study 9766-CL-0017].
Population Pharmacokinetic Model for Pediatric Data
A pediatric population pharmacokinetic model was developed utilizing plasma concentration 
data from 27 subjects administered intravenous isavuconazonium sulfate from Part 1 of Study 
9766-CL-0046, 10 subjects administered oral dose from Part 2 of Study 9766-CL-0046 (12 to 
< 18 years of age) and 24 subjects from the 9766-CL-0018 study, an intravenous study in 
which subjects were administered single dose of 372 mg of isavuconazonium sulfate. The 
model was updated to include plasma concentration data from an additional 9 subjects from 
Part 2 of Study 9766-CL-0046 (6 to < 12 years of age), who were administered oral 
isavuconazonium sulfate.
Data was modeled using a nonlinear relationship with the following equation:
where P is the parameter of interest (clearance [CL] or volume of distribution
[Vd]),
WT is the weight in kg for the individual subject and x for the relevant 
allometriccomponent, which was fixed to 0.75 for CL related parameters and 
one for Vd related parameters
A 3-compartment model with combined zero order absorption, first order absorption and 
linear elimination described the data adequately. Inter-individual variability was observed on 
clearance, volume of distribution of central and peripheral compartment and 
inter-compartmental clearance.
Monte Carlo simulations were performed for 1000 randomly chosen subjects for each age 
group in pediatrics and 1000 to 5000 randomly chosen subjects for adult data. Area under the 
isavuconazole concentration-time curve at steady-state (AUCss) was calculated for each 
simulatedsubject. The dosing schedule for the simulation was similar to that for subjects in 
Study 9766-CL-0046, with subjects weighing ≤ 37 kg administered 10 mg/kg dose and 
subjects > 37 kg receiving the adult dose of 372 mg. 
Figure 2 compares pediatric exposures against exposures from Study 9766-CL-0104 
(SECURE), a successful phase 3 study in adults with IA, in which subjects received 
isavuconazonium sulfate via both intravenous and oral routes of administration and against 
data from Study 9766-CL-0103 (VITAL), a successful phase 3 adult study in subjects with 
IM and other rare invasive fungal infections, in which subjects received isavuconazonium 
sulfate via oral route of administration. The dosage regimen in both adult studies was similar.


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Figure 2
Box Plot of Isavuconazole Exposure Across Age Groups Including Adults 
in Phase 3 Program
Boxes represent the median and 25th and 75th percentiles, whiskers represent the range of 
maximum and minimum values within 1.5 × the interquartile range, and outliers are shown as 
circles. Dashed blue line is the lowest targeted value (25th percentile, with AUCss of 
60 mg*hr/L) based on exposures from SECURE study. Dashed green and orange lines are the 
minimum (233 mg*hr/L) and mean (353 mg*hr/L) AUCss values in a high dose adult study 
(1116 mg) with increased toxicity.
From the figure, it can be seen that exposures predicted for pediatric subjects across all age 
ranges for intravenous and for subjects 6 to < 18 years of age for the oral route of 
administration are within the efficacious range that was observed in adult studies.
An isavuconazonium sulfate dose of 10 mg/kg for all age groups weighing ≤37 kg and the
adult dose for pediatric subjects weighing > 37 kg provide mean exposures that were similar 
to and/or above the 372 mg adult dose and significantly below the 1116 mg dose group, 
where toxicities were observed. For intravenous, across all age groups, > 99% ofthe 
predicted AUCss values were below the mean AUC values for the adult population 
administered 1116 mg isavuconazonium sulfate dose and > 94% of the predicted AUCss
values were below the minimum adult AUCss values for the adult subject population 
administered the supra therapeutic dose clinical (1116 mg) dose [Study 9766-CL-0017]. For 
oral (12 to < 18 years of age), > 99% of the predicted AUCss values and > 98% of the 
predicted AUCss values were below the mean and minimum adult AUCss values from the 
9766-CL-0017 study. For oral (6 to < 12 years of age), > 99% of the predicted AUCss values 
and > 96% of the predicted AUCss values were below the mean and minimum adult AUCss
values from Study 9766-CL-0017.
Also, > 88% and approximately 80% of the predicted AUCss values for the intravenous and 
oral routes of administration were above the 25th percentile of exposure values from the 


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SECURE study in subjects who received 372 mg dose of isavuconazonium sulfate. Table 3 is 
updated based on simulations from the most recent population pharmacokinetic model that 
included oral data from subjects 6 to < 12years of age.
Table 3
Percentage of Pediatric Patients with Predicted AUCss Values of 
Isavuconazole Below or Above the Specified Adult AUC Values
Route
Age Group
% of Subjects 
Below Mean 
Adult AUC24
1116 mg Dose
% of Subjects 
Below Minimum 
Adult AUC24
1116 mg Dose
% of Subjects 
Above the 25th
Percentile Adults 
AUCss 372 mg Dose
Intravenous
1 to < 6 years
100%
97.0%
88.6%
6 to < 12 years
99.7%
94.0%
92.7%
12 to < 18 years
99.9%
98.2%
82.1%
Oral
6 to < 12 years
99.6%
96.4%
90.7%
12 to < 18 years
100%
98.2%
78.8%
Source: Data on file
AUC24: area under the concentration-time curve at 24 hours; AUCSS: area under the concentration-time curve at 
steady state
Based on modeling and simulation results, the proposed daily dose administered either as 
intravenous (across all age groups) or oral (6 years to < 18 years of age and with a body 
weight of at least 12 kg) for the clinical study in pediatric subjects is:
●
10 mg/kg isavuconazonium sulfate for subjects weighing ≤ 37 kg (the maximum loading
and daily maintenance doses to be administered to any subject are 372 mg)
OR
●
372 mg isavuconazonium sulfate for subjects weighing > 37 kg.
NOTE: The oral administration is only available for pediatric subjects 6 years and older due 
to the difficulty in swallowing the oral capsule.
Due to similarity in exposures between intravenous and oral in pediatric subjects, the route of 
administration can be switched from intravenous to oral and oral to intravenous, as needed. 
Currently, interchangeability of administration is permitted in adults in approved product 
labeling (US Package Insert). Isavuconazonium sulfate oral capsules can be administered 
with or without food.
2.3
Endpoints
2.3.1
Safety Endpoints
Safety outcomes will include AEs, vital signs, ECGs and laboratory parameters.
2.3.2
Efficacy Endpoints
The primary efficacy endpoint will be all-cause mortality through day 42. 
The key secondary efficacy endpoint will be all-cause mortality through day 84 and EOT.


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Additional secondary efficacy endpoints will be overall, clinical, radiological and 
mycological response through day 42, day 84 and EOT.
2.3.3
Other Endpoints
Other secondary endpoints encompass pharmacokinetic endpoints, including plasma trough 
(pre-dose) levels on days 7, 14, 21, 42 and 84 or EOT. 
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any one day 
between day 14 and day 42, while the subject is still receiving study drug.
After receiving their first dose of oral capsules, subjects will be asked to assess their initial 
experience with the new oral formulation (i.e., Acceptability Assessment [Appendix 12.7]).
The assessment is being conducted to assess the acceptability of the new oral formulation in a 
pediatric population. Refer to [Section 5.3.3 Oral Dosing Acceptability Assessment] for 
details regarding this assessment.
3
STUDY POPULATION
3.1
Selection of Study Population 
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-approved written informed consent and privacy 
language as per national regulations (e.g., Health Insurance Portability and 
Accountability Act Authorization) must be obtained from the subject’s parent or legal 
guardian and, if required, subject’s assent, prior to any study-related procedures 
(including withdrawal of prohibited medication, if applicable).
2.
Male or female subject 1 year to < 18 years of age diagnosed with IA or IM. A positive 
diagnosis is defined as follows:
●
Proven, probable or possible IFI per the European Organisation for Research and 
Treatment of Cancer/Mycoses Study Group [EORTC/MSG], 2008 criteria.
Note: Subjects with “possible” IFI will be eligible for enrollment; however, 
diagnostic tests to confirm the invasive fungal disease as “probable” or “proven” 
according to the EORTC/MSG criteria should be completed within 10 calendar 
days after the first dose of study drug.
o
Note: In addition to the criteria set for mycological criteria by the 
EORTC/MSG in 2008, and only for subjects with an underlying 
hematologic malignancy or recipients of HSCT who also have clinical and 
radiologic features consistent with invasive fungal infection, the following 
are acceptable: 
i. Galactomannan (GM) levels (optical density index) meeting the below 
criteria are acceptable mycological evidence for enrollment or 
upgrading the diagnosis to probable IA:


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1. A single value for serum or bronchoalveolar lavage (BAL) fluid 
of 1.0 or
2. Two serum GM values of 0.5 from 2 separate samples
3.
Subject has sufficient venous access to permit intravenous administration of study drug
or the ability to swallow oral capsules.
4.
A female subject is eligible to participate if she is not pregnant and at least one of the 
following conditions applies:
a.
Not a subject who is of childbearing potential as defined in [Appendix 12.3
Contraception Requirements].
OR
b. Subject who is of childbearing potential who agrees to follow the contraceptive 
guidance as defined in [Appendix 12.3 Contraception Requirements] throughout 
the treatment period and for at least 30 days after the final study drug 
administration.
5.
Female subject who is of childbearing potential must agree not to breastfeed starting at 
screening and throughout the study, and for 30 days after the final study drug 
administration.
6.
Female subject who is of childbearing potential must not donate ova starting at screening
and throughout the study, and for 30 days after the final study drug administration.
7.
A male subject with female partner(s) of childbearing potential must agree to use 
contraception as detailed in [Appendix 12.3 Contraception Requirements] during the 
treatment period and for at least 30 days after the final study drug administration.
8.
Male subject must not donate sperm starting at screening and throughout the study and 
for 30 days after the final study drug administration.
9.
Subject and subject’s parent(s) or legal guardian agree that the subject will not 
participate in another interventional study while on treatment with the exception of 
oncology trials. 
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject has familial short QT syndrome, is receiving medications that are known to 
shorten the QT interval, or has a clinically significant abnormal ECG.
2.
Subject has evidence of hepatic dysfunction defined as any of the following:
●Total bilirubin (TBL) ≥ 3 times the upper limit of normal (ULN)
●Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 5 times the ULN
●Known cirrhosis or chronic hepatic failure


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3.
Subject has used strong cytochrome P450 (CYP3A4) inhibitors or inducers such as 
ketoconazole, high dose ritonavir, rifampin/rifampicin, long acting barbiturates (e.g., 
phenytoin), carbamazepine and St. John’s Wort in the 5 days prior to the first dose of 
study drug.
4.
Subject has another IFI other than possible, probably or proven IA or IM.
5.
Subject has chronic aspergillosis, aspergilloma or allergic bronchopulmonary 
aspergillosis.
6.
Subject has received mould active systemic antifungal therapy, effective against the 
primary IMI, for more than 4 days during the 7 days preceding the first dose.
Note: Prior use of prophylactic antifungal therapy is acceptable. In case of breakthrough 
IA while on prophylactic mould-active azole class drugs, additional documentation will 
be required to be submitted to the sponsor medical monitor or designee to approve 
subject enrollment.
7.
Subject has known history of allergy, hypersensitivity or any serious reaction to any of 
the azole class antifungals, or any components of the study drug formulation.
8.
Subject has any condition, which, in the investigator’s opinion, makes the subject 
unsuitable for study participation.
9.
Subject is unlikely to survive 30 days in the investigator’s opinion.
10. Subject has received investigational drug, with the exception of oncology drug trials, or 
trials with investigational drugs treating graft versus host disease, within 28 days or 5 
half-lives, whichever is longer, prior to screening.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Study Drug(s)
The test drugs for this study are 372mg isavuconazole sulfate for injection or 74.5 mg 
isavuconazonium sulfate oral capsules.
Intravenous Dosing:
Isavuconazonium sulfate for injection is supplied in a single-dose vial as a sterile lyophilized 
white to yellow powder containing 372 mg of isavuconazonium sulfate, which is equivalent to 
200 mg of isavuconazole.
Store isavuconazonium sulfate for injection vials at 2°C to 8°C (36°F to 46°F) in a refrigerator.
For additional information regarding dosage preparation, refer to the product package insert 
or pharmacy manual.


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Oral Dosing:
Isavuconazonium sulfate will be supplied as oral capsules packaged in aluminum blisters 
with desiccants in secondary child-resistant cards. Each capsule contains 74.5 mg 
isavuconazonium sulfate (40 mg isavuconazole). The capsule is a Swedish orange color.
Store isavuconazonium sulfate capsules at 20°C to 25°C (68°F to 77°F) in the original 
packaging to protect from moisture.
Excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room 
Temperature]. For additional information, refer to the protocol-specific pharmacy manual.
4.1.2
Comparative Drug(s) 
Not applicable.
4.2
Packaging and Labeling
The study drug used in this study is the marketed commercial product, Cresemba® for injection
or investigational study drug for oral dosing. The study drug is prepared, packaged and labeled 
under the responsibilityof qualified staff at Astellas Pharma Global Development (APGD)-
Astellas US Technologies (AUST) or sponsor’s designee in accordance with APGD-AUST or 
sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, International Council for Harmonisation of technical requirements for 
registration of pharmaceuticals for human use (ICH) Good Clinical Practice (GCP) guidelines
and applicable local laws/regulations.
In addition to the commercial labeling, the intravenous study drug will bear a protocol label
conforming to regulatory guidelines, GMP and local laws and regulations that identifies the 
contentsas investigational drug. The oral study drug will only bear a protocol label 
conforming to regulatory guidelines, GMP and local laws and regulations that identifies the 
contents as investigational drug.
4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator/or designee and that:
●
Such deliveries are recorded,
●
Study drug is handled and stored according to labeled storage conditions,
●
Study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
Any unused study drug is returned to the sponsor.
Study drug inventory and accountability records will be kept by the investigator designee. 
Study drug accountability throughout the study must be documented and reconciled. The 
following guidelines are therefore pertinent:
●
The investigator designee agrees not to supply study drugs to any persons, except the 
eligible subjects in this study, in accordance with the protocol.


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●
The investigator designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs.
●
A study drug inventory will be maintained by investigator designee. The inventory will 
include details of material received and a clear record of when they were dispensed and 
to which subject.
●
At the conclusion or termination of this study, the investigator designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned study drug. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.
●
The site staff must return study drug to the sponsor or designee at the end of the study or 
upon expiration unless otherwise approved by the sponsor.
4.4
Blinding
This section is not applicable as this is an open-label study.
4.5
Assignment and Allocation
All subject numbers will be assigned using the Interactive Response Technology (IRT) starting 
at screening. All subjects will have a unique, 10-digit subject number. The first 5 digits of this 
number will be the investigator’s research number. The second 5 digits assigned will represent 
the subject’s accession number. This will be the number that identifies a subject during the 
course of the study.
Only subjects who meet all inclusion criteria and exhibit none of the exclusion criteria will be 
enrolled into the study through IRT. Specific procedures related to the IRT are contained in 
the study procedures manual.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
The isavuconazonium sulfate will be administered as an intravenous infusion or as oral 
capsule(s) per the investigator’s discretion. The 1-hour (± 10 minutes) intravenous infusion 
will be administered through an in-line filter. The start and stop times of the infusion must be
clearly documented. Oral administration is only for subjects 6 to < 18 years of age and with a 
body weight of at least 12 kg. The investigator may determine the appropriate route of 
administration for the subject in the context of the relevant age range. The route of 
administration can be interchangeable from intravenous to oral (6 to < 18 years of age with a 
body weight of at least 12 kg) or oral (6 to < 18 years of age and with a body weight of at 
least 12 kg) to intravenous during the loading dose period and throughout the treatment 


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period, the mg:mg is equivalent in both routes. The details of dose and route of 
administration will be captured in the electronic case report form (eCRF).
Treatment will be administered until the subject has a successful outcome as judged by the 
investigator or for a maximum duration of 84 days (IA) or 180 days (IM), whichever occurs 
first. Table 4 provides guidance to the investigator outlining the elements collectively 
informing a successful outcome. The investigator is encouraged to have clinical resolution of 
symptoms and associated mycological and/or radiologic data supporting the assessment of 
successful outcome.
Table 4
Investigator Guidance for Successful Outcome
Clinical 
Response
Mycological 
Response
Radiological 
Response
Success

Resolution of all attributable 
clinical symptoms and 
physical findings

Partial resolution of 
attributable clinical 
symptoms and physical 
findings

Eradication

Presumed 
Eradication

Improvement 
from screening

No signs on 
radiological 
images at 
screening (only 
for proven IFI
based on other 
investigations)
IFI: invasive fungal infection
Intravenous Dosing:
Subjects weighing ≤ 37 kg:
●
Loading regimen of 10.0 mg/kg isavuconazonium sulfate infusions every 8 hours (± 2) 
for 6 doses (days 1 and 2)
●
Maintenance dose of 10.0 mg/kg isavuconazonium sulfate administered once daily 
starting 12 to 24 hours after the last loading dose
The maximum loading and daily maintenance doses to be administered to any subject are 
372 mg per individual dose.
Subjects weighing > 37 kg:
●
Loading regimen of 372 mg isavuconazonium sulfate infusions (1 vial) every 8 hours 
(± 2) for 6 doses (days 1 and 2)
●
Maintenance dose of 372 mg isavuconazonium sulfate (1 vial) administered once daily
starting 12 to 24 hours after the last loading dose
The maximum loading and daily maintenance doses to be administered to any subject are 
372 mg per individual dose.
The maximum treatment is 84 days for IA subjects and 180 days for IM subjects, whichever 
occurs first.


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Subjects will receive isavuconazonium sulfate as an intravenous infusion. The first 
maintenancedose should start 12 to 24 hours after the administration of the last loading dose.
Subsequent maintenance doses will be administered once daily (24 hours ± 2 hours from the
previous maintenance dose).
Oral Dosing (for subjects 6 to < 18 years of age with a body weight of at least 12 kg):
Subjects will receive an oral loading regimen of isavuconazonium sulfate in a capsule form 
given every 8 hours (± 2 hours) on days 1 and 2 (a total of 6 doses), followed by once-daily 
oral maintenance dosing. The first maintenance dose should start 12 to 24 hours after the 
administration of the last loading dose, with subsequent maintenance doses to be 
administered once daily, 24 hours (± 2 hours) from the previous maintenance dose. Subjects 
who are discharged from the hospital with oral capsules for at-home administration must 
return weekly to receive new oral dosing supplies. Return visits should coincide with days 
when study-related assessments are required. Subjects who begin oral administration are to 
complete the oral dosing acceptability assessment after ingesting their first oral dose.
The daily dose is based on body weight and is intended to deliver a dose approximately equal 
to 10 mg/kg. The oral and intravenous formulations are equivalent on a mg:mg basis. The 
lower limit for oral dosing is 6 years of age and with a body weight of at least 12 kg.
Subjects will receive isavuconazonium sulfate as an oral capsule (the number of capsules will 
correspond to their weight; see Table 5).
Table 5
Oral Dosing Regimen by Body Weight
Body weight 
(kg)
Loading (Day 1 and Day 2)/Total Daily 
Isavuconazonium Sulfate Dose (mg)
Maintenance (up to 84 days [IA] or 
180 days [IM])/Total Daily 
Isavuconazonium Sulfate Dose (mg)
12 to < 18
3 × 2 capsules/447 mg
1 × 2 capsules/149 mg
18 to < 25
3 × 3 capsules/670.5 mg
1 × 3 capsules/223.5 mg
25 to < 32
3 × 4 capsules/894 mg
1 × 4 capsules/298 mg
≥ 32
3 × 5 capsules/1117.5 mg
1 × 5 capsules/372.5 mg
Increase or Reduction in Dose of the Study Drug(s)
The mg/kg dose is to be consistent throughout study conduct. Dose increase or reductions to 
the study drug on a mg/kg basis are not allowed. However, if a subject has substantial weight 
changes, the number of capsules for oral dosing should be reassessed per Table 5.
5.1.2
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy)
Systemic antifungal medications taken for IM or IA or suspected mycoses and other
medication taken within 28 days prior to the screening visit and up to the first dose of study


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drug (investigational period) will be documented as prior antimycotic medications or other
prior medication, respectively.
Medications taken after the first dose of study drug and up to EOS will be documented as 
concomitant medications.
Prior and concomitant medications and nonmedications to be documented include, but arenot
limited to, the following: vitamins, herbal remedies (e.g., St. John’s Wort, valerian) and 
over-the-counter and prescription medications. Any medications taken for treatment ofpain
symptoms will be documented assuch.
Subjects are instructed not to take any concomitant medication without first consulting the
investigator or study coordinator throughout the duration of the study.
Prohibited Therapies:
Treatments with concomitant drugs that are strong inhibitors or inducers of CYP3A4 are 
prohibited, including ketoconazole, high dose ritonavir, rifampin/rifampicin, carbamazepine 
and St. John’s Wort or long acting barbiturates (e.g., phenytoin). Concomitant use of 
sirolimus, atorvastatin, cyclosporine, tacrolimus, midazolam, bupropion, mycophenolate 
mofetil and digoxin should be made with caution.
Treatments with concurrent drugs that are CYP3A4 substrates and have a narrow therapeutic 
range (e.g., vincristine) should be used with caution, and if clinically warranted, consider 
reduction of substrate dose. 
Use of other systemic antifungals is prohibited during study drug administration.
Subjects taking prohibited medications who are willing to discontinue these medications, as
clinically indicated and based upon the investigator’s recommendation, may washout over a 
period of 5 half-lives on a schedule determined by the investigator.
5.1.3
Treatment Compliance
Study drug is administered at the research facility under the supervision of study personnel
while the subject remains as an inpatient.
If the subject is discharged while continuing treatment with intravenous dosing, the subject 
must return to the research facility or other approved location every day to receive the daily 
intravenous dose. Vital signs will be taken pre and post dose. Infusion reaction and other 
safety monitoring will be conducted. 
Subjects who are discharged from the hospital with oral capsules for at-home administration 
must return weekly for study drug accountability and to receive new oral dosing supplies.
Subjects will be provided with approximately 1-week worth of study medication, dosing 
instructions and a daily dosing log for documentation of ingestion of the oral study 
medication.
The subject or parent/legal guardian must record the date and time of oral dosing once the 
first capsule is ingested. The subject should ingest the entire dose within 5 minutes. If the
entire dose is not ingested within 5 minutes, record the reason for dosing delay in the source 


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documentation. If the subject should vomit any of the medication, this is to be recorded as 
well. The dose is NOT to be repeated. Compliance of the study drug will be monitored by 
review of the oral dosing log and the accounting of unused medication returned by the subject 
at each scheduled visit after day 7 and/or at the EOT visit.
When study drug is administered at the research facility, it will be administered under the 
supervision of study personnel. A subject daily dosing log will be collected to record 
date/time and completeness of dosing for each day.
Study subjects and their parents/legal guardians should be counseled on the need to meet 
100% compliance with study drug dosing. The investigator or designee should ensure that 
study subjects adhere to this goal throughout the study.
If compliance is less than 80%, the investigator or designee is to counsel the subject and 
ensure steps are taken to improve compliance. 
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic characteristics will be recorded at the screening visit. This will include age, 
sex, race, ethnicity (if known), height and body weight. Height and weight are to be measured 
while the subject is clothed, but not wearing shoes.
5.2.2
Medical History
The medical history of diseases other than the underlying diseases or conditions or infectious 
diseases will be identified at screening, by means of diagnosis and duration of the disease.
The medical history will include information related to the duration (i.e., the number of 
months or years). Subject’s relevant medical and surgical history must be documented.
5.2.2.1 Underlying Diseases or Conditions
At screening, all underlying diseases or other conditions that predispose the subject to IFIs 
will be recorded.
5.2.2.2 Infectious Disease History
History of all fungal, viral and bacterial infections within 14 days prior to screening will be 
recorded.
5.3
Efficacy and Pharmacokinetic Assessments
5.3.1
Efficacy Assessment
All clinical, mycological, radiological assessments and diagnostic tests performed to 
document the baseline mould infection must be recorded. Criteria for possible, probable and 
proven disease based on the EORTC/MSG criteria require evidence including host factors 
(neutropenia, hematological malignancy, etc.), mycological criteria (positive culture from 
normally sterile site, BAL fluid, serum or BAL GM and histology of tissue demonstrating the 


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presence of fungal elements), and clinical signs and symptoms (radiological evidence of 
fungal disease at the infected body site). These data will be recorded in the eCRF.
During treatment with study drug, record any tests performed to demonstrate changes from 
baseline or evaluate the status of the fungal infection, such as mycological evidence of fungal 
culture or histology results (positive and negative) from the relevant site of infection or any 
new site, new fungal infection, changes in clinical signs and symptoms, including 
radiological findings relevant to the baseline fungal infection under treatment, and any 
serological markers performed (serum GM) and any surgical procedures. Record any 
procedures conducted to further assess or treat the fungal infection such as surgical 
debridement, amputation, etc. and the results of such procedures. Negative results of tests 
demonstrating resolution of infection should also be documented and recorded in the eCRF. 
Mortality status will be assessed per [Table 1 and Table 2 Schedule of Assessments]. 
Every effort should be made to speciate and characterize any fungal organisms grown in 
cultures. Results of susceptibility testing done locally will be collected. Fungal isolates from 
all positive fungal cultures should be stored and a reference laboratory will be made available 
by the sponsor. The reference laboratory will provide confirmation of the fungal genus and 
species, as well as in vitro susceptibility to isavuconazole, as well as relevant mould-active 
antifungal drugs. The reference laboratory results will not be available until after the end of 
the study.
5.3.2
Pharmacokinetic Assessment
Blood samples will be collected for pharmacokinetic analysis of isavuconazole as depictedin 
[Table 1 and Table 2 Schedule of Assessments]. Blood sample collection, handling and 
storage will be described in the laboratory manual.
Blood sampling for the analysis of trough levels will be obtained from all subjects. The 
samples should ideally be drawn immediately prior to the dose of study drug, but must be 
taken no earlier than 1 hour prior to the dose on days 7, 14, 21, 42 and 84 or EOT. 
In addition to the above, 24-hour pharmacokinetic samples for intravenous or oral dosing will 
be obtained on any one day between day 14 and day 42, while the subject is still receiving 
study drug, for subjects who consent to participation in the 24-hour pharmacokinetic
assessment. The goal is to achieve approximately 6 subjects in each age cohort by the time 
enrollment is completed for the study.
The 24-hour intravenous pharmacokinetic samples will be obtained as follows:
1. within 1 hour prior to the start of the intravenous isavuconazonium sulfate infusion (this 
sample will be the same as the trough sample prior to dose if it coincides with scheduled 
days 14, 21 or 42);
2. immediately after the completion of the intravenous infusion (no more than 5 minutes 
after);
3. within 4 to 10 hours after the start of the intravenous infusion; and
4. within 16 to 24 hours after the start of the intravenous infusion (must be obtained before 
the start of the next infusion).


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The 24-hour oral pharmacokinetic samples will be obtained as follows:
1. within 1 hour of next oral dose (this sample will be the same as the trough sample prior 
to dose, if it coincides with scheduled days 14, 21 or 42);
2. 1 hour post dose (± 10 minutes);
3. 3 hours post does (± 10 minutes);
4. 4 hours post dose ( ± 10 minutes);
5. within 6 to 8 hours ( ± 30 minutes) of study drug administration; and
6. 24 hours (within 1 hour before next study drug administration) after study drug 
administration.
5.3.3
Oral Dosing Acceptability Assessment
This assessment will be conducted to assess the acceptability of the new oral formulation in 
this subject population. Subjects who begin oral administration of the study drug will 
complete an assessment shortly after taking their first oral dose. A 5-point hedonic scale 
rating the oral dosing is included on the assessment. There are 5 faces with descriptions from
really bad to really good that rank the response to the following questions:
●
How was the TASTE of the medication?
●
How was it to SWALLOW the medication?
●
How would you FEEL if you took this medication again?
Refer to [Appendix 12.7 Oral Dosing Acceptability Assessment].
5.4
Safety Assessment
5.4.1
Vital Signs
Vital signs (temperature, pulse rate and blood pressure) are to be measured within 1 hour 
before the start and approximately 1 hour after the end of each infusion on dosing days. No 
additional vital signs are needed on dosing days for oral administration. Temperature to be 
taken as per institution’s policy based on age of subject. Vital signs will be collected as 
shown in the schedule of assessments [Table 1 and Table 2]. When vital signs are scheduled 
for the same time as a blood sample, the vital signs will be taken before the blood sample.
5.4.2
Laboratory Assessments
Below is a table of the laboratory tests that will be performed during the conduct of the study 
and assessed by the local laboratory. In the event the protocol-specified clinical laboratoryhas 
already been collected and results available, these data are sufficient for monitoring safety as 
per the protocol and must be recorded in the eCRF. In order to minimize blood draws, it is not 
necessary to draw an additional sample for the sole purposes of the clinical trial.
Clinical laboratory samples should be collected at the same time as other blood samplessuch 
as pharmacokinetic whenever possible to minimize the need for unnecessary blood sampling 
for the subject. See [Table 1 and Table 2 Schedule of Assessment] for study visit days and 
allowed windows for lab sample collection.


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Chemistry:
Hematology:
Sodium
Red blood cells
Potassium
White blood cells (total leukocytes)
Magnesium
Hemoglobin
Calcium
Hematocrit
Chloride
Platelets (thrombocytes)
Glucose
Neutrophils (ANC)
Creatinine
Eosinophils
Creatine phosphokinase/Creatine kinase
Basophils
Alkaline phosphatase (ALP)
Lymphocytes
Monocytes
Blast cells
Hepatic Panel:
Pregnancy Test:
Albumin
Human chorionic gonadotropin (hCG)
Total bilirubin (TBL)
Direct Bilirubin
Other:
Total Protein
Serum galactomannan (GM)
Alanine aminotransferase (ALT)
Partial thromboplastin time/international 
normalized ratio (PTT/INR)
Aspartate aminotransferase (AST)
Clinically significant out-of-range laboratory findings are to be determined and documented 
by the investigator/subinvestigator who is a qualified physician. Clinically significant 
changes will be recorded as AEs. At all scheduled time points during the clinical study, 
should any of the clinical laboratory test results be outside the normal range, the investigator 
may decide to repeat tests on new samples. A urine or serum pregnancy test will be 
performed for female subjects of childbearing potential prior to dosing, day 28, day 42 and 
day 84 (IA) or EOT, day 180 (IM) or EOT.
5.4.3
Physical Examination 
Subjects will be examined by a medically qualified person at the times specified in [Table 1
and Table 2 Schedule of Assessments].
A complete physical examination consisting of an examination of general appearance, eyes,
nose, throat, neck (including thyroid), lymph nodes, chest, lungs, cardiovascular,abdomen, 
skin, extremities, musculoskeletal and neurological system including mental status is to be 
conducted. A symptom-directed physical exam may be performed during subsequent visits, if
necessary.
Height will be measured at screening only. Weight will be measured at screening, day 84 or 
EOT (IA and IM subjects) and/or day 180/EOT (IM subjects).
The screening physical examination also includes significant, ongoing medical conditions.
Any changes between screening and day 1 are to be captured in the medical history.


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Any abnormal finding(s) at screening must not be exclusionary per the eligibility criteria if a 
subject is to be enrolled in the study. Post initial study drug dosing, new abnormal findings or 
a worsening of an ongoing abnormal condition must be recorded as an AE.
5.4.4
Electrocardiogram 
Standard 12-lead ECG recordings will be used for the purposes of safety assessment by the
investigator.
A 12-lead, resting ECG is to be recorded, as indicated in [Table 1 and Table 2 Schedule of 
Assessments]. Subjects should remain supine for at least 5 minutes prior to all ECGs being 
performed. Dates and times may be generated by the machine’s internal clock and are 
considered source data. The results are to be interpreted by qualified personnel in real time. 
The principal investigator/ designee will initial and date and provide his/her clinical 
interpretation on each report. The results (normal, abnormal not clinically significant,
abnormal clinically significant) are to be recorded.
The ECG recorded during screening will be used to determine eligibility for study 
participation. Subjects who have familial short QT syndrome, or a clinicallysignificant 
abnormal ECG, will not be eligible for the study. The interpretation of the ECG from 
screening will be the baseline to which post study drug dosing ECGs will be compared.
ECGs will be performed at screening and prior to study drug administration on each 
scheduled day as indicated in [Table 1 and Table 2 Schedule of Assessments].
Unscheduled ECGs will be performed if clinicallyindicated.
The original printout and an electronic copy of all scheduled and unscheduled ECG tracings 
should be maintained on site as sourcedata.
5.4.5
Order of Assessments 
The following sequence order will be in effect when more than one assessment is required at
a time point with blood sampling for pharmacokinetics being collected nearest to the
scheduled time point:
1.
Vital signs
2.
ECG
3.
Laboratory assessments (hematology, chemistry and hepatic panel) blood draw
4.
Pharmacokinetic blood draw
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject administered a study drug, 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), 
symptom or disease (new or exacerbated) temporally associated with the use of a medicinal 
product whether or not considered related to the medicinal product.


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In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug treatment. AE collection begins after the signing of the ICF and will be 
collected until 60 days after the last dose of study drug or the subject is determined to be a 
screen failure.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.
5.5.1.1 Abnormal Laboratory Findings
Any abnormal laboratory test result (e.g., hematology, clinical chemistry, hepatic panel or 
INR) or other safety assessment (e.g., ECGs, vital signs measurements, physical 
examination), including those that worsen from baseline, that is considered to be clinically 
significant in the medical and scientific judgment of the investigator and not related to 
underlying disease, is to be reported as an SAE or AE ((S)AE).
Any clinically significant abnormal laboratory finding or other abnormal safety assessment 
which is associated with the underlying disease does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition.
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be an 
error does not require reporting as an AE.
5.5.1.2 Potential Cases of Drug-Induced Liver Injury
Refer to [Appendix 12.5 Liver Safety Monitoring and Assessment] for detailed instructions 
on drug induced liver injury. Abnormal values in AST and/or ALT concurrent or with 
abnormal elevations in TBL that meet the criteria outlined in [Appendix 12.5 Liver Safety 
Monitoring and Assessment], in the absence of other causes of liver injury, are considered 
potential cases of drug-induced liver injury (including potential Hy’s Law cases) and are 
always to be considered important medical events and reported per [Section 5.5.5 Reporting 
of Serious Adverse Events].
5.5.1.3 Disease Progression and Study Endpoints
Under this protocol, the following event(s) will not be considered as an (S)AE:
●
Pre-planned and elective hospitalizations or procedures for diagnostic, therapeutic or 
surgical procedures for a pre-existing condition that did not worsen during the course of 
the clinical trial. These procedures are collected per the eCRFs Completion Guidelines.


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5.5.2
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:
●
Results in death
●
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
Results in congenital anomaly or birth defect
●
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE). Hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious.
●
Other medically important events (defined in paragraph below)
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
usually are considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.
5.5.2.1 Always Serious Adverse Events
The sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered by the sponsor to be an SAE per this classification as “always 
serious”, additional information on the event (e.g., investigator confirmation of seriousness,
causality) will be requested.
5.5.3
Criteria for Causal Relationship to Study Drug
A medically qualified investigator is obligated to assess the relationship between the study 
drug and each occurrence of each (S)AE. This medically qualified investigator will use 
medical judgment, as well as the Reference Safety Information (refer to the IB) to determine 
the relationship. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
The medically qualified investigator is requested to provide an explanation for the causality 
assessment for each (S)AE and must document in the medical notes that he/she has reviewed 
the (S)AE and has provided an assessment of causality.


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Following a review of the relevant data, the causal relationship between the study drug and 
each (S)AE will be assessed by answering ‘yes’ or ‘no’ to the question “Do you consider 
that there is a reasonable possibility that the event may have been caused by the study 
drug”.
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study drug (rather than a relationship cannot be 
ruled out) or if there is evidence to reasonably deny a causal relationship:
●
Plausible temporal relationship between exposure to the study drug and (S)AE onset 
and/or resolution. Has the subject actually received the study drug? Did the (S)AE occur 
in a reasonable temporal relationship to the administration of the study drug? 
●
Plausibility; i.e., could the event been caused by the study drug? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and clinical study data, etc.
●
Laboratory or other test results; a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the study drug (e.g., based on values pre-, during 
and post-treatment)
●
Available alternative explanations independent of study drug exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc. and strength of the alternative 
explanation
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that 
the medically qualified investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor. With limited or insufficient 
information about the event to make an informed medical judgment and in absence of any 
indication or evidence to establish a causal relationship, a causality assessment of ‘no’ is to 
be considered. In such instance, the investigator is expected to obtain additional information 
regarding the event as soon as possible and to re-evaluate the causality upon receipt of 
additional information. The medically qualified investigator may revise his/her assessment of 
causality in light of new information regarding the SAE and shall send an SAE follow-up 
report and update the eCRF with the new information and updated causality assessment.
5.5.4
Criteria for Defining the Severity of an Adverse Event
The investigator will use the following definitions to rate the severity of each AE:
●
Mild: 
No disruption of normal daily activities
●
Moderate:Affect normal daily activities
●
Severe: 
Inability to perform daily activities


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5.5.5
Reporting of Serious Adverse Events (SAEs)
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
ICF and will continue until 60 days after last administration of study drug or the subject is 
determined to be a screen failure.
In the case of a SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness).
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by email or fax immediately 
(within 24 hours of awareness).
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
Delegation of Authority Log). Signature confirms accuracy and completeness of the SAE 
data, as well as the investigator causality assessment including the explanation for the 
causality assessment.
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE/Special Situations worksheet to:
Astellas Pharma Global Development – US
Pharmacovigilance
Fax number +1-888-396-3750 or +1-847-317-1241
Email: Safety-US@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's medical monitor/study physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel]. 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should be recorded on the medical records, SAE/Special Situation 
Worksheet and on the eCRF.
The following minimum information is required:
●
International study number/study number,
●
subject number, sex and age,
●
the date of report,
●
a description of the SAE (event, seriousness criteria),
●
causal relationship to the study drug (including reason), and
●
the drug provided (if any).
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality and
expectedness of the events (e.g., Suspected Unexpected Serious Adverse Reaction [SUSAR]
reporting) according to current local/regional regulatory requirements in participating 
countries. The sponsor or sponsor's designee will submit expedited safety reports (e.g., IND 


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Safety Reports, SUSAR, Council for International Organizations of Medical Sciences 
[CIOMS] Form I) to Competent Authorities (CA) and concerned Ethics Committee (cEC) per 
current local regulations, and will inform the investigators of such regulatory reports as 
required. Investigators must submit safety reports as required by their IRB/local Independent 
Ethics Committee (IEC) within timelines set by regional regulations (e.g., EMA, FDA) where 
required. Documentation of the submission to and receipt by the IRB/local IEC of expedited 
safety reports should be retained by the site.
The sponsor will notify all investigators responsible for ongoing clinical studies with the 
study drug of all SUSARs, which require submission per local requirements.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor.
The investigator may contact the sponsor's medical monitor/study physician for any other 
problem related to the safety, welfare or rights of the subject.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator.
If after the protocol defined AE collection period [see Section 5.5.1 Definition of Adverse 
Event], an AE progresses to a SAE, or the investigator learns of any (S)AE including death, 
where he/she considers there is reasonable possibility it is related to the study drug treatment 
or study participation, the investigator must promptly notify the sponsor.
5.5.7
Monitoring of Common Serious Adverse Events
Not applicable for this study.
5.5.8
Special Situations 
Certain special situations observed in association with the study drug, such as incorrect 
administration (e.g., wrong dose of study drug) are collected in the eCRF, as protocol 
deviation per [Section 8.3 Major Protocol Deviations] or may require special reporting, as 
described below. These special situations are not considered AEs, but do require to be 
communicated to Astellas as per the timelines defined below.
If a special situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the special situation and captured as an AE in the eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.5.5 Reporting of 
Serious Adverse Events] and the details of the associated special situation are to be included 
in the clinical description on the SAE worksheet.


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The special situations are:
●
Pregnancy 
●
Medication error, overdose and “off-label use”
●
Misuse/abuse
●
Occupational exposure
●
Suspected drug-drug or other (e.g., food) interaction
●
(Suspicion of) Transmission of infectious agent 
Table 6 provides a list of special situations along with how each should be reported.
Table 6
Special Situations
Special Situation
Collected
SAE/Special
Situations Worksheet
eCRF
Protocol Deviation
[Section 8.3]
Overdose of the medicinal product(s)
[Section 5.5.8.2]
X
Suspected misuse/abuse of the
investigational medicinalproduct
X
X
Occupational exposure
X
Suspected drug-drug or other interaction
X
Off-label use of study drug
X
Pregnancy
X
X
Medication error
X
eCRF: electronic case report form; SAE: serious adverseevent
5.5.8.1 Pregnancy
If a female subject becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 5.5.5 Reporting of Serious Adverse Events] using the 
Pregnancy Reporting Form and in the eCRF.
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 30 days from 
the discontinuation of dosing and report the information to the sponsor according to the 
timelines in [Section 5.5.5 Reporting of Serious Adverse Events] using the Pregnancy 
Reporting Form. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
study subject as an AE in the eCRF or SAE per [Section 5.5.5 Reporting of Serious Adverse 


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Events]. For (S)AEs experienced by a female partner of a male subject, (S)AEs are to be 
reported via the Pregnancy Reporting Form. 
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below:
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion.
●
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the study drug.
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator.
●
Congenital anomaly (including anomaly in miscarried fetus)
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination. (S)AEs 
experienced by the newborn/infant should be reported via the Pregnancy Reporting Form. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.
5.5.8.2 Medication Error, Overdose and “Off-label Use”
If a medication error, overdose or “off-label use” (i.e., use outside of what is stated in the 
protocol) is suspected, refer to [Section 8.3 Major Protocol Deviations]. Any associated (S)AEs 
are to be reported in the eCRF. If the AE meets the definition of a SAE, the SAE is also to be 
reported as described in [Section 5.5.5 Reporting of Serious Adverse Events] together with the 
details of the medication error, overdose and/or “off-label use”.
In the event of suspected isavuconazonium sulfate overdose, the subject should receive 
supportive care and monitoring. At supratherapeutic doses (equivalent to isavuconazole 
600 mg/day maintenance dose) evaluated in a thorough QT study in adults, there were 
proportionally more treatment-emergent adverse events (TEAEs) than in the therapeutic dose 
group (equivalent to isavuconazole 200 mg/day maintenance dose) for the following: headache, 
dizziness, paraesthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhoea, 
oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, 
photophobia and arthralgia. Isavuconazole is not removed by hemodialysis.
There is no specific antidote for isavuconazole.
The medical monitor should be contacted as applicable.
5.5.8.3 Misuse/Abuse
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the special 
situation worksheet to the sponsor by fax or email immediately (within 24 hours of 
awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of a SAE, the SAE is also to be reported as described in [Section 5.5.5 Reporting 
of Serious Adverse Events] together with details of the misuse or abuse of the study drug(s).


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5.5.8.4 Occupational Exposure
If occupational exposure (e.g., inadvertent exposure to the study drug of site staff while 
preparing it for administration to the subject) to the study drug occurs, the investigator must 
forward the Special Situation worksheet to the sponsor by fax or email immediately (within 
24 hours of awareness). Any associated (S)AEs occurring to the individual associated with or 
resulting from the Special Situation are to be reported on the Special Situations worksheet.
5.5.9
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study, as well as 
the regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed. 
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the clinical study.
5.5.10
Urgent Safety Measures
An urgent safety measure (USM) is an intervention, which is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant CA, IRB/IEC, where applicable, in order to protect study participants from 
any immediate hazard to their health and/or safety. Either the investigator or the sponsor can 
initiate an USM. The cause of an USM can be safety, product or procedure related. 
5.5.11
Reporting Urgent Safety Measures
In the event of a potential USM, the investigator must contact the Astellas study physician
(within 24 hours of awareness). Full details of the potential USM are to be recorded in the 
subject’s medical records. The sponsor may request additional information related to the 
event to support their evaluation.
If the event is confirmed to be an USM the sponsor will take appropriate action to ensure the 
safety and welfare of the subjects. These actions may include, but are not limited to, a change 
in study procedures or study treatment, halting further enrollment in the trial, or stopping the 
study in its entirety. The sponsor or sponsor's designee will notify CA and cEC within the 
timelines required per current local regulations, and will inform the investigators as required. 
When required, investigators must notify their IRB/IEC within timelines set by regional 
regulations.
5.6
Test Drug Concentration
Plasma concentrations of isavuconazole will be analyzed to monitor the levels of isavuconazole 
in the subject population during treatment. For the purpose of this study, serial blood samples 
(approximately 1 mL) will be collected in 1-mL potassium ethylenediaminetetraacetic acid.
Vacutainer tubes for each scheduled nominal time point on days 7, 14, 21, 42 and day 84 or 
EOT. The samples should ideally be drawn immediately prior to the dose of study drug, must 
be taken no earlier than 1 hour prior.


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In addition to the above, 24-hour pharmacokinetic samples will be obtained on any day 
between day 14 and day 42, while the subject is still receiving study drug, for subjects who
consent to participation in the 24-hour pharmacokinetic assessment. The goal is to achieve 
approximately 6 subjects in each age cohort by the time enrollment is completed for the study.
The intravenous pharmacokinetic samples will be obtained as follows:
1. within 1 hour prior to the start of the intravenous isavuconazonium sulfate infusion (this 
sample will be the same as the trough sample prior to dose if it coincides with scheduled 
days 14, 21 or 42);
2. immediately after the completion of the intravenous infusion (no more than 5 minutes after);
3. within 4 to 10 hours after the start of the intravenous infusion; and
4. within 16 to 24 hours after the start of the intravenous infusion (must be obtained before 
the start of the next infusion).
The oral pharmacokinetic samples will be obtained as follows:
1. within 1 hour prior to the next oral dose (this sample will be the same as the trough 
sample prior to dose if it coincides with scheduled days 14, 21 or 42);
2. 1 hour post dose (± 10 minutes);
3. 3 hours post dose (± 10 minutes);
4. 4 hours post dose (± 10 minutes); 
5. within 6 to 8 hours (± 30 minutes) of study drug administration; and
6. 24 hours (within 1 hour before next study drug administration) after study drug 
administration.
No additional pharmacokinetic samples will be taken from IM subjects during days 85 to 180.
Immediately after each sample collection, gently invert the blood sample 8 to 10 times and 
place in anice water bath. Within 1 hour of sample collection, centrifuge the blood sample(s) 
at 1200 gfor 10 minutes at approximately 4°C in order to obtain plasma.
Plasma will be harvested and divided equally into 2 (primary and back-up) appropriately 
labeled storage tubes.
Store the plasma samples in a freezer set to maintain -20°C ± 10°C or lowerimmediately 
following centrifugation and separation.
Primary and back-up samples will be shipped separately to the bioanalyticallaboratory.
5.7
Other Measurements, Assessments or Methods
Not applicable.
5.8
Total Amount of Blood
The total blood volume to be collected on subjects 1 to < 18 years of age forthe study 
through day 84 or EOT should not be more than 45 mL. Table 7 provides the amount of 
blood drawn for each laboratory parameters and study visit for these subjects.


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Table 7
Total Amount of Blood Drawn
Parameter
Study Visit
Total 
Volume
Screening
Labs:
Days 7, 28, 
56 and 84 or 
EOT
Pharmaco-
kinetics:
Days 7, 14, 
21, 42 and 84 or 
EOT
Days 3, 14, 21, 
35, 42, 49, 63, 
70 and 77
IV Pharmaco-
kinetics:
24-hour 
Sampling Day 
Anytime 
Between 
Days 14 and 42
Oral Pharmaco-
kinetics: 24-
hour Sampling 
Day Anytime 
Between Days 
14 and 42
Hematology
2 mL
2 mL/visit
(8 mL)
N/A
N/A
N/A
N/A
10 mL
Chemistry
2 mL
2 mL/visit
(8 mL)
N/A
N/A
N/A
N/A
10 mL
Hepatic Panel
*
*
N/A
1 mL/visit
(9 mL)
N/A
N/A
9 mL
Serum GM
2 mL
N/A
N/A
N/A
N/A
N/A
2 mL
Pharmacokinetics
N/A
N/A
1 mL/visit
(5 mL)
N/A
1 mL/time point 
(4 mL)
1 mL/time point 
(7 mL)
9 mL or 12 
mL
PT/INR
1 mL
1 mL/visit
(4 mL)
N/A
N/A
N/A
N/A
5 mL
TOTAL
7 mL
20 mL
5 mL
9 mL
4 mL
7 mL
45 mL 
(IV 24-hr 
PK) 
-OR-
48 mL 
(Oral 24-hr 
PK)
EOT: end of treatment; GM: galactomannan; INR: international normalized ratio; IV: intravenous; N/A: not 
applicable; PK: pharmacokinetics; PT: prothrombin time
* Included with chemistry
The total blood volume to be collected on IM subjects 1 to < 18 years of age during the IM 
follow-up period should not be more than 15 mL. Table 8 provides the amount of blood 
drawn for each laboratory parameters for these subjects.
Table 8
Blood Drawn During IM Follow-up
Parameter
Study Visits
Days 115, 145 and 180 or EOT
Approximate Total 
Volume
Hematology
2 mL/visit (6 mL)
6 mL
Chemistry
2 mL/visit (6 mL)
6 mL
Hepatic Panel
*
N/A
PT/INR
1 mL/visit (3 mL)
3 mL
TOTAL
15 mL
15 mL
*Hepatic panel to be drawn with chemistry panel.
INR: international normalized ratio; PT: prothrombin time
Regarding the protocol-specified clinical laboratory, if clinical safety laboratory resultsare
already available, these data are sufficient for monitoring safety as per the protocol and must 
be recorded in the eCRF. In order to minimize blood draws, it is not necessary to draw an 
additional sample for the sole purposes of the clinical trial.


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6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) From Study Treatment 
A discontinuation from treatment is a subject who enrolled in the study and for whom study 
treatment is permanently discontinued for any reason. The reason for discontinuation from 
study treatment must be documented in the subject’s medical records.
A subject must discontinue study treatment for any of the following reasons:
●
Subject requests to stop treatment. 
●
Any clinical AE, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued treatment is not in the best interest of the subject.
●
Parent(s) or legal guardian withdraws consent.
●
Subject experiences a systemic infusion-related reaction (IRR) such as hypotension,
dyspnea, chills, dizziness, paresthesia and hypoesthesia attributable to study drug during 
or shortly after the intravenous administration; however, in case of an infusion-related 
reaction, the infusion must be stopped immediately and the subject must be discontinued 
from treatment.
Note: If the IRR signs and symptoms are mild and self-limiting, the subject may
continue in the study at the discretion of the investigator.
●
Serious hypersensitivity or severe skin reactions, such as anaphylaxis or Stevens Johnson 
syndrome, have been reported during treatment with other azoles. If subject develops a 
severe hypersensitivity adverse reaction without alternative etiology, the subject must be 
discontinued from treatment.
●
Investigator’s decision that further treatment is not in the best interest of the subject.
●
Female subject becomes pregnant.
●
Subject is lost to follow-up despite diligent efforts to contact.
Discontinuation of the subject from treatment should be considered if a subject experiences 
an increase in liver enzymes. For specific liver abnormalities, refer to [Appendix 12.5].
All subjects who discontinue study treatment will remain in the study and should continue to 
be followed for protocol specific follow-up procedures as outlined in [Table 1 Schedule of 
Assessments]. The only exception to this is when the subject specifically withdraws consent 
for any further contact, with him/her or persons previously authorized by the participant to 
provide this information.
6.1.1
Lost to Follow-up
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments and record outstanding data.
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must
immediately inform the sponsor.


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6.3
Discontinuation of the Study
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
A statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database soft lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the clinical study report.
In general, continuous data will be summarized with descriptive statistics (number of 
subjects, mean, standard deviation, minimum, median and maximum) and frequency and 
percentage for categorical data.
7.1
Sample Size
A sample size of approximately 30 subjects is planned. No formal sample size calculation 
was performed.
Evaluable subjects are subjects who have received at least 1 dose of study drug. Every effort 
will be made to achieve at least 5 evaluable subjects per age cohort: 1 to < 12 years of age 
and 12 to < 18 years of age. The sponsor reserves the right to stop enrollment if the cohort 
requirements are not achieved. There will be no replacements for any subject that is enrolled, 
but later determined to be non-eligible.
7.2
Analysis Sets
Detailed criteria for analysis sets will be laid out in classification specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 
7.2.1
Full Analysis Set (FAS)
The full analysis set (FAS) will consist of all subjects who are enrolled and receive at least 
one dose of study drug. This will be the primary analysis set for efficacy analyses.
7.2.2
Modified Full Analysis Set (mFAS)
The modified FAS (mFAS) will consist of the subset of the FAS subjects who have either 
probable or proven IA or IM diagnosis at baseline or up to 10 days after first dose. The 
mFAS will be a secondary analysis set for efficacy analyses. Select demographic and 
baseline characteristics may also be summarized for the mFAS.


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7.2.3
Safety Analysis Set (SAF)
The safety analysis set (SAF) will consist of all subjects who are enrolled and receive at least 
1 dose of study drug and will be used for safety analyses. For this study, the SAF is the same 
as the FAS. For the statistical summary of the safety data, the SAF will be used.
7.2.4
Pharmacokinetic Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) consists of all subjects who took at least 1 dose of 
study drug and who have at least 1 plasma concentration. Inclusion of subjects in the PKAS 
with missing data or major protocol deviations will be considered by the pharmacokineticist 
on a case-by-case basis.
The PKAS will be used for all summaries and analyses of the pharmacokinetic data.
7.3
Demographics and Baseline Characteristics
Demographics and baseline characteristics (age, sex, race, ethnicity, weight, height and body 
mass index) will be summarized for each analysis set.
7.3.1
Subject Disposition 
The number and percentage of subjects who completed and discontinued treatment and reasons 
for treatment discontinuation will be presented for all enrolled subjects and for subjects in the 
SAF by age cohort and overall. Similar tables for screening disposition, investigational period 
disposition and follow-up disposition will also be presented for all enrolled subjects by age 
cohort and overall. All disposition details and dates of first and last evaluations for each subject 
will be listed.
7.3.2
Previous and Concomitant Medications
All previous and concomitant medications will be summarized for subjects in FAS and SAF 
analysis sets and will also be presented in listings.
7.3.3
Medical History
Medical history for each subject will be presented in a listing.
7.4
Analysis of Efficacy
This is an open-label trial without a comparator group, and its analysis will be descriptive. No 
formal inferential analyses will be performed. Appropriate confidence intervals (CI) will be 
part of the description/summary of the data. Efficacy variables will be summarized with 
frequencies and percentages for the FAS and mFAS sets unless otherwise specified. For each 
efficacy endpoint, a summary will be presented for overall subjects and by subjects in each 
age cohort.


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7.4.1
Analysis of Primary Efficacy Endpoint 
7.4.1.1 Primary Efficacy Analysis
The primary efficacy endpoint of crude rate in all-cause mortality through day 42 will be 
analyzed on FAS population as a primary analysis. Any death that occurred after first dose of 
study drug through day 42 will be included.
Each subject will be classified as either a death or alive. Subjects who died on or before day 
42, as well as subjects who are lost to follow-up before day 42 will be counted as deaths. The 
crude all-cause mortality rate will be calculated by dividing the number of deaths by the 
number of FAS subjects, and a 2-sided exact 95% CI will be calculated.
7.4.1.2 Secondary Efficacy Analysis
The same analysis of the primary endpoint as described in [Section 7.4.1 Primary Analysis]
will be conducted using the mFAS.
7.4.2
Analysis of Secondary Efficacy Endpoints
7.4.2.1 Analysis of Key Secondary Endpoints
Crude rate in all-cause mortality through day 84/EOT is considered as key secondary efficacy 
endpoint, which will be analyzed as described in [Section 7.4.1 Primary Analysis] for FAS and 
mFAS analysis sets. Any death that occurred after first dose of study drug through day 84/EOT 
will be included.
Subjects who die on or before day 84/EOT, as well as subjects who are lost to follow-up 
before day 84/EOT, will be counted as deaths.
7.4.2.2 Analysis of Additional Secondary Endpoints
Additional secondary efficacy endpoints include the overall, clinical, radiological and 
mycological response through day 42, day 84 and EOT. An Adjudication Committee (AC) 
will be utilized to confirm the diagnosis and overall, clinical, radiological and mycological 
response of IA or IM at each time point.
Crude success rates and 2-sided exact 95% CIs will be calculated and summarized for FAS 
and mFAS analysis sets.
7.5
Analysis of Safety
7.5.1
Adverse Events
AEs will be coded using MedDRA.
TEAE is defined as an AE observed after starting administration of the study drug through
30 days after the last dose. The number and percentage of subjects with treatment-emergent 
AEs, SAEs, AEs leading to withdrawal of treatment and AEs related to study drug will be 
summarized by MedDRA system organ class, MedDRA preferred term for overall subjects 
and by subjects in each cohort. The number and percentage of AEs by severity will also be 
summarized. All AEs will be listed.


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A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator.
7.5.2
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline for subjects in the SAF by treatment visit.
Shifts relative to normal ranges from baseline to each time point during treatment period in 
lab tests will also be tabulated. Laboratory data will be displayed in listings.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects in the SAF by treatment visit.
Vital signs data will be displayed in listings.
7.5.4
Physical Examination
Physical examination will be listed.
7.5.5
Routine 12-lead Electrocardiograms
All 12-lead ECG results will be summarized by time point.
7.6
Analysis of Pharmacokinetics
Descriptive statistics (e.g., n, mean, standard deviation, minimum, median, maximum, 
coefficient of variation [CV], geometric mean and geometric CV) will be provided for 
plasma concentrations of isavuconazole.
7.6.1
Analytical Method
Isavuconazole plasma concentration will be determined by a validated LC-MS/MS method 
with a lower limit of quantitation (LLOQ) of 100 ng/mL.
7.6.2
Estimation of Pharmacokinetic Parameters
Plasma trough levels will be measured (pre-dose) on days 7, 14, 21, 42 and 84 or EOT. 
24-hour pharmacokinetic samples will be measured on any day between days 14 and 42, 
while the subject is still receiving intravenous or oral study drug, for subjects who consent to 
participation in the 24-hour pharmacokinetic assessment.
Plasma concentrations will be analyzed using population pharmacokinetic model.
Population pharmacokinetics and/or pharmacokinetic/pharmacodynamics analyses will be 
performed by modeling and simulation scientist. All details of the population 
pharmacokinetic analysis will be described in a separate analysis plan and a separate 
population pharmacokinetic modeling report will be written.


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7.7
Major Protocol Deviations and Other Analyses
Major protocol deviations as defined in [Section 8.3 Major Protocol Deviations] will be 
summarized for all enrolled subjects by site. A data listing will be provided by site and 
subject.
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing.
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned.
7.9
Handling of Missing Data, Outliers, Visit Windows and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start and 
stop dates of AEs and concomitant medication. The imputed dates will be used to allocate the 
concomitant medication and AEs to a treatment group, in addition to determining whether an 
AE is/is not treatment emergent. Listings of the AEs and concomitant medications will present 
the actual partial dates; imputed dates will not be shown.
See the SAP for details of the definition for windows to be used for analyses by visit.
Plasma concentration values below the LLOQ will be set to 0 for calculation of summary 
statistics. If one or more values are less than the LLOQ, the geometric mean will not be 
calculated.
8
OPERATIONAL CONSIDERATIONS
8.1
Data Collection
The investigator or site designee will enter data collected using an electronic datacapture 
system. In the interest of collecting data in the most efficient manner, the investigator or site 
designee should record data (including laboratory values, if applicable) in the eCRF within
5 days after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Concomitant medications will be collected during the study and related only to AE’s/SAE’s 
during the 30- and 60-day follow-up period.
Pharmacokinetic samples will be analyzed at the bioanalytical laboratory. The 
pharmacokinetic data will betransferred electronically to the sponsor or designee at 
predefined intervals during the study.


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All procedures conducted under the protocol must be documented. For screen failures, the
minimum demographic data (sex, birth date, race and ICF/assent date), outcome of eligibility 
assessment (inclusion and exclusion criteria), reason for screen failure and AEs details must 
be documented.
The investigator or designee will be responsible for eCRF completion and that all data and 
queries are accurate, complete and are verifiable with the source. The source should be 
appropriately maintained by the clinical unit.
Electronic data sources and any supporting documents should be availablefor 
review/retrieval by the sponsor/designee at any giventime.
8.1.1
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated IC/assent forms
●
Visit dates
●
Medical history and physical examination details
●
Key pharmacokinetic and safety data, if applicable (as specified in theprotocol)
●
AEs and concomitant medication
●
Results of relevant examinations (e.g., ECG charts, etc.)
●
Laboratory printouts (if applicable)
●
Details of dispensing of study drug
●
Reason for premature discontinuation (if applicable)
●
Subject number (if applicable)
●
Pharmacokinetic sample processing and storage history, including date/time each sample 
is transferred to the freezer, freezer identification and the temperature log for the freezer 
(if applicable)
8.1.2
Clinical Study Monitoring
The sponsor or delegated contract research organization (CRO) is responsible formonitoring
the clinical study to ensure that subject's human rights, safety and well-being are protected, 
that the study is properly conducted in adherence to the current protocol and GCP and study 
data reported by the investigator/subinvestigator are accurate and complete and that theyare
verifiable with study-related records such as source documents. The sponsor is responsible 
for assigning study monitor(s) to this study for proper monitoring. They will monitor the 
study in accordance with planned monitoring procedures.


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8.1.3
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsoror
delegated CRO, as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
[Section 8.1.2] when they are requested by the sponsor monitors and auditors, the IRB/IEC or 
regulatory authorities. The confidentiality of the subject's identities shall be well protected 
consistent with local and national regulations when the source documents are subject to direct 
access.
8.1.4
Data Management
Data management will be coordinated by Astellas Data Science or designee in accordance
with the SOPs for data management. All study-specific processes and definitions willbe 
documented by Astellas Data Management. Completion of eCRFs will be described in the
eCRF instructions. Coding of medical terms and medications will be performedusing
MedDRA and WHO Drug Dictionary, respectively.
8.2
Screen Failures
For screen failures, the demographic data, reason for failing, ICF, inclusion and exclusion 
criteria and AEs will be collected in the eCRF.
8.3
Major Protocol Deviations
A major protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects.
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
The major protocol deviation criteria are as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria,
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment.
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. The sponsor will follow-up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or efficacy OR pharmacokinetic parameters of the subject to determine subject 
continuation in the study. 
If a major deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately. 


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The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the trial master file.
9
END OF TRIAL 
The end of the study is defined as the last visit or scheduled procedure shown in the schedule 
of assessments [Table 1 and Table 2] for the last study participant in the study.
10
STUDY ORGANIZATION
10.1
Data and Safety Monitoring Board (DSMB)
The Data and Safety Monitoring Board’s (DSMB) primary responsibilities will be 
safeguarding the interests of study subjects and assessing the safety of the study treatment(s) 
and study procedures. Safety monitoring by the DSMB will be ongoing during the course of 
the study and provide medical input for activities such as SAE reviews and recommendations 
to Astellas. The organization and operating procedures for the DSMB will be described in a 
separate DSMB Charter. The DSMB members will not be employees of Astellas nor 
otherwise involved with the study conduct; however, members of the DSMB could be 
members of the AC.
The DSMB Charter will mandate that all relevant data be carefully reviewed and 
recommendations will be made whether the study should continue without protocol 
modification, continue with protocol modification, suspend enrollment, continue dose 
escalation or reduction, increase sample size and/or stop study due to safety concerns.
10.2
Adjudication Committee (AC) 
The AC’s primary responsibilities will be to confirm the diagnosis and overall, clinical, 
radiological and mycological response of IA or IM.
The organization and operating procedures for the AC will be described in a separate AC 
Charter. The AC members will not be employees of Astellas nor otherwise involved with the 
study conduct; however, members of the AC could be members of the DSMB.


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11
REFERENCES 
Abidi MZ, Sohail MR, Cummins N, Wilhelm M, Wengenack N, Brumble L, et al. Stability in the 
cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-
risk patients from 1995 to 2011: a comparison of eras immediately before and after the 
availability of voriconazole and echinocandin-amphotericin combination therapies. Mycoses. 
2014;57:687-98.
Al-Rezqi A, Hawkes M, Doyle J, Richardson SE, Allen U. Invasive mold infections in iatrogenically 
immunocompromised children: an eight-yr review. Pediatr Transplant. 2009;13:545-52.
Bitar D, Van Cauteren D, Lanternier, F, Dannaoui E, Che D, Dromer F, et al. Increasing incidence of 
zygomycosis (mucormycosis), France, 1997-2006. Emerg Infect Dis. 2009;15:1395-401.
Burgos A, Zaoutis TE, Dvorak CC, Hoffman JA, Knapp KM, Nania JJ, et al. Pediatric invasive 
aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 
2008;121:e1286-94.
Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy 
significantly increases mortality among patients with hematologic malignancy who have 
zygomycosis. Clin Infect Dis. 2008;47:503-9. Company Report 9766-PK-0005.
Desai AV, Kovanda LL, Hope WW, Andes D, Mouton JW, Kowalski DL, et al. Exposure-Response 
Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous 
Fungi. Antimicrob Agents Chemother. 2017;61(12):e01034-17.
Dornbusch HJ, Manzoni P, Roilides E, Walsh TJ, Groll AH. Invasive fungal infections in children. 
Pediatr Infect Dis J. 2009;28:734-7. 
Espinel-Ingroff A, Chowdhary A, Gonzalez, GM, Lass-Flörl C, Martin-Mazuelos E, Meis J, et al. 
Multicenter study of isavuconazole MIC distributions and epidemiological cutoff values for 
Aspergillus spp. for the CLSI M38-A2 broth microdilution method. Antimicrob Agents 
Chemother. 2013;57:3823-28.
Georgiadou SP, Pongas G, Fitzgerald NE, Lewis RE, Rytting M, Marom EM, et al. Invasive mold 
infections in pediatric cancer patients reflect heterogeneity in etiology, presentation, and 
outcome: a 10 year, single-institution, retrospective study. J Pediatric Infect Dis Soc. 
2012;1:125-35.
Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. 
Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 
2005;41:634-53.
Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, et al. Zygomycosis in Europe: 
analysis of 230 cases accrued by the registry of the European Confederation of Medical 
Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol 
Infect. 2011;17:1859-67.
Sung L, Johnston DL. Approach to febrile neutropenia in the general paediatric setting. Paediatr Child 
Health. 2007;12:19-21.


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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.
Wattier RL, Dvorak CC, Hoffman JA, Brozovich AA, Bin-Hussain I, Groll AH, et al. A prospective, 
international cohort study of invasive mold infections in children. J Pediatric Infect Dis Soc. 
2015;4:313-22.
Zaoutis TE, Heydon K, Chu JH, Walsh TJ, Steinbach WJ. Epidemiology, outcomes, and costs of 
invasive aspergillosis in immunocompromised children in the United States, 2000. Pediatrics. 
2006;117(4):e711-6.


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12
APPENDICES
12.1
Ethical, Regulatory and Study Oversight Considerations
12.1.1
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
12.1.2
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the IB, the ICF and all other forms of subject information related to the study (e.g., 
advertisements used to recruit subjects) and any other necessary documents be reviewed by 
an IEC/IRB. The IEC/IRB will review the ethical, scientific and medical appropriateness of 
the study before it is conducted. IEC/IRB approval of the protocol, ICF and subject 
information and/or advertising, as relevant, will be obtained prior to the authorization of drug 
shipment to a study site.
Any substantial amendments to the protocol will require IRB/IEC approval before 
implementation, except for changes necessary to eliminate an immediate hazard to subjects.
The investigator will be responsible for the following:
●
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies and procedures established by 
the IRB/IEC
●
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
●
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable) and all other applicable local regulations
12.1.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Depending on the nature of the amendment, either IRB/IEC, CA approval or notification may 
be required. The changes will become effective only after the approval of the sponsor, the 
investigator, the regulatory authority and the IRB/IEC (if applicable).
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented. 
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations.


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If there are changes to the ICF, written verification of IRB/IEC approval must be forwarded 
to the sponsor. An approved copy of the new ICF must also be forwarded to the sponsor.
12.1.4
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
12.1.5
Informed Consent of Subjects
12.1.5.1 Subject Information and Consent/Assent
If there are study related procedures that require a separate consent (i.e., pharmacogenetics
sample, tumor biopsy) the consent process for the procedure should be described here.
The investigator or his/her representative will explain the nature of the study to the subject 
and/or parent or legal guardian and answer all questions regarding this study. Prior to any 
study-related screening procedures being performed on the subject, the ICF/assent will be 
reviewed and signed and dated by the subject and/or parent(s) or legal guardian, the person 
who administered the ICF/assent and any other signatories according to local requirements. A 
copy of the signed ICF/assent will be given to the subject and/or parent(s) or legal guardian 
and the original will be placed in the subject’s medical record. An entry must also be made in 
the subject’s dated source documents to confirm that informed consent/assent was obtained 
prior to any study-related procedures and that the subject received a signed copy.
The signed consent/assent forms will be retained by the investigator and made available (for 
review only) to the study monitor and auditor regulatory authorities and other applicable
individuals upon request.
12.1.5.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and whether the subject is willing to remain 
in the study or not must be confirmed and documented.
2.
The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF. A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 


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medical record. An entry must be made in the subject’s records documenting the re-
consent process.
12.1.6
Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are hand-written on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
achieved, retrieved or transmitted electronically via computerized systems (and/or other kind 
of electric devices) as part of regulated clinical trial activities, such systems must be 
compliant with all applicable laws and regulations governing use of electronic records and/or 
electronic signatures. Such systems may include, but are not limited to, electronic 
medical/health records, protocol related assessments, AE tracking and/or drug accountability. 
Paper records from electronic systems used in place of electronic format must be certified 
copies. A certified copy must be an exact copy and must have all the same attributes and 
information as the original. Certified copies must include signature and date of the individual 
completing the certification. Certified copies must be a complete and chronological set of 
study records (including notes, attachments and audit trail information), if applicable. All 
printed records must be kept in the subject file and available for archive. 
12.1.7
Record Retention
The investigator will archive all study data (e.g., subject identification code list, source data, 
CRFs and investigator's file) and relevant correspondence. These documents are to be kept on 
file for the appropriate term determined by local regulation (for US sites, 2 years after 
approval of the NDA or discontinuation of the IND). The sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued. The investigator agrees to obtain the sponsor's agreement prior to 
disposal, moving or transferring of any study-related records. The sponsor will archive and 
retain all documents pertaining to the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subject’s
medical records and/or study progress notes.
12.1.8
Subject Confidentiality and Privacy
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless otherwise the subject provides 
written consent or approval. Additional medical information may be given only after 
approval of the subject to the investigator or to other appropriate medical personnel 
responsible for the subject's well-being.


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The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties. 
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number will identify subject data retrieved by the sponsor. However, 
the sponsor requires the investigator to permit the sponsor, sponsor's representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study.
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and Privacy laws in the US. If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then sponsor shall serve as the controller of such 
data, as defined by the European Union (EU) Data Protection Directive, and Investigator 
and/or third party shall act only under the instructions of the sponsor in regard to personal 
data. If sponsor is not based in the EEA, sponsor must appoint a third party to act as its local 
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the Directive.
12.1.9
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the investigator understands that he/she 
has an obligation to provide the sponsor with all data obtained during the study.
Publication of the study results is discussed in the clinical study agreement.
12.1.10 Insurance of Subjects and Others 
The sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
investigator's file. 
12.1.11 Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report, which forms part of a marketing authorization application, be signed by the 


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representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock.


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12.2
Procedure for Clinical Study Quality Control
12.2.1
Clinical Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/subinvestigator are accurate and complete and that they are verifiable with study-
related records such as source documents. The sponsor is responsible for assigning study 
monitor(s) to this study for proper monitoring. They will monitor the study in accordance 
with planned monitoring procedures.
12.2.2
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO, as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records including source documents 
when they are requested by the sponsor monitors and auditors, the IRB/IEC or regulatory 
authorities. The confidentiality of the subject's identities shall be well protected consistent 
with local and national regulations when the source documents are subject to direct access.
12.2.3
Data Management
Data Management will be coordinated by the Data Science department of the sponsor in 
accordance with the SOPs for data management. All study-specific processes and definitions 
will be documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and WHO Drug Dictionary, respectively.
12.2.4
Quality Assurance
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied.
The sponsor or sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms and source documents. Direct access to these documents will 
be required by the auditors.


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12.3
Contraception Requirements
Subjects who are of childbearing potential participants who choose complete abstinence must 
continue to have pregnancy tests, as specified in schedule of assessments [Table 1 and Table 2].
SUBJECTS WHO ARE OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION DEFINITIONS
A female subjects is considered fertile following menarche and until becoming post-
menopausal unless permanently sterile. 
Female subjects in the following category are not considered subjects who are of 
childbearing potential
●
Premenarchal
Documentation of any of this category can come from the site personnel’s review of the 
female subject’s medical records, medical examination or medical history interview.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD 
BEARING POTENTIAL
One of the highly effective methods of contraception listed below is required at the time of 
informed consent and until the end of relevant systemic exposure, defined as 30 days after the 
final study drug administration.*
Highly Effective Contraceptive Methods (Failure rate of < 1% per year when used 
consistently and correctly)a
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
●
oral
●
intravaginal
●
transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation
●
oral
●
injectable
●
implantable 
Hormonal methods of contraception containing a combination of estrogen and progesterone, 
vaginal ring, injectables, implants and intrauterine hormone-releasing system
●
intrauterine device
●
bilateral tubal occlusion
Vasectomized partner (A vasectomized partner is a highly effective contraception method 
provided that the partner is the sole male sexual partner of the subject who is of childbearing 
potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.)


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Sexual abstinence Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the 
study drug. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. It is not 
necessary to use any other method of contraception when complete abstinence is elected.
* Local laws and regulations may require use of alternative and/or additional contraception methods.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) 
OF CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to the following during treatment and until the end of relevant systemic exposure 
defined as 30 days after final drug administration.*
●
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
●
Male participants are required to use a condom during treatment and until end of relevant 
systemic exposure defined as 30 days after final drug administration.
●
Female partners of male participants who have not undergone a vasectomy with the 
absence of sperm confirmed or a bilateral orchiectomy should consider use of effective 
methods of contraception until the end of relevant systemic exposure, defined as 30 days 
after final drug administration.


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12.4
List of Excluded Concomitant Medications
Treatments with concomitant drugs that are strong inhibitors or inducers of CYP3A4 are 
prohibited, including ketoconazole, high dose ritonavir, rifampin/rifampicin, carbamazepine 
and St. John’s Wort or long acting barbiturates (e.g., phenytoin). Concomitant use of 
sirolimus, atorvastatin, cyclosporine, tacrolimus, midazolam, bupropion, mycophenolate 
mofetil and digoxin should be made with caution.
Treatments with concurrent drugs that are CYP3A4 substrates and have a narrow therapeutic 
range (e.g., vincristine) should be used with caution, and if clinically warranted, consider 
reduction of substrate dose. Use of other systemic antifungals is prohibited during study drug 
administration.


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12.5
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN or bilirubin > 2 × ULN should undergo detailed 
testing for liver enzymes (including at least ALT, AST, alkaline phosphatase [ALP] and 
TBL). Testing should be repeated within 72 hours of notification of the test results. For 
studies for which a central laboratory is used, alerts will be generated by the central 
laboratory regarding moderate and severe liver abnormality to inform the investigator and 
study team. Subjects should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
TBL
Moderate
> 3 × ULN 
or
> 2 × ULN
Severe
> 3 × ULN
and
> 2 × ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN.
●
ALT or AST > 5 × ULN for more than 2 weeks.
●
ALT or AST > 3 × ULN and International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site staff is to complete the liver abnormality 
case report form (LA-CRF). Subjects with confirmed abnormal liver function tests (LFTs)
should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.


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To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases is to be recorded as “AEs” within the eCRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic and/or diabetic subjects, and may be associated with 
fluctuating AT levels. The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.
●
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, is to be entered in the eCRF. Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including: 
○Acute viral hepatitis (A, B, C, D, E or other infectious agents), 
○Ultrasound or other imaging to assess biliary tract disease,
○Other laboratory tests including INR, direct bilirubin.
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Treatment Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, preexisting or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from study treatment. The investigator may determine that it is not in the 
subject’s best interest to continue study treatment. Discontinuation of study treatment should 
be considered if:
●
ALT or AST > 8 × ULN.
●
ALT or AST > 5 × ULN for more than 2 weeks.
●
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued.
*Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10 to 50% mortality 
(or transplant). 


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The 2 “requirements” for Hy’s Law are: 
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase 
in transaminase elevations higher 3 × ULN (2 × ULN elevations are too common in 
treated and untreated subjects to be discriminating). 
2. Cases of increased bilirubin (at least 2 × ULN) with concurrent transaminase elevations at 
least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
ALP) or Gilbert’s syndrome [Temple, 2006].
FDA Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical
Evaluation” issued on July 2009:
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug 
or placebo.
2. Among trial subjects showing such AT elevations, often with ATs much greater than 
3 x ULN, one or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP).
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. [Guidance for Industry titled “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation” issued by FDA on July 2009]
References
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15(Suppl 4):241-3.
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.


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12.6
Common Serious Adverse Events
For this protocol, there is no list of common SAEs anticipated for the study population for the 
purposes of IND safety reporting.


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12.7
Oral Dosing Acceptability Assessment


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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 3
I.  The purpose of this amendment is:
Substantial Changes
1.
Clarify Vital Signs for Subjects who Receive Oral Dosing
DESCRIPTION OF CHANGE:
Additional text is added to specify that no additional vital signs are needed on dosing days 
for oral administration other than screening and end of treatment.
RATIONALE:
This change is made to clarify that no additional vital signs are required for subjects who 
receive oral dosing as the additional vital signs are only required for monitoring of the 
intravenous dosing.
2.
Clarify Pregnancy Testing in the Schedule of Assessments
DESCRIPTION OF CHANGE:
Additional text is added to footnote 12 (Table 1) to clarify that the pregnancy test may be 
either urine or serum.
RATIONALE:
Added text to clarify the type of pregnancy test that is acceptable.
3.
Update Timing of the Return Visit
DESCRIPTION OF CHANGE:
Text is added to specify that the return visit should occur on days when study-related 
assessments are required.
RATIONALE:
Added text to clarify the timing of return study visits to minimize the burden to subjects for 
unnecessary return visits. 
4.
Change Age Requirement for Oral Formulation
DESCRIPTION OF CHANGE:
The lower limit on the age requirement for oral dosing is changed from “12 years of age” to 
“6 years of age and with a body weight of at least 12 kg.” The dose rationale is updated with 
additional data from Part 2 of Study 9766-CL-0046 (6 to < 11 years of age) to support this 
change.
RATIONALE:
Added lower age range and minimum body weight for oral dosing as supported by additional 


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pharmacokinetic modeling data provided.
5.
Add Investigator Guidance for Successful Outcome
DESCRIPTION OF CHANGE:
A table is added to provide guidance to the investigator defining the elements of a successful 
outcome.
RATIONALE:
Added guidance for the investigator regarding the definition of a successful outcome to aid in 
their decision making regarding end of treatment.
6.
Update Inclusion Criterion #2
DESCRIPTION OF CHANGE:
This criterion is updated to extend the timing of diagnostic tests to confirm invasive fungal 
disease to 10 calendar days after the first dose of study drug.
RATIONALE:
Revised the timeframe allowed to confirm invasive fungal infection diagnosis to align with 
time estimated per site’s institutional practice.
7.
Update Inclusion Criterion #3
DESCRIPTION OF CHANGE:
This criterion is updated to clarify that the administration will be intravenous and to specify 
that the subject must be able to swallow oral capsules.
RATIONALE:
Added clarification that subject must either have venous access for intravenous infusion or 
the ability to swallow oral capsules to be eligible for the study.
8.
Update Exclusion Criterion #7
DESCRIPTION OF CHANGE:
This criterion is updated to include allergy, hypersensitivity or serious reaction to “any 
component of the study drug formulation.”
RATIONALE:
Updated the exclusion criterion to include allergy or hypersensitivity to ensure subject safety.
9.
Add Discontinuation Due to Serious Hypersensitivity Adverse Reactions
DESCRIPTION OF CHANGE:


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Text is added to state that subjects who develop serious hypersensitivity adverse reactions 
without alternative etiology will be discontinued from treatment.
RATIONALE:
Added discontinuation criterion for serious hypersensitivity adverse reactions as an 
additional safety precaution.
Nonsubstantial Changes
1.
Update Contact Details of Key Sponsor’s Personnel
DESCRIPTION OF CHANGE: 
The Astellas medical monitor is replaced.
RATIONALE:
Sponsor personnel details are updated based on changes to study team members.
2.
Update Inclusion Criterion #8
DESCRIPTION OF CHANGE:
The phrase “of childbearing potential” is removed from this criterion.
RATIONALE:
This change is made to correct an error.
3.
Add Appendix with Acceptability Assessment
DESCRIPTION OF CHANGE:
The Acceptability Assessment is added to the protocol as Appendix 12.7. Cross references to 
this appendix are added as appropriate.
RATIONALE:
This change is made to include the details of the Acceptability Assessment to be used for this 
study.
4.
Update Packaging of Oral Capsules
DESCRIPTION OF CHANGE:
The packaging information for oral capsules is updated to specify that aluminum blisters 
with desiccants will be used, and then placed in secondary child-resistant cards.
RATIONALE:
Added additional details related to the packaging of oral capsule for packaging identification 
purposes.


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5.
Update Treatment Compliance
DESCRIPTION OF CHANGE:
Additional details are added to the treatment compliance section.
RATIONALE:
Provided additional details regarding treatment compliance for oral dosing to ensure 
appropriate subject compliance and re-education throughout the study.
6.
Clarify that Members of the Data and Safety Monitoring Board (DSMB) could be 
Members of the Adjudication Committee (AC), and Vice Versa
DESCRIPTION OF CHANGE:
Section 10.1 is updated to clarify that members of the DSMB could be members of the AC, 
and Section 10.2 is updated to clarify that members of the AC could be members of the 
DSMB.
RATIONALE:
This change is made to clarify that members may belong to both groups.
7.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol).
RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.


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II.  Amendment Summary of Changes:
IIA. Substantial Changes
IV Synopsis, Dose(s)
WAS:
The investigator may determine the appropriate route of administration for each subject. 
They can change dosing between the 2 routes of administration (intravenous oral) 
throughout the treatment period as needed. 
IS AMENDED TO:
The investigator may determine the appropriate route of administration for each subject. The 
investigator can switchThey can change dosing between the 2 routes of administration 
(intravenous oral) throughout the treatment period as needed. Changes to route of 
administration will be documented.
V Flow Chart and Schedule of Assessments
Table 1 Schedule of Assessments (IA and IM Subjects) – Screening through Day 84 and IA 
Follow-up (30 and 60 Days Post-Day 84 or EOT [Last Dose of Study Drug])
WAS:
3. Diagnosis must be completed within 7 days of first dose.
5. Vital signs are to be measured within 1 hour prior to and approximately 1 hour after 
the end of each infusion.
9. For both intravenous and oral dosing: 24-hour pharmacokinetic samples will be 
obtained on any day between day 14 and day 42, while the subject is still receiving 
study drug, for subjects who consent to participation in the 24-hour pharmacokinetic 
assessment.
12. Pregnancy testing not applicable for male subjects. Not necessary for female subjects 
who are of non-childbearing potential (e.g., premenarchal in the judgment of 
the investigator on day 1 and throughout the study treatment, or documented 
surgically sterile).
15. For both intravenous and oral dosing: Loading doses on days 1 and 2 will be 
administered every 8 (± 2) hours. The first maintenance dose should start 12 to 24 hours 
after the administration of the last loading dose. Subsequent maintenance doses will be 
administered once daily (24 ± 2 hours from the previous maintenance dose). Subjects 
who are discharged from the hospital with oral capsules for at-home administration must 
return weekly to receive new oral dosing supplies.
IS AMENDED TO:
3. Diagnosis must be completed within 107 days of first dose.
5. Vital signs are to be measured within 1 hour prior to and approximately 1 hour after 
the end of each infusion. No additional vital signs are needed on dosing days for 
oral administration.
9. For both intravenous and oral dosing: 24-hour pharmacokinetic samples will be 


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obtained on any one day between day 14 and day 42, while the subject is still 
receiving study drug, for subjects who consent to participation in the 24-hour 
pharmacokinetic assessment.
12. Pregnancy testing not applicable for male subjects. Not necessary for female subjects 
who are of non-childbearing potential (e.g., premenarchal in the judgment of 
the investigator on day 1 and throughout the study treatment, or documented 
surgically sterile). Pregnancy testing may be urine or serum, dependent upon 
institutional standard of care.
15. For both intravenous and oral dosing: Loading doses on days 1 and 2 will be 
administered every 8 (± 2) hours. The first maintenance dose should start 12 to 24 hours 
after the administration of the last loading dose. Subsequent maintenance doses will be 
administered once daily (24 ± 2 hours from the previous maintenance dose). Subjects 
who are discharged from the hospital with oral capsules for at-home administration must 
return weekly to receive new oral dosing supplies. Return visits should coincide with 
days when study-related assessments are required. Oral dosing is allowed for 6 to 
< 18 years of age and with a body weight of at least 12 kg.
V Flow Chart and Schedule of Assessments
Table 2 Extended Schedule of Assessments (IM Subjects) – Day 85 through Day 180 and IM 
Follow-up (30 and 60 days Post-Day 180 [Last Dose of Study Drug])
WAS:
Period
Day
85
Visit window (days)
3. Vital signs are to be measured within 1 hour prior to and approximately 1 hour after the 
end of each infusion.
10. For both intravenous and oral dosing: Subsequent maintenance doses will be 
administered once daily (24 ± 2 hours from the previous maintenance dose). Subjects 
who are discharged from the hospital with oral capsules for at-home administration 
must return weekly to receive new oral dosing supplies.
IS AMENDED TO:
Period
Day
85
Visit window (days)
± 2
3. Vital signs are to be measured within 1 hour prior to and approximately 1 hour after the 
end of each infusion. No additional vital signs are needed on dosing days for oral 
administration.
10. For both intravenous and oral dosing: Subsequent maintenance doses will be 
administered once daily (24 ± 2 hours from the previous maintenance dose). Subjects 
who are discharged from the hospital with oral capsules for at-home administration must 
return weekly to receive new oral dosing supplies. Return visits should coincide with 
days when study-related assessments are required. Oral dosing is allowed for 
subjects 6 to < 18 years of age and with a body weight of at least 12 kg.


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IV Synopsis, Study Design Overview and 2 Study Objective(s), Design and Endpoints
2.2.1 Study Design
WAS:
The subjects will enter into screening anytime between days -5 to day 1 (predose). All 
subjects will be assigned to open-label treatment via intravenous or oral treatment at the 
discretion of the investigator. The oral formulation can only be given to subjects 12 years to 
< 18 years of age.
Subjects who begin oral administration are to complete the oral dosing acceptability 
assessment after ingesting their first oral dose. 
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any day 
between day 14 and day 42, while the subject is still receiving study drug, for subjects who 
consent to participation in the 24-hour pharmacokinetic assessment.  
IS AMENDED TO:
The subjects will enter into screening anytime between days -5 to day 1 (predose). All 
subjects will be assigned to open-label treatment via intravenous or oral treatment at the 
discretion of the investigator. The oral formulation can only be given to subjects 12 6 years 
to < 18 years of age and with a body weight of at least 12 kg.
Subjects who begin oral administration are to complete the oral dosing acceptability 
assessment after ingesting their first oral dose. Isavuconazonium sulfate oral capsules can 
be administered with or without food.
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any one day 
between day 14 and day 42, while the subject is still receiving study drug, for subjects who 
consent to participation in the 24-hour pharmacokinetic assessment. 
2 Study Objective(s), Design and Endpoints
2.2.1 Study Design
WAS:
Visits should occur on days when study related assessments are required.   
IS AMENDED TO:
Investigator guidance of a successful outcome is provided in Table 4.
Return visits should coincide with days when study-related assessments are 
required.Visits should occur on days when study related assessments are required.   
2 Study Objective(s), Design and Endpoints
2.2.2 Dose Rationale
WAS:
Population Pharmacokinetic Model for Pediatric Data
An initial pediatric population pharmacokinetic model was developed utilizing plasma 
concentration data from 27 subjects administered intravenous isavuconazonium sulfate from 


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Part 1 of Study 9766-CL-0046 and 24 subjects from the 9766-CL-0018 study, an intravenous 
study in which subjects were administered single dose of 372 mg of isavuconazonium sulfate. 
The initial model was updated with 10 subjects from Part 2 of Study 9766-CL-0046, who 
were administered oral isavuconazonium sulfate.
A 3-compartment model with combined zero order absorption, first order absorption and 
linear elimination described the data adequately.
Monte Carlo simulations were performed for 1000 to 5000 randomly chosen subjects for each 
age group in pediatrics and adult data. Area under the isavuconazole concentration-time 
curve at steady-state (AUCss) was calculated for each simulated subject. The dosing schedule 
for the simulation was similar to that for subjects in Study 9766-CL-0046, with subjects 
weighing < 40 mg administered 10 mg/kg dose and subjects > 40 kg getting adult dose of 
372 mg.
The figure shown below compares pediatric exposures against exposures from Study 
9766-CL-0104 (SECURE), a successful phase 3 study in adults with IA, in which subjects 
received isavuconazonium sulfate via both intravenous and oral routes of administration and 
against data from Study 9766-CL-0103 (VITAL), a successful phase 3 adult study in subjects 
with IM and other rare invasive fungal infections, in which subjects received 
isavuconazonium sulfate via oral route of administration. The dosage regimen in both adult 
studies was similar.
Red dots are the means. Dashed orange line is the lowest targeted value (25th percentile, with 
AUCss of 60 mg*hr/L) based on exposures from SECURE study.
From the figure, it can be seen that exposure predicted for pediatric subjects across all ranges 
for intravenous and for 12 to < 18 years of age for oral route of administration are within the 
efficacious range that was observed in adult studies.
An isavuconazonium sulfate dose of 10 mg/kg for all age groups weighing > 37 kg and the
adult dose for pediatric subjects weighing > 40 kg provide mean exposures that were similar 
to and/or above the 372 mg adult dose and significantly below the 1116 mg dose group, 
where toxicities were observed. For intravenous, across all age groups, > 97% ofthe 
predicted AUCss values were below the AUC values for the adult population administered 
1116 mg isavuconazonium sulfate dose and > 86% of the predicted AUCss values were below 
the minimum adult AUCss values for the adult subject population administered the supra 
therapeutic dose clinical (1116 mg) dose [Study 9766-CL-0017]. For oral (12 to < 18 years of 
age), > 99% of the predicted AUCss values and > 97% of the predicted AUCss values were 
below the mean and minimum adult AUCss values from the 9766-CL-0017 study.


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Also, > 86% and > 80% of the predicted AUCss values for the intravenous and oral routes of 
administration were above the 25th percentile of exposure values from the SECURE study in 
subjects who received 372 mg dose of isavuconazonium sulfate.
Route
Age Group
% of Subjects Below 
Mean Adult AUC24
1116 mg Dose
% of Subjects Below 
Minimum Adult 
AUC24 1116 mg 
Dose
% of Subjects Above 
the 25th Percentile 
Adults AUCss 372 mg 
Dose
Intravenous
1 to < 6 years
98.8%
91.9%
87.2%
6 to < 12 years
97.9%
88.3%
91.5%
12 to <18 years
97.1%
86.1%
92.0%
Oral
12 to < 18 years
99.8%
97.5%
80.4%
Based on modeling and simulation results, the proposed daily dose administered either as 
intravenous (across all age groups) or oral (12 to < 18 years of age) for the clinical study in 
pediatric subjects is:
Details of modeling and simulation are presented in the modeling report [Study 
9766-PK-0007].
IS AMENDED TO:
Population Pharmacokinetic Model for Pediatric Data
An initial pediatric population pharmacokinetic model was developed utilizing plasma 
concentration data from 27 subjects administered intravenous isavuconazonium sulfate from 
Part 1 of Study 9766-CL-0046, 10 subjects administered oral dose from Part 2 of Study 
9766-CL-0046 (12 to < 18 years of age) and 24 subjects from the 9766-CL-0018 study, an 
intravenous study in which subjects were administered single dose of 372 mg of 
isavuconazonium sulfate. The initial model was updated withto include plasma 
concentration data from an additional 910 subjects from Part 2 of Study 9766-CL-0046 
(6 to < 12 years of age), who were administered oral isavuconazonium sulfate.
A 3-compartment model with combined zero order absorption, first order absorption and 
linear elimination described the data adequately. Inter-individual variability was observed 
on clearance, volume of distribution of central and peripheral compartment and inter-
compartmental clearance.
Monte Carlo simulations were performed for 1000 to 5000 randomly chosen subjects for each 
age group in pediatrics and 1000 to 5000 randomly chosen subjects for adult data. Area 
under the isavuconazole concentration-time curve at steady-state (AUCss) was calculated for 
each simulated subject. The dosing schedule for the simulation was similar to that for 
subjects in Study 9766-CL-0046, with subjects weighing ≤ 37 kg < 40 mg administered 10 
mg/kg dose and subjects > 3740 kg receivinggetting the adult dose of 372 mg.
The figure shown below Figure 2 compares pediatric exposures against exposures from 
Study 9766 CL-0104 (SECURE), a successful phase 3 study in adults with IA, in which 
subjects received isavuconazonium sulfate via both intravenous and oral routes of 
administration and against data from Study 9766-CL-0103 (VITAL), a successful phase 3 
adult study in subjects with IM and other rare invasive fungal infections, in which subjects 
received isavuconazonium sulfate via oral route of administration. The dosage regimen in 
both adult studies was similar.




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values and > 96% of the predicted AUCss values were below the mean and minimum 
adult AUCss values from Study 9766-CL-0017.
Also, > 8886% and >approximately 80% of the predicted AUCss values for the intravenous 
and oral routes of administration were above the 25th percentile of exposure values from the 
SECURE study in subjects who received 372 mg dose of isavuconazonium sulfate. This 
table is updated based on simulations from the most recent population pharmacokinetic 
model that included oral data from subjects 6 to < 12 years of age.
Table 3
Percentage of Pediatric Patients with Predicted AUCss Values of 
Isavuconazole Below or Above the Specified Adult AUC Values
Route
Age Group
% of Subjects 
Below Mean Adult 
AUC24 1116 mg 
Dose
% of Subjects 
Below Minimum 
Adult AUC24
1116 mg Dose
% of Subjects 
Above the 25th
Percentile Adults 
AUCss 372 mg 
Dose
Intravenous
1 to < 6 years
10098.8%
97.091.9%
88.687.2%
6 to < 12 
years
99.797.9%
94.088.3%
92.791.5%
12 to <18 
years
99.997.1%
98.286.1%
82.192.0%
Oral
612 to < 1218
years
99.699.8%
96.497.5%
90.780.4%
12 to < 18 
years
100%
98.2%
78.8%
Based on modeling and simulation results, the proposed daily dose administered either as 
intravenous (across all age groups) or oral (612 years to < 18 years of age and with a body 
weight of at least 12 kg) for the clinical study in pediatric subjects is:
NOTE: The oral administration is only available for pediatric subjects 6 years and 
older due to the difficulty in swallowing the oral capsule.
Details of modeling and simulation are presented in the modeling report [Study 9766 PK 
0007].
Isavuconazonium sulfate oral capsules can be administered with or without food.
IV Synopsis, Inclusion/Exclusion Criteria and 3 Study Population
3.2 Inclusion Criterion #2
WAS:
Male or female subject 1 year to < 18 years of age diagnosed with IA or IM. A positive 
diagnosis is defined as follows:
●
Proven, probable or possible IFI per the European Organisation for Research and 
Treatment of Cancer/Mycoses Study Group [EORTC/MSG], 2008 criteria. 
Note: Subjects with “possible” IFI will be eligible for enrollment; however, 
diagnostic tests to confirm the invasive fungal disease as “probable” or “proven” 
according to the EORTC/MSG criteria must be completed within 7 days after the first 
dose of study drug.


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IS AMENDED TO:
Male or female subject 1 year to < 18 years of age diagnosed with IA or IM. A positive 
diagnosis is defined as follows:
●
Proven, probable or possible IFI per the European Organisation for Research and 
Treatment of Cancer/Mycoses Study Group [EORTC/MSG], 2008 criteria. 
Note: Subjects with “possible” IFI will be eligible for enrollment; however, 
diagnostic tests to confirm the invasive fungal disease as “probable” or “proven” 
according to the EORTC/MSG criteria must should be completed within 7 10 
calendar days after the first dose of study drug.
IV Synopsis, Inclusion/Exclusion Criteria and 3 Study Population
3.2 Inclusion Criterion #3
WAS:
Subject has sufficient venous access to permit administration of study drug and monitoring
of safety laboratories.
IS AMENDED TO:
Subject has sufficient venous access to permit intravenous administration of study drug or 
the ability to swallow oral capsules and monitoring of safety laboratories.
IV Synopsis, Inclusion/Exclusion Criteria and 3 Study Population
3.3 Exclusion Criterion #7
WAS:
Subject has known history of allergy, hypersensitivity or any serious reaction to any of the 
azole class antifungals.
IS AMENDED TO:
Subject has known history of allergy, hypersensitivity or any serious reaction to any of the 
azole class antifungals, or any components of the study drug formulation.
IV Synopsis, Dose(s) and 5 Treatments and Evaluation
5.1.1 Dose/Dose Regimen and Administration Period
WAS:
Oral (only for subjects 12 to < 18 years of age)
Subjects will receive an oral loading regimen of isavuconazonium sulfate in a capsule form 
given every 8 hours (± 2 hours) on days 1 and 2 (a total of 6 doses), followed by once-daily 
oral maintenance dosing. 
The daily dose is based on body weight and is intended to deliver a dose approximately equal 
to 10 mg/kg. The oral and intravenous formulations are equivalent on a mg:mg basis. The 
lower limit for oral dosing is 12 years of age and body weight of 18 kg.
Body Weight 
(kg)
Loading (Days 1 and 2)/Total Daily 
Isavuconazonium Sulfate Dose (mg)
Maintenance (up to 84 days [IA] or 
180 days [IM])/Total Daily Isavuconazonium 


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Sulfate Dose (mg)
18 to 24
3 × 3 capsules/670.5 mg
1 × 3 capsules/223.5 mg
25 to 31
3 × 4 capsules /894 mg
1 × 4 capsules/298 mg
≥ 32
3 × 5 capsules/1117.5 mg
1 × 5 capsules/372.5 mg
IS AMENDED TO:
Oral (only for subjects 612 to < 18 years of age and with a body weight of at least 12 kg)
Subjects will receive an oral loading regimen of isavuconazonium sulfate in a capsule form 
given every 8 hours (± 2 hours) on days 1 and 2 (a total of 6 doses), followed by once-daily 
oral maintenance dosing. Isavuconazonium sulfate oral capsules can be administered 
with or without food.
The daily dose is based on body weight and is intended to deliver a dose approximately equal 
to 10 mg/kg. The oral and intravenous formulations are equivalent on a mg:mg basis. The 
lower limit for oral dosing is 612 years of age and a body weight of at least 1218 kg.
Body Weight 
(kg)
Loading (Days 1 and 2)/Total Daily 
Isavuconazonium Sulfate Dose (mg)
Maintenance (up to 84 days [IA] or 
180 days [IM])/Total Daily Isavuconazonium 
Sulfate Dose (mg)
12 to < 18
3 × 2 capsules/447 mg
1 × 2 capsules/149 mg
18 to < 2524
3 × 3 capsules/670.5 mg
1 × 3 capsules/223.5 mg
25 to < 3231
3 × 4 capsules /894 mg
1 × 4 capsules/298 mg
≥ 32
3 × 5 capsules/1117.5 mg
1 × 5 capsules/372.5 mg
5 Treatments and Evaluation
5.1.1 Dose/Dose Regimen and Administration Period
WAS:
The isavuconazonium sulfate will be administered as an intravenous infusion or as oral 
capsule(s) per the investigator’s discretion. The1-hour (± 10 minutes) intravenous infusion 
will be administered through an in-line filter. The start and stop times of the infusion must be
clearly documented. Oral administration is only for subjects 12 to < 18 years of age. The 
investigator may determine the appropriate route of administration for the subject. The mode 
of administration can be interchangeable from intravenous to oral (12 to < 18 years of age) or 
oral (12 to < 18 years of age) to intravenous during the loading dose period and throughout 
the treatment period, the mg:mg is equivalent in both routes.
The maximum treatment is 84 days for IA subjects and 180 days for IM subjects, whichever 
occurs first.
Mode of Intravenous Administration:
Oral Dosing (only for subjects 12 to < 18 years of age):
Visits should occur on days when study related assessments are required.


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The daily dose is based on body weight and is intended to deliver a dose approximately equal 
to 10 mg/kg. The oral and intravenous formulations are equivalent on a mg:mg basis. The 
lower limit for oral dosing is 12 years of age and body weight of 18 kg.
Body weight 
(kg)
Loading (Day 1 and Day 2)/Total Daily 
Isavuconazonium Sulfate Dose (mg)
Maintenance (up to 84 days [IA] or 
180 days [IM])/Total Daily 
Isavuconazonium Sulfate Dose (mg)
18 to 24
3 × 3 capsules/670.5 mg
1 × 3 capsules/223.5 mg
25 to 31
3 × 4 capsules/894 mg
1 × 4 capsules/298 mg
≥ 32
3 × 5 capsules/1117.5 mg
1 × 5 capsules/372.5 mg
Mode of Oral Administration:
Subjects will receive isavuconazonium sulfate as an oral capsule (the number of capsules 
will correspond to their weight; see table above).
Increase or Reduction in Dose of the Study Drug(s)
Dose increases and reductions to study drug for a given individual subject are prohibited.  
IS AMENDED TO:
The isavuconazonium sulfate will be administered as an intravenous infusion or as oral 
capsule(s) per the investigator’s discretion. The 1-hour (± 10 minutes) intravenous infusion 
will be administered through an in-line filter. The start and stop times of the infusion must be
clearly documented. Oral administration is only for subjects 612 to < 18 years of age and 
with a body weight of at least 12 kg. The investigator may determine the appropriate route of 
administration for the subject in the context of the relevant age range. The routemode of 
administration can be interchangeable from intravenous to oral (612 to < 18 years of age 
with a body weight of at least 12 kg) or oral (612 to < 18 years of age with a body weight 
of at least 12 kg) to intravenous during the loading dose period and throughout the treatment 
period, the mg:mg is equivalent in both routes.. The details of dose and route of 
administration will be captured in the electronic case report form (eCRF).
The maximum treatment is 84 days for IA subjects and 180 days for IM subjects, whichever 
occurs first.
Treatment will be administered until the subject has a successful outcome as judged by 
the investigator or for a maximum duration of 84 days (IA) or 180 days (IM), 
whichever occurs first. Table 4 provides guidance to the investigator outlining the 
elements collectively informing a successful outcome. The investigator is encouraged to 
have clinical resolution of symptoms and associated mycological and/or radiologic data 
supporting the assessment of successful outcome.
Table 4
Investigator Guidance for Successful Outcome
Clinical 
Response
Mycological 
Response
Radiological Response 


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Success

Resolution of all 
attributable clinical 
symptoms and physical 
findings

Partial resolution of 
attributable clinical 
symptoms and physical 
findings

Eradication

Presumed 
Eradication

Improvement from 
screening

No signs on 
radiological images 
at screening (only 
for proven IFI 
based on other 
investigations)
IFI: invasive fungal infection
Mode of Intravenous Administration:
Oral Dosing (only for subjects 126 to < 18 years of age with a body weight of at least 12 
kg):
Return visits should coincide with days when study- related assessments are 
required.Visits should occur on days when study related assessments are required.
The daily dose is based on body weight and is intended to deliver a dose approximately equal 
to 10 mg/kg. The oral and intravenous formulations are equivalent on a mg:mg basis. The 
lower limit for oral dosing is 12 6 years of age and with a body weight of at least 1218 kg.
Subjects will receive isavuconazonium sulfate as an oral capsule (the number of 
capsules will correspond to their weight; see Table 5).
Table 5
Oral Dosing Regimen by Body Weight
Body weight 
(kg)
Loading (Day 1 and Day 2)/Total Daily 
Isavuconazonium Sulfate Dose (mg)
Maintenance (up to 84 days [IA] or 
180 days [IM])/Total Daily 
Isavuconazonium Sulfate Dose (mg)
12 to< 18
3 × 2 capsules/447 mg
1 × 2 capsules/149 mg
18 to < 25 24
3 × 3 capsules/670.5 mg
1 × 3 capsules/223.5 mg
25 to < 32 31
3 × 4 capsules/894 mg
1 × 4 capsules/298 mg
≥ 32
3 × 5 capsules/1117.5 mg
1 × 5 capsules/372.5 mg
Mode of Oral Administration:
Subjects will receive isavuconazonium sulfate as an oral capsule (the number of capsules 
will correspond to their weight; see table above).
Increase or Reduction in Dose of the Study Drug(s)
Dose increases and reductions to study drug for a given individual subject are prohibited.  
The mg/kg dose is to be consistent throughout study conduct. Dose increase or 
reductions to the study drug on a mg/kg basis are not allowed. However, if a subject has 
substantial weight changes, the number of capsules for oral dosing should be reassessed 
per Table 5.






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IV Synopsis, Statistical Methods
WAS:
Pharmacokinetics
Observed plasma trough concentration data for isavuconazole will be presented in listings. 
Spaghetti plots by age cohort will be produced.
IS AMENDED TO:
Pharmacokinetics
Observed plasma trough concentration data for isavuconazole will be presented in listings. 
Spaghetti plots by age cohort will be produced.
V Flow Chart and Schedule of Assessments
Flow Chart
WAS:
Flow Chart
IS AMENDED TO:
Figure 1  Flow Chart
2 Study Objective(s), Design and Endpoints
2.3.3 Other Endpoints
WAS:
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any day 
between day 14 and day 42, while the subject is still receiving study drug.
After receiving their first dose of oral capsules, subjects will be asked to assess their initial 
experience with the new oral formulation (i.e., Acceptability Assessment).
IS AMENDED TO:
In addition to the above, 24-hour pharmacokinetic samples will be obtained on any one day 
between day 14 and day 42, while the subject is still receiving study drug.
After receiving their first dose of oral capsules, subjects will be asked to assess their initial 
experience with the new oral formulation (i.e., Acceptability Assessment [Appendix 12.7]).
IV Synopsis, Inclusion/Exclusion Criteria and 3 Study Population
3.2 Inclusion Criterion #8
WAS:
Male subject who is of childbearing potential must not donate sperm starting at screening and 
throughout the study and for 30 days after the final study drug administration.
IS AMENDED TO:
Male subject who is of childbearing potential must not donate sperm starting at screening and 
throughout the study and for 30 days after the final study drug administration.


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4 Treatment(s)
4.1.1 Study Drug(s)
WAS:
The test drugs for this study are 372 mg isavuconazole sulfate for injection or 74.5 mg 
isavuconazonium oral capsules.
Oral Dosing:  
Isavuconazonium sulfate will be supplied as oral capsules per blister card. Each capsule 
contains 74.5 mg isavuconazonium sulfate (40 mg isavuconazole). The capsule is a Swedish
orange color.
IS AMENDED TO:
The test drugs for this study are 372 mg isavuconazole sulfate for injection or 74.5 mg 
isavuconazonium sulfate oral capsules.
Oral Dosing:  
Isavuconazonium sulfate will be supplied as oral capsules per blister cardpackaged in 
aluminum blisters with desiccants in secondary child-resistant cards. Each capsule 
contains 74.5 mg isavuconazonium sulfate (40 mg isavuconazole). The capsule is a Swedish 
orange color.
5 Treatments and Evaluation
5.1.3 Treatment Compliance
WAS:
If the subject is discharged while continuing treatment with intravenous dosing, the subject 
must return to the research facility or other approved facility every day to receive the daily 
dose. Vital signs will be taken pre and post dose. Infusion reaction and other safety 
monitoring will be conducted. 
Subjects who are discharged from the hospital with oral capsules for at-home administration 
must return weekly for study drug accountability and to receive new oral dosing supplies. 
Subjects will be provided with 1 week worth of study medication, instructions and a daily 
dosing log for documentation of ingestion of the oral study medication.
Study subjects and their parents/legal guardians should be counseled on the need to meet 
100% compliance with study drug. Investigator or designee should ensure that study subjects 
meet this goal throughout the study period.  
The date and time of dosing will be recorded once the first capsule is ingested. The subject 
should ingest the entire dose within 5 minutes. If the entire dose is not ingested within 5 
minutes, record the reason for dosing delay in the source documentation. If the subject 
should vomit any of the medication, this is to be recorded as well. The dose is NOT to be 
repeated. Compliance of the study drug will be monitored by the accounting of unused 
medication returned by the subject at visits. Compliance will be verified by the accounting of 
study drug at the weekly visits after day 7 and/or at the EOT visit.  


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When study drug is administered at the research facility, it will be administered under the 
supervision of study personnel. A subject daily dosing log will be collected to record 
date/time and completeness of dosing for each day.
IS AMENDED TO:
If the subject is discharged while continuing treatment with intravenous dosing, the subject 
must return to the research facility or other approved locationfacility every day to receive the 
daily intravenous dose. Vital signs will be taken pre and post dose. Infusion reaction and 
other safety monitoring will be conducted. 
Subjects who are discharged from the hospital with oral capsules for at-home administration 
must return weekly for study drug accountability and to receive new oral dosing supplies. 
Subjects will be provided with approximately 1-week worth of study medication, dosing
instructions and a daily dosing log for documentation of ingestion of the oral study 
medication.
Study subjects and their parents/legal guardians should be counseled on the need to meet 
100% compliance with study drug. Investigator or designee should ensure that study subjects 
meet this goal throughout the study period.  
The subject or parent/legal guardian must record the date and time of oral dosing will be 
recorded once the first capsule is ingested. The subject should ingest the entire dose within 5 
minutes. If the entire dose is not ingested within 5 minutes, record the reason for dosing 
delay in the source documentation. If the subject should vomit any of the medication, this is 
to be recorded as well. The dose is NOT to be repeated. Compliance of the study drug will be 
monitored by review of the oral dosing log and the accounting of unused medication 
returned by the subject at each scheduled visits. Compliance will be verified by the 
accounting of study drug at the weekly visits after day 7 and/or at the EOT visit.  
When study drug is administered at the research facility, it will be administered under the 
supervision of study personnel. A subject daily dosing log will be collected to record 
date/time and completeness of dosing for each day.
Study subjects and their parents/legal guardians should be counseled on the need to 
meet 100% compliance with study drug dosing. The investigator or designee should 
ensure that study subjects adhere to this goal throughout the study.
5 Treatments and Evaluation
5.3.2 Pharmacokinetic Assessment
WAS:
In addition to the above, 24-hour pharmacokinetic samples for intravenous or oral dosing 
will be obtained on any day between day 14 and day 42, while the subject is still receiving 
study drug, for subjects who consent to participation in the 24-hour pharmacokinetic 
assessment.
IS AMENDED TO:
In addition to the above, 24-hour pharmacokinetic samples for intravenous or oral dosing 
will be obtained on any one day between day 14 and day 42, while the subject is still 
receiving study drug, for subjects who consent to participation in the 24-hour 


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pharmacokinetic assessment.
5 Treatments and Evaluation
5.3.3 Oral Dosing Acceptability Assessment
ADDED:
Refer to [Appendix 12.7 Oral Dosing Acceptability Assessment].
5 Treatments and Evaluation
Table 4 Total Amount of Blood Drawn
WAS:
Table 4 Total Amount of Blood Drawn
IS AMENDED TO:
Table 7 4 Total Amount of Blood Drawn
IV: intravenous;
10 Study Organization
10.1 Data and Safety Monitoring Board (DSMB)
WAS:
The DSMB members will not be employees of Astellas nor otherwise involved with the 
study conduct.
IS AMENDED TO:
The DSMB members will not be employees of Astellas nor otherwise involved with the 
study conduct; however, members of the DSMB could be members of the AC.
10 Study Organization
10.2 Adjudication Committee (AC)
WAS:
The AC members will not be employees of Astellas nor otherwise involved with the study 
conduct.
IS AMENDED TO:
The AC members will not be employees of Astellas nor otherwise involved with the study 
conduct; however, members of the AC could be members of the DSMB.


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12 Appendices
ADDED:
12.7
Oral Dosing Acceptability Assessment


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14
COORDINATING INVESTIGATOR’S SIGNATURE
A Phase 2, Open-Label, Non-Comparative, Multicenter Study to Evaluate the 
Safety and Tolerability, Efficacy and Pharmacokinetics of Isavuconazonium 
Sulfate for the Treatment of Invasive Aspergillosis (IA) or Invasive 
Mucormycosis (IM) in Pediatric Subjects
ISN/Revised Protocol 9766-CL-0107
Version 4.0 Incorporating Substantial Amendment 3
05 Sep 2019
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree that it 
contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
<Insert name, department/affiliation, name of institution>
Date (DD Mmm YYYY)
Printed Name:
Address:


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15
SPONSOR SIGNATURES

SAP_003.pdf: 
Sponsor:  Astellas Pharma Inc. 
SAP Version 1.0 
ISN/Protocol 9766-CL-0107 
 
 
17-Oct-2019 
Version 1.0 
Astellas 
Page 1 of 29 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 1.0, dated 17-Oct-2019 
 
 
A Phase 2, Open-Label, Non-Comparative, Multicenter Study to 
Evaluate the Safety, Efficacy and Pharmacokinetics of 
Isavuconazonium Sulfate for the Treatment of Invasive 
Aspergillosis (IA) or Invasive Mucormycosis (IM) in Pediatric 
Subjects 
 
 
 
 
 
 
 
 
 
ISN: 9766-CL-0107 
 
IND: 72593 
 
 
Astellas Pharma Global Development, Inc. (APGD) 
 
1 Astellas Way 
Northbrook, IL 60062 
 
This document contains confidential information which is the intellectual property of Astellas. By accepting or reviewing 
this document, you agree to hold this information in confidence and not copy or disclose it to others or use it for 
unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) where 
disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of such information 
is made to a member of the investigator’s team who agrees to hold this information in confidence. 


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Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 6 
1 
INTRODUCTION ································
································
··················
 8 
2 
STUDY OBJECTIVE(S) AND DESIGN ································
·······················
 8 
2.1 
Study Objective(s) ································
································
·············
 8 
Safety Objective: To evaluate the safety and tolerability of isavuconazonium sulfate in 
pediatric subjects. ································
································
········  8 
Efficacy Objective: To assess the efficacy of isavuconazonium sulfate for the 
treatment of invasive Aspergillosis (IA) or invasive Mucormycosis (IM) in 
pediatric subjects. ································
································
········  8 
Pharmacokinetic Objective: To evaluate the pharmacokinetics of isavuconazole by 
monitoring the plasma concentrations in pediatric subjects during treatment 
with isavuconazonium sulfate. ································
··························
 8 
2.2 
Study Design ································
································
····················
 8 
2.3 
Randomization································
································
··················
 9 
3 
SAMPLE SIZE ································
································
·····················
 9 
4 
ANALYSIS SETS ································
································
·················
 10 
4.1 
Full Analysis Set ································
································
··············
 10 
4.2 
Modified Full Analysis Set ································
································
··  10 
4.3 
Safety Analysis Set ································
································
···········
 10 
4.4 
Pharmacokinetics Analysis Set ································
······························
 10 
5 
ENDPOINTS ································
································
·······················
 10 
5.1 
Safety Endpoints ································
································
··············
 10 
5.2 
Primary Efficacy Endpoint ································
································
···  11 
5.3 
Secondary Efficacy Endpoint(s) ································
·····························
 11 
5.3.1 
Key Secondary Endpoint(s) ································
····························
 11 
5.3.2 
Additional Secondary Endpoints ································
······················
 11 
5.3.3 
Other Secondary Endpoints ································
····························
 11 
6 
STATISTICAL METHODOLOGY ································
···························
 11 
6.1 
General Considerations ································
································
·······  11 
6.2 
Study Population ································
································
··············
 12 
6.2.1 
Disposition of Subjects ································
································
· 12 


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6.2.2 
Protocol Deviations ································
································
·····  12 
6.2.3 
Demographic and Other Baseline Characteristics ································
···  12 
6.2.4 
Underlying Diseases or Conditions ································
···················
 12 
6.2.5 
Baseline Fungal Culture Information ································
·················
 13 
6.2.6 
Previous and Concomitant Medications ································
··············
 13 
6.2.7 
Infectious Disease History ································
·····························
 13 
6.3 
Study Drug Exposure and Compliance ································
·····················
 13 
6.4 
Analysis of Efficacy ································
································
··········
 14 
6.4.2 
Analysis of Key Secondary Endpoints ································
················
 15 
6.4.3 
Analysis of Additional Secondary Endpoints ································
········  15 
6.4.4 
Other Secondary Endpoints ································
····························
 18 
6.5 
Analysis of Safety ································
································
·············
 19 
6.5.1 
Adverse Events ································
································
··········
 19 
6.5.2 
Clinical Laboratory Evaluation ································
························
 20 
6.5.3 
Liver Safety Assessment ································
·······························
 21 
6.5.4 
Vital Signs ································
································
················
 21 
6.5.5 
Routine 12-lead Electrocardiograms ································
··················
 22 
6.5.6 
Pregnancies ································
································
···············
 22 
6.5.7 
Other Safety-Related Assessments ································
····················
 22 
6.5.8 
Subgroups of Interest for Safety ································
·······················
 22 
6.6 
Analysis of Pharmacokinetic ································
································
 22 
6.6.1 
Estimation of Pharmacokinetic Parameters ································
··········
 22 
6.7 
Other Analyses ································
································
················
 22 
6.8 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 23 
6.9 
Analysis Windows ································
································
············
 23 
6.9.1 
Outliers ································
································
···················
 25 
7 
REVISION AND RATIONALE ································
································
 25 
7.1 
List of Changes in SAP Version 2.0 from Version 1.0 ································
···  25 
7.2 
List of Changes in SAP Version 3.0 from Version 2.0 ································
···  26 
8 
REFERENCES ································
································
····················
 26 
9 
APPENDICES ································
································
·····················
 27 
9.1 
Appendix 1 Visit Windows ································
································
··  27 


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9.2 
Appendix 2 Key Contributors ································
·······························
 28 
9.3 
Appendix 3 Author and Approver Signatures ································
·············
 29 
 
 
 


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Signature 
Date 
 
 
 
, Astellas 
 
 
______________ 
 
 
 
, Phastar 
 
 
______________ 
 
 
 
, Astellas 
 
 
______________ 
 
 
 
, Astellas 
 
 
______________ 
 
 
 
, Astellas            
 
 
______________ 
 
 
PPD
PPD
PPD
PPD
PPD


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations  
Abbreviations 
Description of abbreviations 
AC 
Adjudication Committee 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Intervals 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
GM 
Galactomannan 
hCG 
Human chorionic gonadotropin 
HLT 
High Level Term 
IA 
Invasive Aspergillosis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFD 
Invasive Fungal Disease 
IM 
Invasive Mucormycosis 
INR 
International normalized ratio 
IV 
Intraveneous 
K-M 
Kaplan-Meier 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Sample Size 
PD 
Protocol Deviation 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetics Analysis Set 
PPK 
Population Pharmacokinetics  
PT 
Preferred Term 
PTT 
Partial thromboplastin time 
QTc 
Corrected Q-T Interval 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS  
Statistical Analysis Software 
SD 
Standard Deviation 


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Abbreviations 
Description of abbreviations 
AC 
Adjudication Committee 
SOC 
System Organ Class 
TBL 
Total bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organization 
 
 
 
 
 
List of Key Terms 
Terms 
Definition of terms 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a 
subject or clinical investigation subject who has been administered 
a pharmaceutical product (remark: this means any investigational 
medicinal product) and which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, 
whether or not related to the medicinal product. 
Baseline 
Baseline is the time point prior to the first dose of study 
medication. The last measurements/evaluation prior to first dose 
of therapy is considered the baseline measure/evaluation. 
Investigational 
period 
Period of time where major interests of protocol objectives are 
observed, and where the test drug is usually given to a subject, 
and continues until the last assessment after completing 
administration of the test drug as stated in the protocol regarding 
V5 (End of Trial). 
Screening 
Process for retrieving candidates for the study. Process for 
checking the eligibility of subjects usually done during the “pre-
investigational period”. Screening evaluations will be performed 
on the same day of study enrollment. 
Screening failure 
Evaluated subject but did not fulfill protocol inclusion and/or 
exclusion criteria and failed to receive randomized or open label 
study treatment or decided not to participate anymore (withdrew 
consent) prior to completing pre-investigational treatment period. 


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Serious Adverse 
Event 
An adverse event is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following 
outcomes: results in death; a life-threatening adverse drug 
experience (subject is at immediate risk of death.); insubject 
hospitalization or prolongation of existing hospitalization, not 
associated with planned study procedures; a persistent or 
significant disability/incapacity; or a congenital anomaly/birth 
defect in the offspring of a subject who received study drug or a 
medically important events that may not be immediately life 
threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one 
of the other outcomes listed above. 
1 INTRODUCTION 
This Statistical Analysis Plan (SAP) contains technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes procedures for 
executing the statistical analysis to fulfill the objectives of the study. 
Changes to the planned analyses in the final SAP will be justified in the Clinical Study 
Report (CSR). 
 
2 STUDY OBJECTIVE(S) AND DESIGN 
2.1 
Study Objective(s)  
Safety Objective: To evaluate the safety and tolerability of isavuconazonium sulfate in 
pediatric subjects. 
Efficacy Objective: To assess the efficacy of isavuconazonium sulfate for the treatment of 
invasive Aspergillosis (IA) or invasive Mucormycosis (IM) in pediatric subjects. 
Pharmacokinetic Objective: To evaluate the pharmacokinetics of isavuconazole by 
monitoring the plasma concentrations in pediatric subjects during treatment with 
isavuconazonium sulfate. 
2.2 
Study Design 
This is a phase 2, open-label, non-comparative, multicenter study to assess the safety, 
efficacy and pharmacokinetics of isavuconazonium sulfate in pediatric subjects for the 
treatment of IA or IM. 
An approved informed consent form (ICF) must be obtained from the subject’s parent or 
legal guardian, and, if required, child assent prior to any study related procedures being 
performed. 


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Approximately 30 centers in the United States (US) and European Union (EU) are planned to 
enroll approximately 30 subjects ages 1 to < 18 years of age 
The subjects will enter into screening anytime between days -5 to day 1 (predose).  All 
subjects will be assigned to open-label treatment.  Treatment will begin on day 1 and then 
subjects are followed for 60 days  after the last dose for safety.    Treatment will be 
administered until the subject has a successful outcome as judged by the investigator or for a 
maximum duration of 84 days (IA) or 180 days (IM), whichever occurs first. 
After successful screening, all subjects will receive a loading regimen of isavuconazonium 
sulfate, which consists of a dose every 8 hours (± 2 hours) on days 1 and 2 (for a total of 6 
doses), followed by once daily maintenance dosing for up to 84 days (IA) or day 180 (IM) of 
dosing. The first maintenance dose should start 12 to 24 hours after the administration of the 
last loading dose. Subsequent maintenance doses will be administered once daily (24 hours ± 
2 hours from the previous maintenance dose). 
Blood sampling for the analysis of trough levels will be obtained from all subjects. The 
samples should ideally be drawn immediately prior to the next dose of study medication, but 
must be taken no earlier than 1 hour prior to the next dose on days 7, 14, 21, 42 and 84 or end 
of treatment (EOT). In addition to the above, 24-hour pharmacokinetic samples will be 
obtained on any day between day 14 and day 42, while the subject is still receiving study 
drug, for subjects that consent to participation in the 24-hour pharmacokinetic 
assessment. No additional samples are taken from IM subjects between day 84 through day 
180.   
Throughout the study, safety and tolerability will be assessed by the recording of AEs, vital 
signs, electrocardiograms (ECGs) and safety laboratory evaluations. All subjects will 
complete 2 follow-up visits (via telephone at the discretion of the investigator), 30 and 60 
days, after the subject’s day 84 (IA) /day 180 (IM) or EOT visit. 
If subject discontinues study drug prior to day 84 or day 180 (for IM), all EOT procedures 
must be completed. If subject continues to allow consent, end of study (EOS) information 
will be collected 30 and 60 days after EOT. 
Details of the schedule of clinical assessments are available in the protocol. 
2.3 
Randomization 
This is an open-label study with no randomization.  
3 SAMPLE SIZE  
The sample size of approximately 30 subjects is planned. No formal sample size calculation 
was performed. 
Evaluable subjects are subjects that have received at least 1 dose of study drug. Every effort 
will be made to achieve at least 5 evaluable subjects per age cohort: 1 to < 12 years of age 
and 12 to < 18 years of age. The sponsor reserves the right to stop enrollment if the cohort 


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requirements are not achieved. There will be no replacements for any subject that is enrolled 
but later determined to be non-eligible. 
4 ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
The determination of whether subjects are included or excluded from the safety and efficacy 
analysis sets may require using data which will arrive after database hard-lock.  
4.1 
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who are enrolled and receive at least 
one dose of study drug. This will be the primary analysis set for efficacy analyses. 
4.2 
Modified Full Analysis Set 
The modified FAS (mFAS) will consist of the subset of the FAS subjects who have either 
probable or proven IA or IM diagnosis at baseline or up to 10 days after first dose. Subjects 
with a possible diagnosis of IA or IM will not be included in this subset. The mFAS will be a 
secondary analysis set for efficacy analyses.  Select demographic and baseline characteristics 
may also be summarized for the mFAS. 
4.3 
Safety Analysis Set  
The safety analysis set (SAF) will consist of all subjects who are enrolled and receive at least 
1 dose of study drug. For this study, the SAF is the same as the FAS.  For the statistical 
summary of the safety data, the SAF will be used. 
4.4 
Pharmacokinetics Analysis Set  
The pharmacokinetic analysis set (PKAS) consists of all subjects who took at least 1 dose of 
study drug and who have at least 1 plasma concentration. Inclusion of subjects in the PKAS 
with missing data or major protocol deviations will be considered by the pharmacokineticist 
on a case-by-case basis. 
The PKAS will be used for all summaries and analyses of the pharmacokinetic data. 
5 ENDPOINTS  
5.1 
Safety Endpoints  
Safety endpoints will include adverse events (AEs), vital signs, electrocardiogram (ECGs) 
and laboratory parameters.  
 


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5.2 
Efficacy Endpoints 
5.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be all-cause mortality through day 42. Any death that 
occurred after first dose of study through day 42 will be included.  Any lost to follow-up 
between first dose and day 42 will be considered a death. 
5.2.2 
Secondary Efficacy Endpoint(s) 
5.2.2.1 Key Secondary Endpoint(s) 
The key secondary efficacy endpoints will be all-cause mortality through day 84 and EOT.  
Any death that occurred after first dose of study drug through day 84 and EOT will be 
included. Any lost to follow-up between first dose and day 84 and EOT will be considered a 
death. 
5.2.2.2 Additional Secondary Endpoints 
Additional secondary efficacy endpoints will include: 
• Adjudication Committee (AC) and Investigator assessment of clinical, radiological 
and mycological response through day 42, day 84 and EOT.  
• AC assessment of overall response at day 42, day 84 and EOT 
5.3 
Other Endpoints 
Other endpoints encompass pharmacokinetic variables, including plasma trough (pre-dose) 
levels on days 7, 14, 21, 42 and 84 or EOT.  
6 STATISTICAL METHODOLOGY   
6.1 
General Considerations 
Continuous data will be summarized descriptively including the number of subjects (n), 
mean, standard deviation (SD), median, minimum and maximum.  Categorical data will be 
summarized by frequencies and percentages with 95% confidence interval (CI). Efficacy data 
will be summarized by type of infection including IA, IM and mixed IA/IM infected subjects.  
Safety summaries will also be presented for by type of infection.   The IA group will 
comprise subjects with IA infection without known IM infection; the IM group will comprise 
subjects with IM without known IA infection; and the IA/IM group will comprise subjects 
with mixed IA/IM infection. Analysis Windows will be used and, for those parameters with 
weekly data collection, are illustrated below in Section 6.9.  For those parameters collected 
less often appropriate windows will be defined.  Note that, IM and IA/IM infected subjects 
will be reported to conclusion of treatment and 60 day follow-up although day 180 is not 
considered an endpoint analysis.  Kaplan Meier (K-M) analyses for mortality will incorporate 
all survival data to day 240 if IM subjects are included. 


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All data summarization and analyses will be performed using SAS® Version 9.1.3 or higher. 
Specifications for table, figures and data listing formats can be found in the Tables, Listings, 
and Figures (TLF) specifications. 
6.2 
Study Population 
In general, data such as subject disposition, demographics and baseline characteristics will be 
summarized for FAS population. 
6.2.1 
Disposition of Subjects 
Disposition of subjects will be summarized for all subject.   
Number of subjects who complete or prematurely discontinue from treatment or study (i.e., 
follow up period) will be summarized. For each discontinuation, the primary reason reported 
by the investigator will be summarized. Number and percentage of subjects for each analysis 
population will be summarized.  
6.2.2 
Protocol Deviations  
The number and percentage of subjects with the following protocol deviation (PD) criteria 
will be summarized for each criterion. Subjects deviating from a criterion more than once 
will be counted once for the corresponding criterion. 
 Some unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment. 
6.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized descriptively for FAS 
and mFAS.   Descriptive statistics for age, weight, body mass index (BMI) and height at 
study entry will be presented.  Frequency tabulations for sex, ethnicity, age cohorts and race 
will be presented.  
Please note that all Physical Examination Data will be reported in listing. For Post-Baseline 
visits, recorded abnormal findings/conditions that have worsened from Screening/Baseline, 
and are clinically significant, will be recorded on the Adverse Events form. 
6.2.4 
Underlying Diseases or Conditions  
All primary underlying diseases and risk factors will be reported using the FAS and mFAS 
populations.  Primary underlying disease diagnosis will be listed with full status of disease 
diagnosis, timing, severity and/or resolution level. This data will be tabled using Medical 
Dictionary for Regulatory Activities (MedDRA) codes and listed alphabetically. The number 
and percentage of subjects will be summarized by diagnosis [system organ class/preferred 


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term (PT)] and presentation status (New Diagnosis, Remission and Relapse).  The summary 
will also include solid organ transplant and bone marrow or other progenitor cell transplant 
by type. 
6.2.5 
Baseline IFI  
The descriptive summary includes subjects in each category of fungal infection site and 
fungal culture organism(s) by genus at baseline using the FAS and mFAS populations.  
Baseline will include all data collected from Day -28 to Day 10, as relavant.  These include 
Host factors, Clinical factors, Mycological Criterion and Other invasive fungal disease (IFD) 
signs.   
In addition, categorization of patient’s fungal infection will include Proven, Probable or 
Possible.   This categorization is evaluated again on Day 10.  Day 10 may provide more 
information than baseline given time for additional confirmatory laboratory results for 
subjects that may upgrade or downgrade fungal diagnosis.  For example, a final baseline 
evaluation of subject status Proven, Probable or Possible will be determined using the 
combination of data collected. 
6.2.6 
Previous and Concomitant Medications 
Prior, concomitant and post medications will be summarized by therapeutic subgroup 
(Anatomical Therapeutic Chemical [ATC] 2nd level) and chemical subgroup (ATC 4th level) 
and preferred World Health Organization (WHO) using the FAS and mFAS populations. 
Subjects taking the same medication multiple times will be counted once per medication and 
investigational period. A medication which can be classified into several chemical and/or 
therapeutic subgroups is presented in all chemical and therapeutic subgroups.  Systemic 
antifungal therapies will be reported separately.  
Previous medications are defined as medications that subjects started and ended prior to first 
administration of study medication. Analysis Windows will be used, See below Section 6.9. 
Concomitant medications are defined as any medications that subjects took after the first dose 
of study medication and through 60 days post EOT. Medications that started prior to first 
administration of study drug  and  continued while study drug was given will be counted in 
both previous and concomitant medications. 
6.2.7 
Infectious Disease History 
History of all fungal, viral and bacterial infections within 14 days prior to screening will be 
reported among FAS and mFAS. The data will be coded using MedDRA. The number and 
percent of subjects in each PT will be presented in alphabetic order. All medical history will 
be included in the listings. 
6.3 
Study Drug Exposure and Compliance  
Study drug exposure will be descriptively summarized for the SAF and mFAS population. 
Extent of exposure is defined as the number of days between the start and the end date of 
study drug, where the duration will be calculated by: (end date – start date+1). Additionally 


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average daily mg dose and average daily mg/kg doses, for LD and maintenance, IV and Oral 
summaries will be presented using descriptive statistics for continuous data. 
 
The number and percent of subjects with an extent of exposure will be summarized within 
the following day ranges: >0 to ≤ 2 days, >2 to ≤ 7 days, >7 to ≤ 14 days, >14 to ≤ 21 days, 
>21 to ≤ 42 days, >42 to ≤ 56 days, >56 to ≤ 84 days, and >84 days.  In addition, cumulative 
exposure will be summarized by the number and percent of subjects for the following 
categories: ≥ 1 day, ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 42 days, 
≥ 56 days and ≥ 84 days. 
6.4 
Analysis of Efficacy  
Efficacy variables will be summarized for IA, IM and IA/IM disease groups using FAS and 
mFAS populations. No formal inferential analyses will be performed.  Frequencies, 
percentages, min/max and 95% CIs will be part of the description/summary of the data.   
6.4.1.1 Analysis for Primary Efficacy Endpoint(s)  
The primary efficacy endpoint will be all-cause mortality through day 42. Any death that 
occurred after first dose of study drug through day 42 will be included where each subject 
will be either classified as a dead or alive. Subjects who died on or before day 42, as well as 
subjects who are lost to follow-up before day 42 will be counted as deaths. The crude all-
cause mortality rate will be calculated by dividing the number of deaths by the number of 
FAS subjects, and a 2-sided exact 95% CI will be calculated.  
6.4.1.2 Other Analysis of Primary Efficacy Endpoint(s)  
All-cause mortality rate over time will be estimated using Kaplan-Meier method. This 
analysis will generate a survival function from Day 1 through Day 42. A subject without 
reported death will be censored on the patient’s last assessment day. The cumulative 
probabilities of mortality rates (100%-survival rates) by Day 42 will be presented.  
6.4.1.3 Sensitivity Analysis for Primary Efficacy Endpoint  
The primary efficacy endpoint will be analyzed as in Section 6.4.1.1 using the mFAS 
population. In addition mFAS patients taking excluded concomitant medications used to treat 
IFDs will be eliminated for analysis of primary endpoint.  
A secondary sensitivity analysis will apply a condition on the crude success rate of overall 
outcome of treatment evaluated by the AC on Day 42. Patients who die before or on Day 42 
will be considered failures even if the DRC considers them successes. The crude success rate 
of overall outcome of treatment evaluated by the AC at Day 42 incorporating this condition 
will be summarized. A 95% CI for this crude success rate of overall outcome of treatment 
evaluated by the AC at Day 42 will be calculated using exact confidence limits. This 
sensitivity analysis will only be performed if any patient died by Day 42 is considered a 
success for treatment by the AC. 
 
 


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6.4.1.4 Subgroup Analysis for Primary and Secondary Efficacy Endpoint 
Primary and secondary efficacy endpoints will be analyzed as in Section 6.4.1.1 for the 
following subgroups: 
Grouping variable 
Subgroups 
Age groups 
  
1 to < 12 years of age 
12 to < 18 years of age   
Organism  
 
IA 
IM  
Mixed IA/IM 
Other 
 
Site of Infection 
Considered ad hoc depending on number of sites. 
 
6.4.2 
Analysis of Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints will be all-cause mortality through day 84 and EOT.   
The crude mortality rate will be calculated by dividing the number of deaths by the number 
of FAS and mFAS subjects, and a 2-sided 95% exact CI will be calculated. All deaths, which 
occurred on Day 1 (after initial dosing) to days 84 and EOT. 
6.4.2.1 Other Analysis of Key Secondary Efficacy Endpoint(s)  
Rate of death over time will be estimated using K-M which will generate a survival function 
from Day 1 through 84 and for Day 1 through EOT. A subject obsevred to endpoint time, and 
without reported death, will be censored on the subject’s last assessment day. The cumulative 
probabilities of mortality rates (100%-survival rates) by the end of study will be presented. 
K-M curve for time to death will be generated.  
6.4.3 
Analysis of Additional Secondary Efficacy Endpoints 
Additional secondary efficacy endpoints will be overall, clinical, radiological and 
mycological response through day 42, day 84 and EOT. AC will assess all endpoints, 
Investigator’s assessment include all endpoints except the overall response.  
 
Each endpoint with the assessment criteria defined below will be summarized descriptively 
for FAS and mFAS populations through day 42, day 84 and EOT. Frequencies and 95% CI 
will be reported. All data will be represented in Listings by subject. 
 
6.4.3.1 Investigator-assessed Clinical Response 
Category 
Outcome 
Success 
• resolution of all attributable signs and 
symptoms OR 


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• resolution of attributable clinical 
symptoms and physical findings 
Failure 
• no resolution of any attributable signs 
and symptoms OR  
• no resolution of any attributable signs 
and symptoms (no change) or worsening 
of any attributable signs and symptoms 
Not Evaluable 
• Results not available /subject 
unevaluable OR  
• No attributable signs and symptoms 
 
6.4.3.2 Investigator-assessed Mycological Response  
Category 
Outcome 
Success 
• Eradicated  
• Presumed Eradication 
Failure 
• Persistence  
• Presumed persistence 
Not Evaluable 
• Indeterminate  
• No Mycological Follow-up Results 
Available 
No Mycological evidence at screening  (up 
to day 104) 
Remains as is 
No baseline signs, not applicable for 
response. 
Remains as is 
 
6.4.3.3 Investigator-assessed Radiological Response  
Category 
Outcome 
Success 
• ≥ 90% improvement 
• ≥ 50% to < 90% improvement  
• ≥ 25% to 50% improvement (for Day 42 
only) 
Failure 
• < 25% improvement at any time  
• No Signs or Radiological Images 
Not Evaluable 
• Results Not Evaluable 
• No Radiological Data Available 
6.4.3.4 AC-assessed Clinical Response  
Clinical response will be defined as follows: 
Summary 
Category 
Outcome 
Success 
Complete 
• Resolution of all attributable 
clinical symptoms and 
physical findings 


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Partial 
• Resolution of at Least some 
of the clinical symptoms and 
physical findings associated 
with IFD  
Failure 
Stable 
• Minor of no change in 
clinical symptoms and 
physical findings associataed 
with IFD 
Progression 
Worsening or new clinical 
symptoms and physical findings 
associated ith IFD, or if 
alternative systemic antifungal 
treatment is required 
Not Evaluable 
Not Assessed 
 
No clinical signs or symptoms 
at baseline 
 
 
6.4.3.5 AC-assessed Mycological Response  
 
Category 
Outcome 
Success 
Eradication 
No growth of the original (at 
baseline) causative organism on 
culture or identified by 
histology/cytology on post 
baseline (after day 7) cultures 
and/or histology/cytology 
Presumed eradication 
Missing post baseline 
documentation of eradication of 
the original causative organism at 
baseline PLUS resolution of all or 
some clinical symptoms/physical 
finding 
Failure 
Persistence 
Persistence of the original 
causative organism cultured or 
identified by histological 
/cytology at baseline or ?? 
Presumed Persistence 
Missing post baseline 
documentation of the persistence 
of the original causative organism 
at baseline PLUS no resolution or 
worsening of any clinical 
symptoms/physical findings 
Not Evaluable 
No Mycological Evidence 
 
 


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6.4.3.6 AC-assessed Radiological Response  
Summary 
Category 
Outcome 
Success 
Complete: 
≥ 90% improvement 
 
Partial 
At least < 25% response at day 42 and 
at least 50% by Day 84  
Failure 
Stable 
Minor or no change in radiographic 
abnormalities associated with IFD, but 
no signs of progression 
Progression 
Worsening or new radiological 
abnormalities associated with IRD 
Not Evaluable 
No Post baseline 
Radiology 
No post baseline Radiology available 
with baseline evidence of radiolical 
disease  
Radiology 
Radiology not applicable at baseline 
 
6.4.3.7  AC-assessed Attributable Mortality   
Category 
Outcome 
Directly Due to IFD 
Death directly due to consequences of 
progressive IFD (clear evidence that 
mortality is due to progressive IFD) 
Evidense Death Associated with IFD 
Death associated with evidence of 
residual or ongoing IFD at time of 
death, but death may be due to IFD or 
progression of underlying disease  
No Evidense Death Associated 
Death associated with no evidence of 
residual or ongoing IFD) 
Indeterminant 
Indeterminant Cause 
No Known Death 
No Known Death 
 
6.4.3.8  AC-assessed Overal Response  
Category 
Outcome 
Success 
• Complete-Success 
• Partial-Success 
Failure 
• Stable-Failure 
• Progression-Failure 
Not Evaluable 
• Results Not Evaluable 
 
6.4.4 
Other Secondary Endpoints 
Population pharmacokinetics and/or pharmacokinetic/pharmacodynamics analyses will be performed 
by modeling and simulation scientist. All details of the population pharmacokinetic analysis will be 


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described in a separate analysis plan and a separate population pharmacokinetic modeling report will 
be written. 
6.5 
Analysis of Safety 
All safety data will be presented for the SAF population. AEs will be coded using MedDRA.  
Frequency and percentage will be presented for each category. 
6.5.1 
Adverse Events 
TEAE is defined as an AE observed after starting administration of the study drug through 30 
days after EOT. The number and percentage of subjects with treatment-emergent AEs, 
serious adverse events (SAEs), AEs leading to withdrawal of treatment, and AEs related to 
study drug will be summarized by MedDRA system organ class, MedDRA High Level term, 
and MedDRA preferred term for overall subjects and by subjects in each age cohort. The 
number and percentage of AEs by severity will also be summarized. All AEs will be listed. 
A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator. The incidence of treatment emergent AEs will be summarized by relationship to 
study drug and severity for all subjects and by each age cohort.  The protocol defines how 
Treatment Emergent AEs are determined.  Although all AEs are collected, the summary 
Table will be based on the TEAEs.  
Clinically significant out-of-range laboratory findings are to be determined and documented 
by the investigator/subinvestigator who is a qualified physician. Clinically significant 
changes will be recorded as AEs. 
An overview table will include the following: 
● 
Number of TEAEs, 
● 
Number and percentage of subjects with TEAEs, 
● 
Number of drug related TEAEs, 
● 
Number and percentage of subjects with drug related TEAEs, 
● 
Number of serious TEAEs, 
● 
Number and percentage of subjects with serious TEAEs, 
● 
Number of serious drug related TEAEs, 
● 
Number and percentage of subjects with serious drug related TEAEs, 
● 
Number of TEAEs leading to permanent discontinuation of study drug, 
● 
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, and 
● 
Number of deaths.  
 
The number and percentage of subjects with TEAEs, as classified by SOC, High Level Term 
(HLT), and PT will be summarized. Summaries will be provided for the following: 
 
● 
TEAEs 


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● 
drug related TEAEs,  
● 
serious TEAEs,  
● 
drug related serious TEAEs,  
● 
TEAEs leading to permanent discontinuation of study drug,  
● 
drug related TEAEs leading to permanent discontinuation of study drug,  
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by time interval. For each adverse event in a particular interval, a subject will be 
counted if there is an onset of a treatment-emergent adverse event regardless of onset in other 
intervals. 
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by subgroups defined in Section 6.5.7. 
6.5.2 
Clinical Laboratory Evaluation 
Clinical laboratory samples will be collected and reported based on timepoints as listed in the 
Protocol Table 1 and Table 2 in Section 1 based on lab sample collection visits. 
Clinical Laboratory variables will be created for each of the following: 
Chemistry: 
Hematology: 
Sodium 
Red blood cells 
Potassium 
White blood cells (total leukocytes) 
Magnesium 
Hemoglobin 
Calcium 
Hematocrit 
Chloride 
Platelets (thrombocytes) 
Glucose 
Neutrophils (ANC) 
Creatinine 
Eosinophils 
Creatine phosphokinase/Creatine kinase 
Basophils 
Alkaline phosphatase (ALP) 
Lymphocytes 
 
Monocytes 
 
Blast cells 
Hepatic Panel: 
Pregnancy Test: 
Albumin 
Human chorionic gonadotropin (hCG) 
Total bilirubin (TBL) 
 
Direct Bilirubin 
Other: 
Total Protein 
Serum galactomannan (GM) 
Alanine aminotransferase (ALT) 
Partial thromboplastin time/international 
normalized ratio (PTT/INR) 
Aspartate aminotransferase (AST) 
 
The baseline value will be the last non-missing value taken on or prior to first dose of study 
drug. Quantitative values evaluated by the central laboratory including hematology and 
biochemistry will be summarized using mean, standard deviation, minimum, maximum and 
median at each analysis visit. Additionally, a within-subject change will be calculated as the 
post-baseline measurement minus the baseline measurement and summarized in the same 


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way. Clinical Laboratory data will be reported using the SAF population by Clinical 
Laboratory Tests collected at baseline and days 7, 28, 56 and 84 (or EOT).  
Shifts relative to normal ranges from baseline to each time point during treatment period in 
lab tests will also be tabulated.  Laboratory data will be displayed in listings. For quantitative 
laboratory measurements descriptive statistics will be used to summarize results and change 
from baseline for subjects.  
Each laboratory result will be classified as low, normal, or high at each visit according to the 
laboratory supplied reference ranges as specified in the Protocol. 
6.5.3 
Liver Safety Assessment 
The liver safety assessments will be summarized by the categories below based on the 
measurement from Alkaline Phasphatase (ALP), Alanine Transaminase (ALT), total bilirubin 
(TIBILI), Aspartate Transaminase (AST), and their combination.  These parameters will be 
based on measurements from a central laboratory. 
The subjects highest value from Day 1 to Day 84 IA or Day 180 IM or EOT will be used. 
This criterion is without regards to the subjects baseline value.   
• ALT > 3xULN, > 5xULN, > 10xULN, > 20xULN 
• Total Bilirubin > 2xULN 
• (ALT or AST > 3xULN) and Total Bilirubin > 2xULN 
• (ALT or AST > 3xULN) and ALP < 2xULN and Total Bilirubin > 2xULN 
The last 2 criteria to where 2 or more parameters are evaluated will be with the 
measurements on the same day or up to 1 day apart.  The samples within 1 day to be 
considered. For example, if ALT is on day 10, ALP in on day 11 and TIBILI in on day 12, 
this data should be considered.  If ALT and ALP is on day 10, and TBILI is on day 11, this 
data should be considered. 
 The samples within 1 day apart can be used however the last criterion with 2 parameters, all 
3 should be from the same day to be considered. For example, if ALT in on day 10   
An eDish display plot of all patients will be created. The step-one eDISH including ALT 
alanine aminotransferase, TBL total bilirubin, eDISH evaluation of drug-induced serious 
hepatotoxicity, ULRR upper limit of reference range or normal will be created with all 
patients plotted.   
6.5.4 
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects in the SAF by treatment day from day 1 to day 84 (or EOT).  
Vital signs data will be displayed in listings.  


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The baseline visit (screening predose period day -5 to 5) is the last non-missing measurement 
value taken prior to initial study drug administration.  Post baseline visits will include vital 
signs measured prior to and again approximately 1 hour after the end of each infusion. 
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate and 
temperature) will be summarized using mean, standard deviation, minimum, maximum and 
median by Treatment Visit. Within subject change in vital sign values between visits will be 
summarized from baseline on.   
6.5.5 
Routine 12-lead Electrocardiograms 
Number and percent of subjects with 12 lead ECG abnormalities as well as number. and 
percent of subjects whose 12 lead ECG reading changed from normal at baseline to abnormal 
will be tabulated by Analysis Visit.  
The number and percentage of subjects who have treatment emergent changes toward worst 
category in the ECG interpretations assessed by investigators will be caluculated.  The 
interpretations are the followings: Normal, Abnormal-clinically relevant and Abnormal-not 
clinically relevant.  Subjects who have both baseline and at least one post-baseline value will 
be included.  
6.5.6 
Pregnancies  
A detailed listing of all pregnancies will be provided. 
6.5.7 
Other Safety-Related Assessments  
None. 
6.5.8 
Subgroups of Interest for Safety 
Safety data will be summarized for for IA, IM and mixed IA/IM groups separately. Selected 
safety variables (treatment emergent adverse events and vital signs) will be summarized 
using summary statistics for the subgroups defined on the basis of the categorized variables 
listed below: 
Grouping variable 
Subgroup 
Age group 
< 12 years 
 
>= 12 years 
 
 
6.6 
Analysis of Pharmacokinetic  
6.6.1 
Estimation of Pharmacokinetic Parameters 
Sampling times along with plasma concentrations of isavuconazonium sulfate levels will be 
displayed in listings. Descriptive statistics (e.g. n, mean, SD, minimum, median, maximum, 
coefficient of variation (CV), geometric mean and geometric CV will be provided for plasma 
concentrations of isavuconazole.   


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Plasma concentration data from this study will be used to support a population 
pharmacokinetic (PK) model developed for Isavuconazonium Sulfate.   The results and the 
model development will be described in detail in a separate PPK report. All details of the 
pharmacokinetic analysis will be described in a separate analysis plan and a separate 
population pharmacokinetic modeling report will be written. 
Existing population pharmacokinetic model will be updated based on isavuconazole plasma 
concentration data obtained from subjects who have at least 1 pharmacokinetic sample.  
Population pharmacokinetics and/or pharmacokinetic/pharmacodynamics analyses will be 
performed by modeling and simulation scientist.  
6.7 
Other Analyses  
None. 
6.8 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
No interim analyses are planned for this study. 
 
6.9 
Analysis Windows  
AEs and Vital signs will be summarized using Analysis Windows as below:  
 
Analysis Visits 
Analysis Windows  
Baseline 
Day(s) <=1 up to initiation 
of first dose 
Day 2 
Day 2 
Day 3 
Day 3 
Day 7 
Day 5 to 9 
Day 14 
Day 12 to 16 
Day 21 
Days 19 to 23  
Day 28 
Days 26 to 30 
Day 35 
Days 33 to 37 
Day 42 
Days 40 to 44 
Day 49 
Days 47 to 51 
Day 56 
Days 54 to 58 
Day 63 
Day 61 to 65 
Day 70 
Days 68 to 72 
Day 77 
Days 75 to 79 
 
 
 
Cont. 
 


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Day 84 
Days 80 to 91 
Day 110 
Days 103 to 117 
Day 140 
Days 133 to 147 
Day 851 
Days 81 to 100  
Day 1151 
Days 101 to130 
Day 1451 
Days 143 to 147 
Day 2101 
Days 203 to 217 
Day 2401 
Days 233 to 247 
1Applies to IM and IA/IM subjects. 
See Appendix 1 for details of parameters for visit windows. 
 
6.9.1 
Imputation Rules for Incomplete Dates  
As a general principle, no imputation of missing data will be done. Exceptions are the start and 
stop dates of AEs and concomitant medication. The imputed dates will be used to allocate the 
concomitant medication and AEs to Treatment Visit and to determine whether an AE is/is not 
treatment emergent. Listings of the AEs and concomitant medications will present the actual 
partial dates; imputed dates will not be shown. 
In case of missing partial start and stop dates for AEs and concomitant medications, the 
following rules will be used: 
If the start date is missing or partial: 
● 
if the month is missing, use January 
● 
if the day is missing, use the first day of the month under consideration 
● 
if the year is missing, use year of the informed consent date 
● 
if the entire date is missing, use informed consent date 
If the stop date is missing or partial: 
● 
if the month is missing, use December 
● 
if the day is missing, use the last day of the month under consideration 
● 
if the year or the entire date is missing, set the stop date to December 31st, 2019 
If the imputed start date is after the stop date, then the imputed start date will be 1 day prior 
to the stop date. 
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 
If an onset date is missing or only the year is known, the imputed onset date will be the date 
of first dose of study drug. 


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If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates: 
● 
Date of first dose of study drug  
● 
January 1 of the year of AE onset date  
If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
● 
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date. 
● 
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates: 
○ Date of first dose of study drug 
○ Surrogate onset date 
If the imputed onset date is after the adverse event end date, the imputed 
onset date will be the same as the adverse event end date. 
If more than one observation exists within the analysis window, the observation closest to the 
scheduled visit day will be selected for that visit.  If there are two observations that have the 
same distance from the scheduled day, the value that is after the scheduled day will be 
selected in the analysis.  If more than one observation is made on the same day, an average 
value if continuous or the worst value if categorical will be included in the analysis. 
6.9.2 
Outliers  
Clinically significant out-of-range laboratory findings are to be determined and documented 
by the investigator/subinvestigator who is a qualified physician. At all scheduled time points 
during the clinical study, should any of the clinical laboratory test results be outside the 
normal range, the investigator may decide to repeat tests on new samples.  
7 REVISION AND RATIONALE  
7.1 
List of Changes in SAP Version 2.0 from Version 1.0 
The changes from the approved SAP Version 2.0 (Dated dd-Mmm-yyyy) to Version 3.0 that 
impact analyses are listed with the rationale in the table below. 
SAP 
Sections 
Description 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 


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7.2 
List of Changes in SAP Version 3.0 from Version 2.0 
The changes from the approved SAP Version 1.0 (Dated dd-Mmm-yyyy) to Version 2.0 that 
impact analyses are listed with the rationale in the table below. 
SAP 
Sections 
Description 
Rationale 
xxx 
yyyy 
zzzzz 
aaaa 
bbbb 
cccc 
8 REFERENCES 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 


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9 APPENDICES 
 
9.1 
Appendix 1 
Visit Windows  
 
The value used is that which is closest to the defined assessment day and also within visit day 
windows.  If two values are equally close, the latter is used in the analysis.  
 All the assessments will be allocated to electronic Case Report Form (eCRF) visit based on 
the table below. 
Visit Windows 
Protocol visit 
Target day 
Visit window  
Visit number 
Screening and 
Baseline 
≤D1 
D-5 to D1 
Pre dose period 
V1 (Day1) 
D1 
D1 
Visit 1 
V2 
D2 
D2 
Visit 2 
V3 
D3 
D3  
Visit 3 
V4 
D7 
D5 to D9 
Visit 4 
V5 
D14 
D12 to D16 
Visit 5 
V6 
D21 
D19 to D23 
Visit 6 
V7 
D28 
D26 to D30 
Visit 7 
V8 
D35 
D33 to D37 
Visit 8 
V9 
D42 
D40 to D44 
Visit 9 
V10 
D49 
D47 to D51 
Visit 10 
V11 
D56 
D54 to D58 
Visit 11 
V12 
D63 
D61 to D65 
Visit 12  
V13 
D70 
D68 to D72 
Visit 13 
V14 
D77 
D75 to D79 
Visit 14 
V15  
D84 
IA D77 to D91 
or 
IM D82 to D86 
Visit 15 
IA EOT  
IA EOS 
D110  
D103 to D117 
IA Follow-up 
IA EOS  
D140 
D133 to D147 
IA Follow-up 
V16 
D115 
D113 to D117 
IM Visit 16 
V17 
D145 
D143 to D1146 IM Visit 17 
V18 
D180 
D173 to D187 
IM Visit 18  
EOT 


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IM EOS 
D210  
(or 30 day 
EOS) 
D203 to D217 
IM Follow-up 
IM EOS 
D240 
 (or 60 day 
EOS) 
D233 to D247 
IM Follow-up 
9.2 
Appendix 2 
Key Contributors  
 
 
 
, Astellas 
 
, Phastar 
 
, Astellas 
 
, Astellas 
 
, Astellas 
 
PPD
PPD
PPD
PPD
PPD


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9.3 
Appendix 3 
Author and Approver Signatures  
<Approve in MAGIC and retain the text indicating that “e-signatures are attached at end of 
document.”  If wet signatures are obtained, delete the above statement about e-signature.> 
<Create more signature lines  as appropriate in each region. Note that MAGIC does not 
require a box frame around although the older SAP template included.> 
STANDARD TEXT 
(E-signatures are attached at the end of document) <state once for all e-signatures.> 
<If someone has to provide a wet signature, add the following text “E-signatures are 
attached at end of document” above the MAGIC signatories to minimize any potential 
confusion for having the space blank while some have wet signatures. A hypothetical sample 
is below  where 
 provided a wet signature and 
 and 
 approved in 
MAGIC.> 
 
PPD
PPD
PPD
PPD