Patterns of Real-World Isavuconazole Use, Effectiveness, Safety, and Healthcare Resource Utilization-a Retrospective Chart Review Study of Patients With Mucormycosis or Invasive Aspergillosis (PRISMA)
Conditions: Invasive Aspergillosis, Mucormycosis
Sponsor: Pfizer

Cresemba® (isavuconazole)
C3791008 PRISMA NON-INTERVENTIONAL STUDY PROTOCOL
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NON-INTERVENTIONAL STUDY (NIS) PROTOCOL
Study information
Title
Patterns of Real-World Isavuconazole use, 
Effectiveness, Safety, and Healthcare 
Resource Utilization—a Retrospective Chart 
Review Study of Patients With 
Mucormycosis or Invasive Aspergillosis 
(PRISMA)
Protocol number
C3791008
Protocol version identifier
Final version 1.1
Date 
27 July 2020
Active substance
Isavuconazole (ATC code J02AC05)
Medicinal product
Cresemba®
Research questions and objectives
Primary objectives:

To document real-world clinical 
outcomes (all-cause mortality, 
overall response) of isavuconazole in 
patients with invasive aspergillosis or 
mucormycosis who are receiving 
treatment in routine clinical practice 
in Europe (France, Germany, Italy, 
Spain, and the United Kingdom).

To assess real-world safety 
(isavuconazole-related adverse 
events or serious adverse events) of 
isavuconazole in patients with 
invasive aspergillosis or 
mucormycosis receiving treatment in 
routine clinical practice in Europe.
Secondary objectives:

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
To describe demographic and clinical 
characteristics of patients with 
invasive aspergillosis or 
mucormycosis receiving 
isavuconazole in routine clinical 
practice in Europe.

To document treatment patterns 
among patients with invasive 
aspergillosis or mucormycosis 
receiving isavuconazole in routine 
clinical practice in Europe.

To quantify HCRU among patients 
with invasive aspergillosis or 
mucormycosis receiving 
isavuconazole in routine clinical 
practice in Europe.
Authors
 PhD
Pfizer Inc.
235 East, 42nd Street
New York, NY 10017 USA
 MD, MScPH
Evidera
The Ark, 201 Talgarth Rd.
London W6 8BJ United Kingdom
Co-authors
 MPH
Pfizer Inc.
235 East, 42nd Street
New York, NY 10017 USA
 MD, MBA
Pfizer Inc.
Eastern Point Road
Groton, CT 06340 USA
 PhD
Evidera
The Ark, 201 Talgarth Rd.
London W6 8BJ United Kingdom
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

Cresemba® (isavuconazole)
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 MD
 
PPD
Suite 1400, 7101 Wisconsin Ave.
Bethesda, MD 20814 USA
 PhD
Evidera
Suite 404, 7575 Trans-Canada Hwy.
St-Laurent, Québec, H4T 1V6 Canada
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD
PPD
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................4
2. LIST OF ABBREVIATIONS................................................................................................6
3. RESPONSIBLE PARTIES....................................................................................................8
4. ABSTRACT...........................................................................................................................9
5. AMENDMENTS AND UPDATES.....................................................................................13
6. MILESTONES.....................................................................................................................13
7. RATIONALE AND BACKGROUND................................................................................14
7.1. Study Background...................................................................................................14
7.2. Invasive Aspergillosis .............................................................................................14
7.3. Mucormycosis .........................................................................................................15
7.4. Study Rationale .......................................................................................................15
8. RESEARCH QUESTION AND OBJECTIVES .................................................................15
9. RESEARCH METHODS ....................................................................................................16
9.1. Study Design ...........................................................................................................16
9.2. Setting......................................................................................................................17
9.2.1. Study Sites ..................................................................................................17
9.2.2. Inclusion Criteria ........................................................................................17
9.2.3. Exclusion Criteria.......................................................................................18
9.3. Data Source and Data Collection Process...............................................................18
9.3.1. Study Periods..............................................................................................18
9.3.1.1. Index Event ...............................................................................18
9.3.1.2. Eligibility Period .......................................................................18
9.3.1.3. Data Collection (Chart Abstraction) Periods ............................19
9.4. Variables..................................................................................................................20
9.4.1. Demographic and Clinical Characteristics .................................................20
9.4.2. Isavuconazole Treatment Patterns ..............................................................25
9.4.3. Clinical Effectiveness.................................................................................29
9.4.4. Safety..........................................................................................................31
9.4.5. Survival Status............................................................................................35
9.4.6. Health Care Resource Utilization...............................................................35
9.5. Study Size................................................................................................................37

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9.6. Data Management ...................................................................................................38
9.6.1. Case Report Forms .....................................................................................38
9.6.2. Record Retention ........................................................................................39
9.7. Data Monitoring ......................................................................................................40
9.8. Data Cleaning..........................................................................................................40
9.9. Data Analysis ..........................................................................................................40
9.9.1. Missing Data...............................................................................................41
9.9.2. Planned Analysis ........................................................................................41
9.9.2.1. Analysis Plan for Primary Objectives .......................................41
9.9.2.2. Analysis Plan for Secondary Objectives ...................................41
9.9.3. Interim Analysis..........................................................................................42
9.10. Quality Control......................................................................................................42
9.11. Strengths and Limitations of the Research Methods.............................................42
9.12. Other Aspects ........................................................................................................43
10. PROTECTION OF HUMAN SUBJECTS ........................................................................44
10.1. Patient Information................................................................................................44
10.2. Patient Consent......................................................................................................44
10.3. Patient Withdrawal................................................................................................45
10.4. IRB or IEC ............................................................................................................45
10.5. Ethical Conduct of the Study ................................................................................46
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS AND/OR 
ADVERSE REACTIONS...................................................................................................47
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........48
12.1. Results Dissemination...........................................................................................48
12.2. Communication of Issues......................................................................................48
13. REFERENCES ..................................................................................................................49
14. LIST OF TABLES.............................................................................................................50
15. LIST OF FIGURES ...........................................................................................................50
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................50
ANNEX 2. ADDITIONAL INFORMATION.........................................................................50

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AEM
Adverse Event Monitoring
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
BAL
bronchoalveolar lavage
BDG
beta-(1,3)-D-glucan
CI
confidence interval
CIOMS
Council for International Organization of Medical Sciences
CMV
cytomegalovirus
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease of 2019
CRF
Case report form; also referred to as electronic data record
CRO
contract research organization
CSA
clinical study agreement
CT
computed tomography 
DHHS
Department of Health and Human Services
EDC
electronic data capture
EMA
European Medicines Agency
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
EORTC/MSG
European Organization for Research and Treatment of 
Cancer/Mycosis Study Group 
ER
emergency room
EU
European Union
FDA
Food and Drug Administration
FWA
Federal-Wide Assurance
FU
follow up
GEP 
Good Epidemiological Practice
GM
galactomannan
GPP 
Good Pharmacoepidemiology Practices
HCP
healthcare provider
HCRU
health care resource utilization
HEOR
health economics and outcomes research
ICD-9
International Classification of Diseases, 9th Revision
ICD-10
International Classification of Diseases, 10th Revision
ICF
informed consent form
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
ID
Identifying number

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Abbreviation
Definition
IEA
International Epidemiological Association
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and Outcomes 
Research
KM
Kaplan-Meier
LOS
Length of stay
MRI 
magnetic resonance imaging 
NIS
non-interventional study
NISMF 
NIS master file
OHRP
Office for Human Research Protections
PRISMA
Patterns of Real-World Isavuconazole use, Effectiveness, Safety, 
and Healthcare Resource Utilization—a Retrospective Chart 
Review Study of Patients With Mucormycosis or Invasive 
Aspergillosis
QT
QT interval
RTI
Research Triangle Institute
RTI-HS
RTI Health Solutions
RWE
real world evidence
SAE
serious adverse event
SAP
Statistical Analysis Plan
SECURE
A Phase III, Double-Blind, Randomized Study to Evaluate Safety 
and Efficacy of BAL8557 Versus Voriconazole for Primary 
Treatment of Invasive Fungal Disease Caused by Aspergillus 
Species or Other Filamentous Fungi
SOP
standard operating procedure
TDM
therapeutic drug monitoring
UK
United Kingdom
US
United States 
VITAL
Open-Label Study of Isavuconazole in the Treatment of Patients 
with Aspergillosis and Renal Impairment or of Patients with 
Invasive Fungal Disease Caused by Rare Moulds, Yeasts or 
Dimorphic Fungi

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
Anita H. Sung, PhD
Director Global 
HEOR 
Pfizer Inc.
235 East 42nd Street, 
New York, NY 10017 USA
Katherine Stull, MSc
Director, Health 
Economics
RTI Health Solutions
3040 East Cornwallis Road, 
Research Triangle Park, 
NC 27709 USA

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4. ABSTRACT
Study title: Patterns of Real-World Isavuconazole Use, Effectiveness, Safety, and Healthcare 
Resource Utilization—a Retrospective Chart Review Study of Patients With Mucormycosis 
or Invasive Aspergillosis (PRISMA)
Rationale and background: Invasive aspergillosis and mucormycosis are rare, life-
threatening fungal infections associated with high mortality.1,2 Treatment of invasive 
aspergillosis usually includes antifungal medications such as voriconazole or isavuconazole.1
Initial treatment of mucormycosis typically includes surgery to remove infected tissues and 
antifungal treatment with amphotericin B.1
Cresemba® (isavuconazole) is an antifungal agent whose mechanism of action involves 
blocking the production of a key component of the cell membrane of fungi, thus weakening 
the membrane and preventing fungal cell growth.3 Isavuconazole demonstrated non-
inferiority compared to voriconazole with improved safety profile in the SECURE clinical 
trial for patients with invasive aspergillosis (phase 3, randomized, double-blind, 
comparative-group; NCT00412893).4 Additionally, in the VITAL clinical trial (single-arm, 
open-label; NCT00634049), isavuconazole was well tolerated and showed activity against 
mucormycosis with efficacy comparable to that of amphotericin B in a matched case-control 
analysis.5 Isavuconazole was subsequently approved by the United States (US) Food and 
Drug Administration (FDA) and the European Medicines Agency (EMA) in 2015.
Following market authorization in 2015, real-world evidence (RWE) from European Union
(EU) is needed for further insight into isavuconazole use outside of a trial setting. The current 
study is a retrospective, multi-country chart review to be conducted in five European 
countries (France, Germany, Italy, Spain, and the United Kingdom [UK]), designed to obtain 
RWE to increase the knowledge of isavuconazole patterns of use, clinical response, HCRU, 
and safety in clinical practice.
Research objectives: The primary objectives are to document real-world clinical outcomes 
(all-cause mortality, overall response) and assess real-world safety (isavuconazole-related 
adverse events [AEs] and serious adverse events [SAEs]) of isavuconazole for patients with 
invasive aspergillosis or mucormycosis receiving treatment in routine clinical practice in 
Europe (France, Germany, Italy, Spain and the United Kingdom). The secondary objectives 
include describing demographic and clinical characteristics, documenting treatment patterns,
and quantifying health care resource utilization (HCRU) among patients with invasive 
aspergillosis or mucormycosis receiving isavuconazole in routine clinical practice in Europe.
Study design: A retrospective observational cohort study will be conducted, involving the 
review and abstraction of data from the medical records of patients diagnosed with invasive 
aspergillosis or mucormycosis who received treatment with isavuconazole. The target sample 
is approximately 600 patients across 22 sites located in Europe.a De-identified data on patient 
demographics, disease characteristics, treatment effectiveness, safety outcomes,
                                                
a Dependent on interest in participation and the number of eligible patients each site can contribute, the total number of sites enrolled 
as well as patients per site could increase/decrease.

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isavuconazole treatment patterns, and HCRU will be collected from patient medical records
and entered into an electronic data capture (EDC) system by site staff. As this study is 
retrospective, information pertaining to patient care will already be documented in patient 
medical records at the time of chart abstraction.
Population: Adult patients (aged ≥18 years) who received isavuconazole for the treatment of 
invasive aspergillosis or mucormycosis in the hospital setting.
Study sites: Although the target number of sites is 22 sites, the total number of sites enrolled 
will depend on site interest, availability of its staff (considering the COVID-19 pandemic), 
and access to eligible medical records. Invasive aspergillosis and mucormycosis are rare 
fungal infections; thus, it is expected that the pool of potential patients across sites will be 
small. The sites will be hospital based; thus, the patient population will consist of those who 
were either hospitalized or attending a hospital at the initiation of isavuconazole therapy.
Patient population: Inclusion criteria: Patients must be aged ≥18 years at isavuconazole 
initiation, have a record of a diagnosis of invasive aspergillosis or mucormycosis at the time 
isavuconazole was initiated (regardless of whether this diagnosis is suspected or confirmed),b
and have received at least one dose of isavuconazole during the eligibility period 
(October 15, 2015, to June 30, 2019).
Exclusion criteria: Patients who did not receive at least one dose of isavuconazole for 
treatment of invasive aspergillosis or mucormycosis within the eligibility period.
Data source/data collection: Retrospective data will be abstracted from the medical records
of patients and entered into an EDC system by trained local site staff. It is estimated that data 
abstraction will be completed in approximately 7 months from the point at which the first 
patient is included in the study (estimated to be from August 2020 to March 2021 for all 
countries except Italy, and from October 2021 to January 2022 for Italy).c
                                                
b Documented cases of invasive aspergillosis or mucormycosis will be included (providing the patient meets all other study inclusion 
criteria), regardless of whether the diagnosis is classified as being ‘suspected’ or confirmed via mycological or radiological assessments
(this includes European Organization for Research and Treatment of Cancer/Mycosis Study Group [EORTC/MSG] classification of 
“proven,” “probable,” and “possible” invasive fungal disease). All available sources will be used to confirm diagnosis (including any text in 
the medical records [eg, discharge diagnosis] and International Classification of Diseases, 10th Revision [ICD-10] codes, if available). The 
level of documentation in the medical records is expected to vary by healthcare provider (HCP) and by site/country.
c Dates of medical record abstraction are subject to change based on the volume of potentially eligible patients during the timeframe 
of the current eligibility period, the timing of study start-up, and the impact of the COVID-19 pandemic on site staff availability.

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Patients who initiate isavuconazole treatment (index event) during the eligibility period 
(October 15, 2015, to June 30, 2019)d will be identified and screened for inclusion/exclusion 
criteria for enrollment into the study. The two main study periods for data collection from 
each patient’s medical chart are as follows:

Pre-index event period: Baseline data on demographics and medical history will be 
collected based on all available information in medical records before the index 
event.

Post-index event period: The timeframe for follow-up data collection will begin one 
day post-index treatment initiation and end at the earliest of the following: six-months
post-index treatment discontinuation, death, loss to follow-up, or December 31, 2019. 
Key timepoints of interest for assessment of clinical outcomes (mortality and overall 
response), and safety will be assessed at 6 weeks, 12 weeks, and 24 weeks after 
initiation of index treatment.
Variables: Categories to be abstracted from the medical records if available include, but are 
not limited to, the following:

Demographic, medical history, and clinical characteristics (eg, age, sex, history of 
invasive fungal infection and prior antifungal treatments, fungal disease 
characteristics such as diagnosis, mycological confirmation, date of diagnosis, and 
other comorbidities including underlying illness/risk factors for invasive aspergillosis
and mucormycosis).

Clinical outcomes (eg, overall response [including clinical response, mycological 
response, radiological response], and mortality).

Safety outcomes (AEs and SAEs).

Isavuconazole treatment patterns (eg, formulation, dosage [loading and maintenance], 
duration, treatment changes (including dosage adjustments, switching, and 
discontinuation), and concomitant medication).

Health care resource utilization (eg, length of stay [LOS], emergency room [ER] 
visits, intensive care unit [ICU] visits and LOS, inpatient hospitalizations, and 
planned and unplanned outpatient visits).
Study size: Precision estimates were generated based on the all-cause mortality rate at 
day 42 for patients with invasive aspergillosis who received isavuconazole in the SECURE 
trial.4 A sample size of 150 to 200 patients is expected to yield a reasonable margin of error 
(between 5.00% and 6.25%) for estimating a 95% confidence interval (CI) for the mortality 
                                                
d The eligibility period end date is subject to change based on timing of medical record abstraction and anticipated number of 
potentially eligible patients during the proposed eligibility timeframe.

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rate. However, 95% CIs may be wider for analyses of rare events or analyses conducted in 
small subgroups.
As mucormycosis is rare, sample size for this population is expected to be low and limited by 
the availability of patient medical records at sites. All eligible patients with mucormycosis 
will be included. Based on the observed weighted all-cause mortality rate in the sample of 
mucormycosis patients (n = 37) in the VITAL trial of 33%, such a sample would allow to 
estimate the mortality rate within a precision of 15%.
Data analysis: Data analysis will be primarily descriptive. Mean, standard deviation, 
median, minimum, and maximum, interquartile range, and range will be provided for 
continuous variables; numbers and percentages for each category will be provided for 
categorical variables. Time to event outcomes will be assessed using the Kaplan-Meier (KM) 
method and will be reported as descriptive statistics (eg, median time to event) with 95% CIs. 
The statistical analysis plan (SAP) will provide a detailed description of analytic populations, 
analyses to be performed, and methods to deal with missing data and censoring.
Milestones:
Completion of feasibility assessment: October 15, 2019
Start of data collection: August 10, 2020
End of data collection: January 22, 2022
Interim study report (ex-Italy): July 22, 2021
Final study report: May 26, 2022

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5. AMENDMENTS AND UPDATES
None.
6. MILESTONES
Milestone
Planned date
Completion of feasibility assessment
October 15, 2019
Start of data collection 
August 10, 2020
End of data collection
January 22, 2022
Interim study report (ex-Italy)
July 22, 2021
Final study report
May 26, 2022e
                                                
e Anticipated date; subject to change based on the impact of the COVID-19 pandemic on the availability of members of ethics 
review committee, staff at the institutional review board, and site staff.

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7. RATIONALE AND BACKGROUND
7.1. Study Background
Invasive aspergillosis and mucormycosis are rare, life-threatening fungal infections 
associated with high mortality.1,2 Causative agents for fungal infections can vary across 
geographic locations; however, Aspergillus fumigatus and Rhizopus arrhizus are associated 
with the majority (approximately 70%) of invasive aspergillosis and mucormycosis cases, 
respectively.1 Although the epidemiology of rare fungal diseases is not well studied, the 
incidence rates (per 100,000 persons) for invasive aspergillosis and mucormycosis are 
estimated to be 4.6 and 0.09 in the UK, 2.8 and 0.04 in Spain, and 1.8 and 0.1 in France, 
respectively.2 Incidence rates are difficult to estimate due to a lack of a reliable 
denominator.2,5
Cresemba® (isavuconazole) is an antifungal agent that contains the active substance 
isavuconazole. Its mechanism of action involves blocking the production of a key component 
of the cell membrane of fungi, thus weakening the membrane and preventing fungal cell 
growth.3 Isavuconazole can be administered orally or by infusion. Isavuconazole 
demonstrated non-inferiority compared to voriconazole with improved safety profile in the 
SECURE clinical trial for patients with invasive aspergillosis (phase 3, randomized, double-
blind, comparative-group; NCT00412893).4 Isavuconazole was approved by the EMA on 
October 15, 2015, for use in adults for the treatment of (i) invasive aspergillosis and (ii) 
mucormycosis in patients for whom amphotericin B is inappropriate.
7.2. Invasive Aspergillosis
Invasive aspergillosis usually occurs in immunocompromised patients with hematological 
malignancies, oncology patients receiving chemotherapy, and immunosuppressed patients 
(eg, as a result of taking immunosuppressive drugs after transplant surgery). Other risk 
factors include comorbidities such as diabetes, renal or liver dysfunction, chronic obstructive 
pulmonary disease, and neutropenic sepsis. Patients with comorbidities also are at higher risk 
for stays in the ICU.6 Diagnosis of invasive aspergillosis is typically made by the 
combination of host status, imaging, and mycological findings.1 Treatment of invasive 
aspergillosis usually includes antifungal medications such as voriconazole or isavuconazole.1
The SECURE clinical trial (NCT00412893) was a phase 3 randomized, double-blind, 
comparative-group study designed to compare the efficacy and safety of isavuconazole vs. 
voriconazole in the treatment of patients with invasive aspergillosis. The primary outcome 
measure was all-cause mortality at day 42. In the intention-to-treat population, all-cause 
mortality was 19% for isavuconazole and 20% for voriconazole, adjusted treatment 
difference = –1.0% (95% CI: –7.8, 5.7).4 Patients treated with isavuconazole also had a lower 
frequency of hepatobiliary disorders (9% vs. 16%; P = 0.016), eye disorders (15% vs. 27%; 
P = 0.002), and skin or subcutaneous tissue disorders (33% vs. 42%; P = 0.037). 
Additionally, treatment-related AEs were reported in 42% and 60% of patients receiving 
isavuconazole and voriconazole, respectively (P < 0.001). Guidelines therefore recommend 
isavuconazole and voriconazole for first-line treatment of invasive aspergillosis.

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7.3. Mucormycosis
The main risk factors for mucormycosis include diabetes mellitus, hematological 
malignancies, stem cell/organ transplantations, corticosteroid therapy, and neutropenia.2
Mucormycosis is usually diagnosed through identification of causative agents by 
histopathological analysis of tissue specimens, in patients showing symptoms of the 
infection.1 However, diagnosis is challenging, and cultures are only occasionally positive. 
Initial treatment of mucormycosis typically includes surgery to remove infected tissues and 
antifungal treatment with amphotericin B.1
The VITAL clinical trial (NCT00634049) was a single-arm, open-label trial, that included an 
assessment of the efficacy and safety of isavuconazole for treatment of mucormycosis in 
37 patients. The primary outcome was independent data review committee-determined 
overall response (complete or partial response [treatment success] or stable or progressive 
disease [treatment failure]) at day 42, day 84, and end of treatment. The results demonstrated 
that by day 42, 11% of patients had a partial response, 43% had stable disease, 3% had 
disease progression, 8% had missing assessments, and 35% had died.7 The efficacy of 
isavuconazole and amphotericin B was also compared in a matched case-control analysis.7 At 
day 42, all-cause mortality was similar in cases with isavuconazole as the primary treatment 
and amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs. 41%; 
P = 0.595).7
Although the use of some antifungals are restricted in patients with renal impairment, in a 
pooled analysis of the SECURE and VITAL trials, isavuconazole was reported to be well 
tolerated in patients with renal impairment.8
7.4. Study Rationale
Isavuconazole obtained market authorization in the US and the EU in 2015. The generation 
of RWE will provide additional insight into isavuconazole use and related outcomes in 
clinical practice. The current study is a retrospective cohort study based on a multi-country 
chart review to be conducted in five European countries (France, Germany, Italy, Spain, and 
the UK), designed to obtain RWE of isavuconazole patterns of use, clinical response, HCRU, 
and safety in clinical practice.
8. RESEARCH QUESTION AND OBJECTIVES
Primary objectives:

To document real-world clinical outcomes (all-cause mortality, overall response) of 
isavuconazole in patients with invasive aspergillosis or mucormycosis receiving 
treatment in routine clinical practice in Europe (France, Germany, Italy, Spain, and 
the United Kingdom).

To assess real-world safety (isavuconazole-related AEs and SAEs) of isavuconazole 
in patients with invasive aspergillosis or mucormycosis receiving treatment in routine 
clinical practice in Europe.

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Secondary objectives:

To describe demographic and clinical characteristics of patients with invasive 
aspergillosis or mucormycosis receiving isavuconazole in routine clinical practice in 
Europe.

To document treatment patterns among patients with invasive aspergillosis or 
mucormycosis receiving isavuconazole in routine clinical practice in Europe.

To quantify HCRU among patients with invasive aspergillosis or mucormycosis 
receiving isavuconazole in routine clinical practice in Europe.
9. RESEARCH METHODS
9.1. Study Design
This is an observational retrospective cohort study involving the review and abstraction of 
pertinent data from the medical records of patients diagnosed with invasive aspergillosis or 
mucormycosis who received treatment with isavuconazole (index event) between October 
15, 2015, and June 30, 2019.f The target sample size for this study is approximately 
600 patients (with a minimum of 200) across 22 sites located in Europe.g
De-identified data (ie, anonymous to non-site staff) on patient demographics, disease 
characteristics, isavuconazole treatment patterns, clinical response, safety outcomes, and 
HCRU will be collected from patient medical records and entered into an EDC system by site 
staff between August 2020 and March 2021 for Germany, Spain, and the UK, and between 
October 2021 and January 2022 for Italy.h The differences in the data abstraction timelines 
are due to ethics and contracting processes in Italy taking between 6 to 12 months to 
complete, compared with an estimated maximum of 4 months in the remaining countries. As 
this study is retrospective, information pertaining to patient care will already be documented 
in patient medical records at the time of chart abstraction.
A steering committee composed of experts within hematology and infectious diseases will 
provide input and guidance on the study design and implementation, as well as the 
interpretation of results.
                                                
f The eligibility period end date is subject to change based on timing of medical record abstraction and 
anticipated number of potentially eligible patients during the proposed eligibility timeframe.
g Dependent on interest in participation and the number of eligible patients each site can contribute, the total 
number of sites enrolled as well as patients per site could increase/decrease.
h Dates of medical record abstraction are subject to change based on the volume of potentially eligible patients 
during the timeframe of the current eligibility period and the timing of study start-up.

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9.2. Setting
9.2.1. Study Sites
A feasibility assessment was conducted, and a total of 22 sites meeting the study criteria were 
identified: 6 in Germany, 5 in Italy, 5 in Spain, 4 in the UK, and 2 in France. All sites are 
hospital-based facilities and had access to eligible medical records of patients treated within 
oncology, hematology, and/or transplantation wards and ICUs. During this feasibility
assessment, sites were evaluated on the following parameters, to determine their suitability 
for participation:

Number of eligible patients treated with isavuconazole for either invasive 
aspergillosis or mucormycosis.

Location of medical records and continuity of data across wards and staff resources,
to be able to abstract the required data.

Frequency and availability of follow-up data.
The total number of sites who participate in the study may differ from the anticipated number 
(22), depending on a site’s interest and the availability of its staff (considering the COVID-
19 pandemic), and access to eligible medical records. The sites will be hospital based; thus, 
the patient population will consist of those who were either hospitalized or attending a 
hospital at the initiation of isavuconazole therapy. As invasive aspergillosis and 
mucormycosis are rare fungal infections, we expect that the pool of potential patients across 
sites will be small. The total number of patients eligible patient records to which the sites 
have access was estimated to be about 583.
9.2.2. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Patient must be aged ≥18 years at the time of isavuconazole initiation.
2. Patient must have a record of a diagnosis of invasive aspergillosis or mucormycosis 
in their medical record at the time isavuconazole was initiated (regardless of whether 
this diagnosis is suspected or confirmed).i
3. Patient must have received at least one dose of isavuconazole during the eligibility 
period (October 15, 2015, to June 30, 2019).j
                                                
i Documented cases of invasive aspergillosis or mucormycosis will be included (providing the patient meets all other study inclusion 
criteria), regardless of whether the diagnosis is classified as being ‘suspected’ or confirmed via mycological or radiological assessments
(this includes EORTC/MSG classification of “proven,” “probable,” and “possible” invasive fungal disease). All available sources will be 
used to confirm diagnosis (including any text in the medical records [eg, discharge diagnosis] and ICD-10 codes, if available). The level of 
documentation in the medical records is expected to vary by HCP and by site and/or country.
j The eligibility period end date is subject to change based on timing of medical record abstraction and anticipated number of 
potentially eligible patients during the proposed eligibility timeframe.

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9.2.3. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Patients who did not receive at least one dose of isavuconazole for treatment of 
invasive aspergillosis or mucormycosis within the eligibility period.
9.3. Data Source and Data Collection Process
The source for all data collected will be patient medical records. Retrospective data will be 
abstracted from the medical records of patients and entered into an EDC system by trained 
local site staff. It is estimated that data abstraction will be completed in approximately 
7 months from the point at which the first patient is included in the study for Germany, 
France, Spain, and the UK (estimated to be from August 2020 to March 2021). For Italy, data 
collection is anticipated to begin at a later date, and data abstraction will be completed in 
approximately 3 months from the point at which the first patient is enrolled (estimated to be 
from October 2021 to January 2022).k
9.3.1. Study Periods
9.3.1.1. Index Event
This is defined as the first initiation of isavuconazole treatment for the invasive fungal 
infection that was diagnosed during the eligibility period.
9.3.1.2. Eligibility Period
The eligibility period, wherein potentially eligible patients are identified for enrollment, will 
be from October 15, 2015 (date of isavuconazole approval by the EMA in the EU), to 
June 30, 2019.l The end date of the eligibility period ensures that the latest date of 
isavuconazole initiation will occur at least 6 months before the end of December 2019 (after 
which point the medical records may contain data related to the COVID-19 pandemic, which 
is not of interest for this study). This will allow a minimum of 6 months of follow-up from 
the date of isavuconazole initiation unless the patient dies or is lost to follow-up within this 
timeframe (see Figure 1).
                                                
k Dates of medical record abstraction are subject to change based on the volume of potentially eligible patients during the timeframe 
of the current eligibility period, the timing of study start-up, and the effect of the COVID-19 pandemic on the availability of members of 
ethical review boards, institutional review boards, and availability of site staff.
l The eligibility period end date is subject to change based on the timing of medical record abstraction and the anticipated number of 
potentially eligible patients during the proposed eligibility timeframe.

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Figure 1.
Overview of Study Periods and Examples of Eligible Cases
9.3.1.3. Data Collection (Chart Abstraction) Periods
Patients who initiate isavuconazole treatment (index event) during the eligibility period 
(October 15, 2015, to June 30, 2019)m will be identified and screened for inclusion/exclusion 
criteria for enrollment into the study. 
The two main study periods for data collection from each patient’s medical chart are:

Pre-index event period: Baseline data on demographics and medical history will be 
collected based on all available information in medical records before the index 
event.
                                                
m The eligibility period end date is subject to change based on timing of medical record abstraction and anticipated number of 
potentially eligible patients during the proposed eligibility timeframe.

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
Post-index event period: The timeframe for follow-up data collection will begin one 
day post-index treatment initiation and end at the earliest of the following: 6 months
after post-index treatment discontinuation, death, or loss to follow-up, or December 
31, 2019 (see Figure 1 and Figure 2). Key timepoints of interest for assessment of 
clinical response and safety will be at 6 weeks, 12 weeks, and 24 weeks after 
initiation of index treatment (see Figure 2).
Figure 2.
Data Collection Periods and Timepoints for Each Patient
FU = follow up.
9.4. Variables
Categories of variables to be abstracted from the medical records if available include, but are 
not limited to, the following (a detailed description of variables and timepoints will be 
provided in the SAP):
9.4.1. Demographic and Clinical Characteristics
Category
Variable
Timepoint
Demographics and 
medical history
Age (years)
Index date, closest 
assessment to index
Sex:

Male;

Female.
Height (centimeters [cm] or feet ['] and 
inches ["], depending on the country)
Weight (kilograms [kg] or stones [st] and 
pounds [lb], depending on the country)
Ethnic/racial group (country-specific 
options to be used)
Smoking status:

Current smoker;

Previous smoker;

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Category
Variable
Timepoint

Never smoked;

Unknown.
History of illicit drug use:

Yes; specify drug (if documented);

No;

Unknown.
If “yes” to history of illicit drug use, 
specify route of administration:

Inhalation;

Nasal administration;

Intravenous injection;

Intramuscular injection;

Oral administration;

Other (specify).
History of alcohol abuse:

Yes;

No;

Unknown.
Comorbid medical 
conditions
Note: this refers to 
comorbidities
documented in the
chart during the 30 
days prior to index 
and the date of index. 
However, the onset of 
the comorbidity may 
have occurred prior to 
this.

AIDS;

Asthma;

Autoimmune disease;

Bronchiectasis;

Chronic granulomatous disease;

COPD;

Congestive heart failure;

Coronary artery disease;

Cytomegalovirus infection;

Diabetes mellitus or uncontrolled 
hyperglycemia;

Drug-related AEs;

Fever and neutropenia;

Fungal infection, (specify: fungal, 
bacterial, other);

Influenza;

Iron overload;

Liver cirrhosis;

Graft-versus-host disease;

Hematologic malignancy;

Herpes virus (including VZV, CMV, 
etc.);

Hypertension;

Major trauma;
30 days prior to 
index date, index 
date

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Category
Variable
Timepoint

Moderate-to-severe renal disease;

Neutropenia;

Severe burns;

Solid tumor (specify);

Solid organ transplantation (specify);

Stem cell transplantation (specify);

Tuberculosis;

Other (specify);

Unknown.
Fungal disease 
characteristics
Disease type

Invasive aspergillosis;

Mucormycosis.
At index date or 
closest assessment 
to index during the 
pre-index period. If 
no assessments are 
available in the pre-
index period, then 
assessments closest 
to index in the post-
index period will be 
used.
Date of suspected diagnosis (DD MMM 
YYYY)
Date of confirmed diagnosis (DD MMM 
YYYY)
Note: Documented cases of invasive 
aspergillosis or mucormycosis will be 
included (providing the patient meets all 
other study inclusion criteria), regardless 
of whether the diagnosis is classified as 
being “suspected” or confirmed via 
mycological or radiological assessments 
(this includes EORTC/MSG classification 
of “proven,” “probable,” and “possible” 
invasive fungal disease). All available 
sources will be used to confirm diagnosis 
(including any text in the medical records
[eg, discharge diagnosis] and ICD-10 
codes, if available). The level of 
documentation in the medical records is 
expected to vary by HCP and by 
site/country.
Mycological confirmation:

Yes;

No;

Unknown.
Date of mycological confirmation 
(DD/MMM/YYYY) (if applicable)
Mycological examination type (if 
applicable):

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Category
Variable
Timepoint

Blood or tissue culture;

Bronchoalveolar lavage;

Urine sample;

Biopsy specimen;

Other (specify);

Unknown.
Radiological confirmation:

Yes;

No;

Unknown.
Date of radiological confirmation 
(DD/MMM/YYYY) (if applicable)
Radiological assessment type (if 
applicable):

Chest X-ray;

CT scan;

Ultrasound;

MRI;

Other (specify);

Unknown.
Radiographic assessment location:

Brain;

Lungs;

Liver;

Kidney;

Stomach;

Intestines;

Other (specify);

Unknown.
Other confirmation type:

Yes (specify);

No;

Unknown.
EORTC/MSG disease classification (if 
available):

Proven;

Probable;

Possible;

Unknown.
Localization (all that apply):

Lungs;

Sinus;

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Category
Variable
Timepoint

Skin;

Stomach;

Intestines;

Central nervous system;

Bones;

Liver;

Kidney;

Blood;

Other (specify);

Unknown.
Antifungal drug use 
prior to index 
treatment
Antifungal type:

Liposomal amphotericin B;

Voriconazole;

Posaconazole;

Caspofungin;

Anidulafungin;

Micafungin;

Other (specify);

Unknown.
1 year prior to index 
date
Reason for switch to index treatment (if 
applicable):

Lack of response to treatment;

AE;

Patient decision (unrelated to AEs);

Other (specify);

Unknown.
Date of initiation (DD MMM YYYY)
Date of discontinuation (DD MMM 
YYYY)
Other prior treatment 
history

Antibiotic (specify);

Surgery (specify);

Corticosteroid (specify);

Immunosuppressant (specify);

Chemotherapy (specify);

Other (specify);

Unknown.
30 days prior to 
index date
AE = adverse event; COPD = chronic obstructive pulmonary disease; CT = computed tomography;
EORTC/MSG = European Organization for Research and Treatment of Cancer/Mycosis Study Group; 
HCP = healthcare provider; ICD-10 = International Classification of Diseases, 10th Revision; MRI = magnetic 
resonance imaging.

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9.4.2. Isavuconazole Treatment Patterns
Category
Variable
Timepoint
Index treatment 
(isavuconazole) 
administration 
Setting of treatment administration:

Inpatient setting:

Oncology ward;

Hematology ward;

Transplantation ward;

ICU;

General medicine ward;

Other ward (specify).

Outpatient setting;

Other (specify);

Unknown.
Index date, post-
index period
Loading-dose method of administration:

Infusion;

Oral;

Unknown;

Not applicable.
Date of first loading-dose 
administration (DD MMM YYYY)
Date of last loading-dose administration 
(DD MMM YYYY)
Loading dose:

372 mg of isavuconazonium sulfate;

Other (specify).
Loading-dose frequency:

Every 8 hours for 48 hours (ie, 
6 doses);

Other (specify).
Maintenance therapy method of 
administration:

Infusion;

Oral;

Maintenance therapy not 
administered;

Unknown;

Not applicable.
Date of first dose of maintenance 
therapy (DD MMM YYYY)
Date of last dose of maintenance 
therapy (DD MMM YYYY)
Maintenance dose (mg):

372 mg of isavuconazonium sulfate;

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Category
Variable
Timepoint

Other (specify).
Maintenance dose frequency:

Every 24 hours (ie, once daily);

Other (specify).
Modification of index 
treatment
Treatment modification (eg, dose 
adjustment, mode of administration 
change):

Yes;

No;

Unknown.
Post-index 
period
Date of index therapy modification (DD 
MMM YYYY)
Type of therapy modification (all that 
apply):

Change from infusion to oral 
capsule;

Change from oral capsule to 
infusion;

Dose increase;

Dose decrease;

Frequency increase;

Frequency decrease;

Other (specify);

Unknown.
Reason for index therapy modification:

Lack of response to treatment;

AE;

Patient decision (unrelated to AEs);

TDM;

Drug-drug interaction;

Other (specify);

Unknown.
TDM
Was TDM conducted?

Yes;

No;

Unknown.
Post-index 
period
Date of TDM (DD MMM YYYY)
Outcome of TDM:

Treatment modification;

Treatment discontinuation;

None;

Other (specify);

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Category
Variable
Timepoint

Unknown.
Discontinuation of index 
treatment
Discontinuation of index treatment:

Yes;

No;

Unknown.
Post-index 
period
Date of discontinuation (DD MMM 
YYYY)
Reason for discontinuation:

Patient completed planned course of 
treatment;

Lack of response to treatment;

AE;

Patient decision (unrelated to AEs);

Treatment success (resolution of 
invasive fungal infection);

Death (unrelated to therapy);

TDM;

Drug-drug interaction;

Other (specify);

Unknown.
Switch to a new antifungal 
drug after discontinuation of 
index treatment
Switch to a new antifungal agent after 
discontinuation:

Yes;

No;

Unknown.
Post-index 
period
Start date of subsequent antifungal 
agent (DD MMM YYYY)
End date of subsequent antifungal agent 
(DD MMM YYYY)
Type of new antifungal agent:

Liposomal amphotericin B;

Voriconazole;

Posaconazole;

Caspofungin;

Anidulafungin;

Micafungin;

Other (specify);

Unknown.
Other subsequent antifungal 
use after end of index 
treatment
Type of new antifungal drug:

Liposomal amphotericin B;

Voriconazole;

Posaconazole;
Post-index 
period

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Category
Variable
Timepoint

Caspofungin;

Anidulafungin;

Other (specify);

Unknown.
Start date of subsequent antifungal 
agent (DD MMM YYYY)
End date of subsequent antifungal agent 
(DD MMM YYYY)
Index treatment 
administered as part of 
antifungal combination 
therapy 
Index treatment administered as part of 
antifungal combination therapy:

Yes;

No;

Unknown.
Index date, post-
index period
Type of therapy administered in 
combination with isavuconazole:

Liposomal amphotericin B;

Voriconazole;

Posaconazole;

Caspofungin;

Anidulafungin;

Micafungin;

Other (specify);

Unknown.
Start date of therapy administered in 
combination with isavuconazole (DD 
MMM YYYY)
End date of therapy administered in 
combination with isavuconazole (DD 
MMM YYYY)
Other concomitant 
treatments (not including 
combination therapy)

Antibiotic agent (specify);

Corticosteroid agent (specify);

Immunosuppressant agent (specify);

Chemotherapy (specify);

Other (specify);

Unknown.
Index date, post-
index period
Start date of concomitant treatment (DD 
MMM YYYY)
End date of concomitant treatment (DD 
MMM YYYY)
AE = adverse event; ICU = intensive care unit; TDM = therapeutic drug monitoring.

Crese m ba ® (isa v uc o naz ole)
C 3 7 9 1 0 0 8 P RI S M A N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
Fi nal 1. 1, 2 7 J ul y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9 of 5 0
9. 4. 3. Cli nic al Effecti ve ness
C ate g or y
V ari a ble
Ti me p oi nt
Cli nical res p o nse n
Date of assess me nt ( D D M M M 
Y Y Y Y)
P ost -i n de x peri o d
Cli nical res p o nse stat us d oc u me nte d 
i n t he me dical c hart :

Cli nical res p o nse ;

Cli nical fail ure ;

U n k n o w n .
Re -acti vati o n of sa me or 
ne w i nfecti o n 
Re -acti vati o n d oc u me nte d i n t he 
me dical c hart :

Yes ;

N o .
P ost -i n de x peri o d
Assess me nt date ( D D M M M Y Y Y Y)
Ra di ol o gical 
assess me nts
Ra di o gra p hic assess me nt date ( D D 
M M M Y Y Y Y)
P ost -i n de x peri o d
Ra di o gra p hic e xa mi nati o n t y pe:

C hest X -ra y;

C T sca n;

Ultras o u n d ;

M RI ;

Ot her (s pecif y );

U n k n o w n .
Ra di o gra p hic e xa mi nati o n l ocati o n

Brai n ;

L u n gs ;

Li ver ;

Ki d ne y ;

St o mac h;

I ntesti nes;

Ot her (s pecif y );

U n k n o w n .
Ra di ol o gical res p o nse o
Ra di ol o gical e xa mi nati o n date ( D D 
M M M Y Y Y Y )
P ost -i n de x peri o d
                                                
n Cli nical res p o nse will be e val uate d acc or di n g t o t he f oll o wi n g m ut uall y e xcl usi ve m o dalities: Cli nic al res p o nse : res ol uti o n or 
partial res ol uti o n of all attr i b uta ble cli nical s y m pt o ms a n d p h ysical fi n di n gs. Cli nic al f ail ure : n o res ol uti o n of a n y attri b uta ble cli nical 
s y m pt o ms a n d p h ysical fi n di n gs a n d/ or w orse ni n g. W he n me dical rec or d d oc u me ntati o n is n ot clear f or t he a bstract or o n w hic h c ate g ories 
t o s pecif y, t he i n vesti gat or s h o ul d re vie w all a vaila ble me dical rec or d d oc u me ntati o n t o deter mi ne classificati o ns. If t he i n vesti gat or
deter mi nes t here is n ot e n o u g h me dical rec or d d oc u me ntati o n t o ma ke t he classificati o n, t he y will i n dicate u n k n o w n. Si nce cli nical res p o nse 
classificati o n is i m p orta nt t o t he st u d y, partici pati n g sites will be selecte d f or partici pati o n i n t he st u d y base d o n re p ort i n g t o ha ve dili ge nt 
me dical rec or d d oc u me ntati o n f or res p o nse.
o Ra di ol o gical res p o nse will be e val uate d acc or di n g t o t he f oll o wi n g criteria: R a di ol o gic al res p o nse : ≥5 0 % i m pr o ve me nt fr o m 
i nitial assess me nt, or i m pr o ve me nt of at least 2 5 % fr o m t he i nitial assess me nt f or t he f oll o w-u p at 6 wee ks (i e, Da y 4 2 [± 1 4 da ys ]) or if 
e n d of treat me nt occ urre d bef ore t his ti me. . W h e n me dical rec or d d oc u me ntati o n is n ot clear f or t he a bstract or o n w hic h cate g ories t o 
 

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Category
Variable
Timepoint
Radiological examination type

Chest X-ray;

CT scan;

Ultrasound;

MRI;

Other (specify);

Unknown.
Radiological response documented in 
the medical chart:

Yes;

No;

Not applicable (initial 
assessment);

Unknown.
Mycological assessments
Mycological examination date (DD 
MMM YYYY)
Post-index period
Mycological examination type:

Blood or tissue culture;

Bronchoalveolar lavage;

Urine sample;

Biopsy specimen;

Other (specify);

Unknown.
Mycological responsep
Mycological examination date (DD 
MMM YYYY)
Post-index period
Mycological examination type:

Blood or tissue culture;

Bronchoalveolar lavage;

Urine sample;

Biopsy specimen;

Other (specify);

Unknown.

Eradication;

Presumed eradication;
                                                
specify, the investigator should review all available medical record documentation to determine classifications. If the investigator 
determines there is not enough medical record documentation to make the classification, they will indicate unknown. Since radiological
response classification is important to the study, participating sites will be selected for participation in the study based on reporting to have 
diligent medical record documentation for response.
p Mycological response will be evaluated according to the following criteria: eradication or presumed eradication of the original 
causative organism cultured. Failure will be defined as persistence or presumed persistence. When medical record documentation is not 
clear for the abstractor on which categories to specify, the investigator should review all available medical record documentation to 
determine classifications. If the investigator determines there is not enough medical record documentation to make the classification, they 
will indicate unknown. Since mycological response classification is important to the study, participating sites will be selected for 
participation in the study based on reporting to have diligent medical record documentation for response.

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Category
Variable
Timepoint

Failure;

Not applicable (initial 
assessment);

Unknown.
Biomarkers

Galactomannan (GM), Serum;

Galactomannan (GM), 
Bronchoalveolar lavage (BAL);

(1→3)-β-D-Glucan (BDG), serum.
Index date, post-index 
period

Test date (DD MMM YYYY).
CT = computed tomography; MRI = magnetic resonance imaging.
9.4.4. Safety
Category
Variable
Timepoint
AEs
Type of event (documented by ICD-9 
code, ICD-10 code or record in the 
medical chart):

Blood and lymphatic AE:

Neutropenia;

Thrombocytopenia;

Pancytopenia;

Leukopenia;

Anemia;

Other (specify).

Immune system AE:

Hypersensitivity;

Other (specify).

Metabolism and nutrition AE:

Hypokalemia;

Decreased appetite;

Hypomagnesemia;

Hypoglycemia;

Hypoalbuminemia;

Malnutrition;

Other (specify).

Psychiatric AE:

Delirium;

Depression;

Insomnia;

Other (specify);

Nervous system AE:

Headache;

Somnolence;

Convulsion;
Index date, post-index 
period

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Category
Variable
Timepoint

Syncope;

Dizziness;

Paresthesia;

Encephalopathy;

Presyncope;

Peripheral neuropathy;

Dysgeusia;

Other (specify).

Ear and labyrinth AE:

Vertigo;

Other (specify).

Cardiac AE:

Atrial fibrillation;

Tachycardia;

Bradycardia;

Palpitations;

Atrial flutter;

Electrocardiogram QT 
shortened;

Supraventricular tachycardia;

Ventricular extrasystoles;

Supraventricular extrasystoles;

Other (specify).

Vascular AE:

Thrombophlebitis;

Circulatory collapse;

Hypotension;

Other (specify).

Respiratory, thoracic and 
mediastinal AE:

Dyspnea;

Acute respiratory failure;

Bronchospasm;

Tachypnoea;

Hemoptysis;

Epistaxis;

Other (specify).

Gastrointestinal AE:

Vomiting;

Diarrhea;

Nausea;

Abdominal pain;

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Category
Variable
Timepoint

Dyspepsia;

Constipation;

Abdominal distension;

Other (specify).

Hepatobiliary AE:

Elevated liver chemistry tests
(alanine aminotransferase 
[ALT], aspartate 
aminotransferase [AST], 
alkaline phosphatase, bilirubin);

Hepatomegaly;

Hepatitis;

Other (specify).

Skin and subcutaneous tissue AE:

Rash;

Pruritus;

Petechiae;

Alopecia;

Drug eruption;

Dermatitis;

Other (specify).

Musculoskeletal and connective 
tissue AE:

Back pain;

Other (specify).

Renal and urinary AE:

Renal failure;

Other (specify).

General disorders and 
administration site condition AE:

Chest pain;

Fatigue;

Injection site reaction;

Edema peripheral;

Malaise;

Asthenia;

Other (specify).

Other AE (specify).
AE onset date (DD MMM YYYY)
AE resolution:

Yes;

No;

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Category
Variable
Timepoint

Unknown.
AE resolution date (DD MMM YYYY)
AE seriousness:

Was life-threatening;

Required inpatient hospitalization
or prolongation of existing 
hospitalization;

Resulted in persistent or significant 
incapacity or disability;

Was a congenital anomaly/birth 
defect;

Was a medically important event;

Resulted in death;

None of the above;

Unknown.
AE severity:

Mild;

Moderate;

Severe;

Unknown.
Documented relationship to 
isavuconazole:

Yes;

No;

Unknown.
Action taken with isavuconazole:

Treatment discontinuation;

Dose reduced;

Dose increased;

Dose delayed;

Dose not changed;

Not applicable;

Unknown.
Outcome of event:

Resolved;

Resolving;

Resolved with sequelae;

Not resolved;

Fatal;

Unknown.
AE = adverse event; ICD-9 = International Classification of Diseases, 9th Revision; ICD-10 = International 
Classification of Diseases, 10th Revision.

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9.4.5. Survival Status
Category
Variable
Timepoint
Survival status
Date of death (DD MMM YYYY)
Post-index period
Primary cause of death:

Complications related to invasive 
aspergillosis or mucormycosis;

Other disease complications;

SAE related to isavuconazole 
treatment;

SAE unrelated to isavuconazole 
treatment;

Other (specify);

Unknown.
SAE = serious adverse event.
9.4.6. Health Care Resource Utilization
Category
Variable
Timepoint
Inpatient 
hospitalizations
(including specialty 
wards, ICU, ER, general 
medicine ward, or other)
Inpatient hospitalization occurring 
after index treatment initiation

Yes;

No;

Unknown.
Post-index period
Primary reason for hospitalization:

Invasive aspergillosis or 
mucormycosis disease monitoring;

Other disease monitoring;

AE related to invasive 
aspergillosis or mucormycosis;

Other (specify);

Unknown.
Location for inpatient hospitalization:

Oncology ward;

Hematology ward;

Transplantation ward;

ICU;

ER;

General medicine ward;

Other ward (specify);

Unknown.
Use of a mechanical ventilator:

Yes;

No;

Unknown.
Admission date (DD MMM YYYY)

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Category
Variable
Timepoint
Discharge date (DD MMM YYYY)
Discharge location (if applicable):

Transferred to another ward for 
inpatient care;

Discharged to home or self-care 
(routine discharge);

Discharged to long term care 
facility/hospice;

Not applicable;

Other (specify);

Unknown.
Outpatient visits (not 
associated with a 
hospital stay)
Outpatient visit/referral occurring after 
index treatment initiation:

Yes;

No;

Unknown.
Post-index period
Health care professional visit or 
referral:

Primary care visit (general 
practitioner);

Secondary care visit (specialist);

Secondary care referral 
(specialist);

ER visit.
Primary reason for visit/referral:

Planned visit/referral for invasive 
aspergillosis or mucormycosis 
disease monitoring;

Unplanned visit/referral for 
invasive aspergillosis or 
mucormycosis disease 
monitoring;

Planned visit/referral for other 
disease monitoring;

Unplanned visit/referral for other 
disease monitoring;

Unplanned visit/referral for AE 
related to invasive aspergillosis or 
mucormycosis;

Other;

Unknown.
Type of health care professional:

Infectious disease specialist;

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Category
Variable
Timepoint

Oncologist;

Hematologist;

General internist;

Gastroenterologist;

Cardiologist;

Obstetrician/gynecologist;

Neurologist;

Radiologist;

Dermatologist;

Psychiatric;

Surgeon;

Specialty nurse;

Other (specify);

Unknown.
Date of outpatient visit/referral (DD 
MMM YYYY)
AE = adverse event; ER = emergency department; ICU = intensive care unit.
9.5. Study Size
As the study is primarily descriptive in nature, formal sample size calculations are not 
required. Given the rarity of invasive aspergillosis and mucormycosis, we will include all 
eligible patients identified from sites, up to a target sample size of 600 patients.
Table 1 shows the width of the CI that can be obtained from different sample sizes. Precision 
estimates were generated based on the all-cause mortality rate at day 42 for patients with 
invasive aspergillosis who received isavuconazole in the SECURE trial.4 These estimates 
suggest that a sample size of 150 to 200 patients initiating isavuconazole would be expected 
to yield a reasonable margin of error (between 5.00% and 6.25%) for estimating a 95% CI for 
the mortality rate; thus, an overall sample size of up to 600 patients would yield a reasonable 
margin of error. However, 95% CIs may be wider for analyses of rare events or analyses 
conducted in small subgroups.

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Table 1.
Wilson 95% CI Based on All-Cause Mortality Rate at Day 42 for Patients 
With Invasive Aspergillosis Who Received Isavuconazole in the SECURE 
Trial
Sample Size (N)
95% CI Width
All-cause mortality rate at day 
42 in SECURE trial = 19% 
292
9.0
237
10.0
152
12.5
106
15.0
CI = confidence interval.
Because mucormycosis is rare, sample size for this population is expected to be low and 
limited by the availability of patient medical records at sites; therefore, all eligible patients 
will be included. Based on the observed weighted all-cause mortality rate of 33% in the 
sample of mucormycosis patients (n = 37) in the VITAL trial, such a sample would allow to 
estimate the mortality rate within a precision of 15%.
9.6. Data Management
9.6.1. Case Report Forms
Screening results for inclusion and exclusion criteria will be captured in the EDC system for 
all patients in the initial target cohort.
As used in this protocol, the term CRF should be understood to refer to an electronic data 
record.
A CRF is required and should be completed for each included patient.
In this study, the clinical research organization (CRO) will provide a password-protected,
web-based EDC system to serve as an integrated, transparent tool to collect and manage data 
and track study progress at the center and at the patient level. Data in the EDC system will be 
kept in a central location and all data will be transmitted to a central database.
The completed original CRFs are the sole property of Pfizer and should not be made 
available in any form to third parties, except for authorized representatives of Pfizer or 
appropriate regulatory authorities, without written permission from Pfizer. The investigator 
shall ensure that the CRFs are securely stored in encrypted electronic form and will be 
password protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 

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documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
The investigator also has ultimate responsibility for ensuring that data entered are accurate, 
authentic/original, attributable, complete, consistent, legible, timely (contemporaneous), 
enduring, and available when required. The investigator or authorized staff member must
attest that the data entered in the EDC are true.
The source documents are the hospital or the physician's chart. In these cases, data collected 
on the CRFs must match those charts. 
Site staff will be trained by the CRO to perform the medical record abstraction, including 
data entry and how to retrieve and respond to data queries in the EDC system. To participate 
in this study, all sites must be able to access the EDC system and complete data entry into the 
CRFs via the EDC system.
The EDC system will include logic checks to minimize data entry errors. Data 
inconsistencies outside the logic checks will be managed by manual queries issued by data 
management within the EDC system for site completion. All queries will be monitored until 
resolution within the EDC through the electronic query report.
9.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent/assent documents (if applicable), safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports). The records should 
be retained by the investigator according to local regulations or as specified in the clinical 
study agreement (CSA), whichever is longer. The investigator must ensure that the records 
continue to be stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless the CRO and Pfizer have expressly agreed to a different period of retention 
via a separate written agreement. Record must be retained for longer than 15 years if required 
by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.

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9.7. Data Monitoring
The CRO will supervise and monitor de-identified data abstraction by site staff into the EDC 
system.
Quality-control mechanisms (eg, verification of data completeness, validations, and edit 
checks), which will be automated at the time of data entry, will be built into the EDC. 
Queries will be generated by the CRO for resolution by site staff within the EDC system.
9.8. Data Cleaning
The EDC system will have built-in methods for data validation (eg, drop-down lists, value 
range controls, and standardized response formats). However, a data cleaning method will 
furthermore be employed to correct inconsistencies or errors that were not captured during 
data entry (eg, outliers or conflicting data). Data will be generated for site resolution. The 
CRO will follow up on the identified data queries until they are resolved by the site.
9.9. Data Analysis
This study is primarily descriptive in nature. Categorical variables will be reported as counts 
(n) and frequencies (%). Continuous variables will be reported using mean, standard 
deviation, median, minimum and maximum, interquartile range, and range. Time to event 
outcomes will be assessed using the KM method and will be reported as descriptive statistics 
(eg, median time to event) with 95% CI. Results will be presented for the overall group (both 
disease types) and separately for invasive aspergillosis and mucormycosis.
The statistical analysis plan (SAP) will provide a detailed description of analytic populations, 
analyses to be performed, and methods to deal with missing data and censoring.
Depending on the overall sample size, subgroup analyses may be conducted for main study 
outcomes (eg, by country, by diagnosis).
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a SAP, which will be dated, filed, and maintained by the sponsor. The SAP 
may modify the plans outlined in the protocol; any major modifications of primary outcome
definitions or their analyses would be reflected in a protocol amendment. The SAP will 
define all planned analytic populations and subpopulations, including definitions of overall 
response and AEs of interest. The SAP will further provide a detailed description of analyses 
to be performed.
Any known deviations from the planned analyses, the reason for such deviations and all 
alternative/additional statistical analyses that may be performed as well as the final statistical 
analysis must be described in a revised SAP before completion of data collection.

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9.9.1. Missing Data
It is anticipated that the degree of completeness for the study variables may vary due to 
unknown or undocumented data in the medical records. The number of patients with missing 
data for each variable will be summarized and reported. With the exception of the imputation 
of partial missing date values, no other imputation of missing values is anticipated; however, 
the impact of missing data on interpretation of findings will be acknowledged and discussed 
in the final study report. The SAP will further provide a detailed description of methods to 
deal with missing data and censoring.
9.9.2. Planned Analysis
9.9.2.1. Analysis Plan for Primary Objectives
Mortality/survival rates will be summarized and reported. Clinical, radiological, and 
mycological response documented in the medical record will be summarized using 
proportions and counts for each category. Details of radiological and mycological 
assessments will be reported in a descriptive manner, including the type of assessment and 
the assessment findings. Definitions of response will be provided in the SAP. Time to 
response and all-cause mortality will be analyzed using the KM method and quartiles and 
95% CIs will be reported.
Descriptive statistics will be used to describe all AEs and SAEs reported during the medical 
record review. The safety data described will include event type, relationship to 
isavuconazole treatment (where known), event severity, event seriousness, action taken with 
isavuconazole treatment and outcome of the event. Definitions of AEs and SAEs will be 
described in the SAP. Time from index treatment to first AE onset will be summarized.
Key timepoints of interest for assessment of treatment effectiveness, safety and survival 
outcomes will be at 6 weeks, 12 weeks, and 24 weeks after initiation of index treatment. In 
the cases that usual care visits do not directly coincide with these timepoints, the time 
windows for assessment of outcomes will be defined in the SAP.
9.9.2.2. Analysis Plan for Secondary Objectives
Basic summaries of site and patient counts included in the study will be produced. Patients 
will be characterized by fungal disease type (invasive aspergillosis or mucormycosis) at the 
time of isavuconazole initiation, in terms of demographics, disease characteristics, medical 
history, treatment history, prognostic factors, and other factors which may be predictive of 
clinical outcome.
For isavuconazole treatment patterns, descriptive statistics will be used to summarize details 
of isavuconazole administration (eg, location, therapy duration, loading dose and frequency, 
and maintenance dose and frequency), modifications to index therapy, details of therapeutic 
drug monitoring (therapeutic drug monitoring [TDM], eg, assay type, outcome), 
discontinuation, switching, antibiotic use before and after index therapy, and concomitant
medication.

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Health care resource utilization during the post-index period will be reported at 6 weeks, 
12 weeks, and 24 weeks after initiation of index therapy. HCRU will include counts and 
proportions of patients with inpatient visits, outpatient visits, ICU admissions and ER visits
and use of mechanical ventilators. Reason for visits and duration of visits will be described. 
Inpatient LOS and ICU LOS will be derived using admission and discharge dates.
9.9.3. Interim Analysis
There are no planned interim analyses.
9.10. Quality Control
The development of the protocol and SAP will follow Pfizer’s internal standard operating 
procedures (SOPs), which include detailed review rounds. Quality control of the statistical 
programming will follow the CRO’s SOPs.
The CRO will follow SOPs and quality-control processes that address patient data security to 
ensure that patient data (as well as other confidential data) remain secure and intact. The 
EDC system has built-in edit checks and validations and supports electronically generated 
and manual queries.
Patient confidentiality will be strictly maintained. Access to the EDC system will be
regulated via a hierarchical username and password control. Subject data will be de-
identified through design of data entry fields that do not permit the entry of identifying 
information such as initials, date of birth, date of diagnoses/treatments/admissions, or center-
assigned patient identifiers. Only trained site staff will enter data into the electronic CRFs. 
Patients’ ages in whole years, but not date of birth, will be entered. Dates related to 
diagnosis, treatments, hospital admissions, discharges, etc. will be entered by the physician;
the EDC system will calculate durations. Dates will not be stored by the EDC system and 
will not exist within the data set. No patient identifiers used by sites will be entered; rather 
the EDC program will automatically assign a study identifying number (ID) to each patient. 
The de-identified data as entered into the EDC system will be visible to the CRO and the 
Sponsor, but only center staff will be able to trace a study ID number to a patient identity, a 
necessary measure to allow center staff to respond to data queries raised by the CRO later.
9.11. Strengths and Limitations of the Research Methods
In the absence of a suitable existing database, this retrospective medical record review will 
allow the collection of real-world data in adult patients who received isavuconazole for the 
treatment of invasive aspergillosis or mucormycosis in the hospital setting. Unlike a
prospective study, retrospective cohort designs are not sensitive to the Hawthorne effect (ie, 
alteration of behavior and/or prescribing practices as a result of being observed).
Limitations of this retrospective study design are acknowledged and will be documented 
within the study report:

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
Data quality will be dependent on completeness and accuracy of the data abstraction 
and the data documentation in the medical records. Differences in how each site 
operates, the connections to other health care facilities within the medical record, and 
the extent to which specific details are documented will affect data availability across 
medical records. For example, it is expected that the timing of follow-up visits may 
vary across sites. Additionally, some data are less likely to be comprehensively 
documented, including reasons for treatment modification/discontinuation/switching, 
TDM, mycological/radiological response status at end of treatment, AEs, and reason 
for HCP visits/referrals. Moreover, visits that occur at a different site may not be 
documented within the medical record to which the site has access; thus, the data may 
not provide an accurate representation of the true health care burden. A rigorous data 
review and cleaning process will be undertaken to ensure that the data which is 
collected is of the highest quality for analysis.

The study sites will be chosen based on a convenience sampling approach. That is, 
sites that indicated interest in study participation and that retain pertinent data within 
patient medical records that meet the study eligibility criteria were identified during 
the feasibility assessment. Therefore, by study design, the sites are unlikely to be fully 
representative of all sites in which cases of invasive aspergillosis or mucormycosis 
are managed with isavuconazole therapy. Thus, the data are unlikely to be 
representative of the overall usual care patterns for invasive aspergillosis or 
mucormycosis in Europe, and the study results should not be considered to be 
generalizable.

Since invasive aspergillosis and mucormycosis are rare fungal infections, it is 
expected that the pool of potential patients across sites will be small and will vary by 
country.

The sample size might not yield reliable estimates for rare safety outcomes. However, 
this study will allow assessment of whether commonly occurring safety events in 
clinical trials also are observed in real-world setting.

As target patients are likely to have underlying severe diseases, we have designed this 
study specifically for a patient population found in a hospital setting, including the 
ER, ICU, or oncology, hematology and/or transplantation wards.

Inpatients may change wards during isavuconazole treatment, which may impact the 
availability of follow-up data. Additionally, patients may be discharged from hospital 
but will continue to receive treatment with isavuconazole. It is possible that the 
abstracting HCP does not have access to data related to these instances.
9.12. Other Aspects
Not applicable.

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10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient Information
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws.
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access. No patient-
identifying information will be collected for this study or transferred to Pfizer or the CRO. 
The study site will implement appropriate technical and organizational measures to ensure 
that the personal data can be recovered in the event of disaster. In the event of a potential 
personal data breach, the study site shall be responsible for determining whether a personal 
data breach has in fact occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, the data will not contain patient names (none will be collected). Rather, individual 
cases will be indicated by a single, specific, numerical code, based on a numbering system 
defined by Pfizer. The study will not collect any identifiable data; in this way, such data 
cannot be transferred to Pfizer or other authorized parties. The investigator site will maintain 
a confidential list of patients who participated in the study, linking each patient’s numerical 
code to his or her actual identity. In case of data transfer, Pfizer will maintain high standards 
of confidentiality and protection of patients’ personal data consistent with the CSA and 
applicable privacy laws.
10.2. Patient Consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required and 
exemption of informed consent will be requested to the Institutional Review Boards (IRBs)
or Independent Ethics Committees (IECs). However, informed consent may be required in 
accordance with local country regulations. If informed consent is required, bias will be 
introduced into the study since the eligible patient population must be alive at the time of 
data collection. Where relevant, this will be fully documented in the study report.
If informed consent is required:

The informed consent form (ICF) will be in compliance with local regulatory 
requirements and legal requirements. The ICF will be drafted using the Pfizer ICF 
template, with privacy language per country as required. Additionally, the final ICF 
and any subsequent amended versions during the study will be prospectively 
approved by both the IRB or IEC and Pfizer before use.

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
Informed consent will be obtained by site study staff prior to data abstraction. The 
person obtaining consent will be responsible for ensuring that each participant fully 
understands the nature, purpose, risks, and benefits of the study. Each participating 
patient will be provided with a copy of his or her signed ICF.

It will be the investigator's responsibility to ensure that each study patient, or his or 
her legally acceptable representative, is fully informed about the nature and objectives 
of the study and possible risks associated with participation. The investigator, or a 
person designated by the investigator, will obtain written informed consent from each 
patient or the patient’s legally acceptable representative before any study-specific 
activity is performed. The investigator will retain the original of each patient's signed 
consent form.
10.3. Patient Withdrawal
Not applicable.
10.4. IRB or IEC
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (eg, ICFs, if applicable) from the relevant IRBs or IECs. All 
correspondence with the IRB or IEC must be retained. Copies of IRB and IEC approvals 
must be forwarded to Pfizer.
Before study initiation this study will undergo IRB review and clearance in the US by the 
CRO's IRB, RTI International Committee for the Protection of Human Subjects Research. 
RTI International, of which RTI Health Solutions (RTI-HS) is a business unit, holds a 
Federal-Wide Assurance (FWA) (#3331) from the US Department of Health and Human 
Services (DHHS) Office for Human Research Protections (OHRP) that allows it to review 
and approve protocols involving human subjects. The committee also is registered with 
OHRP for both DHHS- and FDA-regulated research. Our FWA requires IRB review for all 
studies conducted by RTI-HS that involve human subjects, regardless of the funding source 
or geographic location from which data are being collected. Depending on the level of risk 
and the nature of the research, a study may be ruled as exempt from IRB review by an IRB 
chair or designated IRB member. Studies that are not exempt must be approved either by an 
IRB chair or designated IRB member (if the study qualifies for expedited review) or by a full 
IRB committee.
RTI International currently has an IRB committee available to review research protocols. The 
committee meets monthly to review biomedical clinical trials and has appropriate medical 
expertise among its members. The IRB has been audited by the FDA and is fully compliant 
with applicable regulatory requirements. The committee reviews research studies to ensure 
adherence to appropriate regulations that govern human subjects research, including 
45 CFR 46, 21 CFR 50 and 56, and to all applicable Helsinki Declarations and provisions of 
the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use for conduct of multinational studies. All studies involving human subjects 
undergo a continuing IRB review at least once per year.

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A request to classify the study as a 'non-interventional, not human data' research project will 
be submitted. If the IRB classifies the study as such, no additional reviews will be required.
In addition to review by RTI International's IRB, the protocol will be submitted for review 
and approval to the appropriate central and/or local IRBs and/or IECs. With assistance from 
the CRO, each principal investigator will be responsible for obtaining the necessary approval 
of the study protocol, protocol amendments, and ICFs (if needed), and other relevant 
documents, if applicable, from the central and/or local IRBs and/or IECs and for ensuring 
that the study complies with local legislation relating to data protection and privacy. When 
local approval is obtained, the documentation indicating the IRB’s or IEC’s (if applicable) 
approval and the names and qualifications of the committee members must be sent by the 
principal investigator to the CRO, who will send these documents to the study sponsor before 
the recruitment process begins.
10.5. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in:

Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE);

Good Epidemiological Practice (GEP) guidelines issued by the International 
Epidemiological Association (IEA);

Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR);

Good practices for real-world data studies of treatment and/or comparative 
effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on 
RWE in health care decision making;

International Ethical Guidelines for Epidemiological Research issued by the Council 
for International Organizations of Medical Sciences (CIOMS);

EMA European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Guide on Methodological Standards in 
Pharmacoepidemiology;

The ENCePP Code of Conduct for scientific independence and transparency in the 
conduct of pharmacoepidemiological and pharmacovigilance studies;

US FDA Guidance for Industry: Good Pharmacovigilance Practices and 
Pharmacoepidemiologic Assessment.

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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS AND/OR 
ADVERSE REACTIONS 
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report AEs with explicit 
attribution to any Pfizer drug that appear in the reviewed information (defined per the patient 
population and study period specified in the protocol). Explicit attribution is not inferred by a 
temporal relationship between drug administration and an AE but must be based on a definite 
statement of causality by an HCP linking drug administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) Adverse-
Event Monitoring (AEM) Report Form to Pfizer Safety are as follows:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the CRF and reported, within 
24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form.

Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form.
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted.
All research staff members must complete the following Pfizer training requirements:

“YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”.
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format. Copies of all signed training certificates must be provided to Pfizer. Re-training must 
be completed on an annual basis using the most current “Your Reporting Responsibilities”
training materials.

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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
12.1. Results Dissemination
A final study report will be developed. Development of an abstract for presentation at a 
suitable conference and a study manuscript suitable for submission to an appropriate journal 
will be considered. All forms of dissemination will describe the rationale for the study, 
methods, results, and the implications of those findings.

Final study report: A final study report will be developed based on analysis of the 
final locked dataset and will include all final study tables.

Abstract/poster: In the case that results yield material suitable for generation of a 
conference abstract, an abstract will be prepared. If selected, the study results (either 
interim or final) will be used to develop a poster/presentation for the conference.

Peer-reviewed publication: In the case that results yield material suitable for
publication of a manuscript in a peer-reviewed journal, a manuscript will be 
developed. All authors will have to meet the International Committee of Medical 
Journal Editors (ICMJE) guidelines for authorship.
12.2. Communication of Issues
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.

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13. REFERENCES
1.
Persichino JG, Can AD, Van TT, Matthews MN, Filler SG. Invasive pulmonary 
mucormycosis and aspergillosis in a patient with decompensated hepatic cirrhosis. Med 
Mycol Case Rep. 2018;21:12-15.
2.
Prakash H, Chakrabarti A. Global Epidemiology of Mucormycosis. J Fungi (Basel). 
2019;5(1).
3.
Pfizer. Summary of Product Characteristics: CRESEMBA 200 mg powder for 
concentrate for solution for infusion. 
https://www.medicines.org.uk/emc/product/5069/smpc. Published 2019. Accessed June 
19, 2019.
4.
Maertens JA, Raad, II, Marr KA, et al. Isavuconazole versus voriconazole for primary 
treatment of invasive mould disease caused by Aspergillus and other filamentous fungi 
(SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 
2016;387(10020):760-769.
5.
Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucormycosis in 
Europe. Clin Microbiol Infect. 2014;20 Suppl 6:67-73.
6.
Baddley JW. Clinical risk factors for invasive aspergillosis. Med Mycol. 2011;49 Suppl 
1:S7-S12.
7.
Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. Isavuconazole treatment for 
mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect 
Dis. 2016;16(7):828-837.
8.
Mullane KM, et al. Safety and Outcomes in Invasive Aspergillosis Patients with Renal 
vs. No Renal Impairment Treated with Isavuconazole: Experience from the SECURE 
(Randomised) and VITAL Trials. Paper presented at: 25th European Congress of 
Clinical Microbiology and Infectious Diseases (ECCMID) 2015; Copenhagen, 
Denmark.

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14. LIST OF TABLES
Table 1.
Wilson 95% CI Based on All-Cause Mortality Rate at Day 42 for Patients 
With Invasive Aspergillosis Who Received Isavuconazole in the SECURE Trial
15. LIST OF FIGURES
Figure 1.
Overview of Study Periods and Examples of Eligible Cases
Figure 2.
Data Collection Periods and Timepoints for Each Patient
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 2. ADDITIONAL INFORMATION
Not applicable.