Clinical trial NCT03572049
Conditions: Invasive Fungal Infections
Keywords: Histoplasmosis Coccidioidomycosis Blastomycosis
Sponsor: University of Alabama at Birmingham
Start date: 2018-09-17; Completion date: 2022-04-29
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, multi-center, randomized, open-label parallel arm study involving patients with proven or probable invasive endemic fungal infection to ascertain the pharmacokinetics, safety, efficacy, tolerability and health economics of oral SUBA-itraconazole compared to conventional itraconazole. Patients will receive randomized open-label study drug (SUBA-itraconazole or conventional itraconazole) over a 42 day period and then continue therapy until Day 180. Patients will be stratified based on clinically reported infection with the human immunodeficiency virus (HIV).

Detailed description:
This is a prospective, multi-center, randomized, open-label parallel arm study involving patients with proven or probable invasive endemic fungal infection to ascertain the pharmacokinetics, safety, efficacy, and tolerability of oral SUBA-itraconazole or itraconazole. Patients will receive randomized open-label study drug (either SUBA- itraconazole 130 mg twice daily or itraconazole 200 mg twice daily) over a 42-day period and then continue on their assigned open-label therapy until day 180.

The study sample size will be 80 evaluable patients - target enrollment (three arms: approximately 40 histoplasmosis, 20 coccidioidomycosis, 20 other endemic fungal infections).

Arms: arm 1: Stage 1: Day 1-3 two 65 mg capsules three times daily with food. Days 4-42 two 65 mg capsules twice daily with food.

Stage 2 : Days 43-180 two 65 mg capsules twice daily with food arm 2: Stage 1: Day 1-3 two 100 mg capsules three times daily with food. Days 4-42 two 100 mg capsules twice daily with food.

Stage 2 : Days 43-180 two 100 mg capsules twice daily with food
Interventions: intervention 1: SUBA itraconazole intervention 2: Conventional itraconazole
Intervention descriptions: intervention 1: SUBA itraconazole study drug will consist of two 65 mg capsules to be taken three times a day with food for days 1-3 of study. For days 4-180 of study, two 65mg capsules will be taken twice daily with food. intervention 2: Conventional itraconazole comparator drug will consist of two 100 mg capsules to be taken three times a day with food for days 1-3 of study. For days 4-180 of study, two 100 mg capsules will be taken twice daily with food.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
SUBA-itraconazole versus conventional itraconazole in the 
treatment of endemic mycoses: a multi-center, open-label, 
randomized comparative trial 
 
 
MSG-15 
 
NCT03572049 
 
 
August 19, 2020 
 
 
Peter G. Pappas, MD, Principal Investigator 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 
 
 
 
 
 
 
 
 


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SUBA-itraconazole versus conventional itraconazole in the treatment 
of endemic mycoses: a multi-center, open-label, randomized 
comparative trial 
 
MSG Protocol Number: 15 
ClinicalTrials.gov#: Registration in Progress 
IRB # 300001222 
WIRB # 20180840 
IND # Pending 
Cross-referenced to IND #078675  
Mayne Pharma International Pty. Ltd. 
 
Version 5.0 
August 19, 2020 
 
Pharmaceutical Support Provided by: Mayne Pharma International Pty. Ltd. 
Principal Investigators: 
George R. Thompson III, M.D 
Associate Professor of Medicine 
Department of Medical Microbiology & Immunology 
Department of Internal Medicine, Division of Infectious Diseases 
University of California - Davis 
One Shields Ave, Tupper Hall 
Davis, CA 95616 
Phone: +1-530-752-3545 
Email: grthompson@ucdavis.edu 
 
Andrej Spec, M.D., MSCI 
Assistant Professor of Medicine 
Department of Internal Medicine, Division of Infectious Diseases 
Washington University in St. Louis 
4523 Clayton Ave, Campus Box 8051 
St. Louis, MO 63110 
Phone: +1-314-747-1725 
Email: andrejspec@wustl.edu 
 
Peter G. Pappas, M.D. 
William E Dismukes Professor of Medicine 
Principal Investigator, Mycoses Study Group 
Department of Internal Medicine, Division of Infectious Diseases 
University of Alabama at Birmingham 
1900 University Blvd, THT 229 
Birmingham, AL 35294-0006 
Phone: +1-205-934-9951 
Email: ppappas@uabmc.edu 


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Record of Protocol Versions 
 
Description 
Date 
Version # 
Initial Version 
4 October 2017 
1.0 
Clarification of Pharmacokinetics;  Sponsor Name 
Revised 
15 February 2018 
2.0 
Addition of LAR Language to Inclusion Criteria (page 
8);  
Addition of Detail to Schematic (page viii);  
Clarification of Exclusion Criteria and Screening to 
include no more than 14 days of Antifungal 
Medications prior to initiation of Study Drug (pages 15 
and 16)  
27 April 2018 
3.0 
Addition of Pharmacokinetics on Day 7 
Changed Medical Outcomes Study Survey to SF-12 
Version 2 
Addition of Contact for Mayne Pharma Associate 
Director 
Formatting Corrections to Headers 
07 June 2018 
4.0 
Eligibility revisions of exclusion criteria for 
coccidioidomycosis patients 
Change in reproductive health language as 
recommended by FDA 
Clarification to description of Withdrawal from study 
Addition of telemedicine and home visits for COVID-19 
precautions 
Addition of optional site pharmacy shipment of IP to 
study participants 
19 August 2020 
5.0 


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STATEMENT OF COMPLIANCE 
 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by 
the following (use applicable regulations depending on study location and sponsor 
requirements; samples follow): 
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (21 
CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
 
ICH Efficacy Guideline: E6 R2 Good Clinical Practice (GCP), November 2016 
http://www.ich.org 
 
All key personnel (all individuals responsible for the design and 
conduct of this study) have completed Human Subjects Protection 
Training. 


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SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according 
to local legal and regulatory requirements and applicable US federal regulations and ICH 
guidelines. 
 
 
 
SITE INVESTIGATOR 
 
 
 
 
____________________________________________  
_________________ 
 
Signature 
 
 
 
 
 
 
Date 
 
 
 
 
____________________________________________ 
Title  
 


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TABLE OF CONTENTS 
 
Page 
Statement of Compliance 
iii 
Signature Page 
iv 
Table of Contents 
v 
List of Abbreviations 
viii 
Protocol Summary 
x 
1 
Key Roles 
1 
2 
Background Information and Scientific Rationale 
3 
2.1 
Background Information ..................................................................................................... 3 
2.2 
Rationale ............................................................................................................................... 4 
2.3 
Potential Risks and Benefits .............................................................................................. 4 
2.3.1 Potential Risks ........................................................................................................ 4 
3 
Objectives 
6 
3.1 
Study Objectives .................................................................................................................. 6 
3.2 
Study Outcome Measures .................................................................................................. 6 
3.2.1 Primary and Secondary Outcome Measures – Stage I (Open-Label 
Parallel Group) ........................................................................................................ 6 
3.2.2 Primary and Secondary Outcome Measures - Stage II (Open-Label 
Extension) ................................................................................................................ 6 
4 
Study Design 
7 
5 
Study Enrollment and Withdrawal 
8 
5.1 
Subject Inclusion Criteria .................................................................................................... 8 
5.2 
Subject Exclusion Criteria .................................................................................................. 8 
5.3 
Treatment Assignment Procedures .................................................................................. 9 
5.3.1 Randomization Procedures ................................................................................... 9 
5.3.2 Reasons for Withdrawal ...................................................................................... 10 
5.3.3 Handling of Withdrawals ...................................................................................... 10 
5.3.4 Termination of Study ............................................................................................ 10 
6 
Study Intervention/Investigational Product 
11 
6.1 
Study Product Description ................................................................................................ 11 
6.1.1 Acquisition ............................................................................................................. 11 
6.1.2 Formulation, Packaging, and Labeling .............................................................. 11 
6.1.3 Product Storage and Stability ............................................................................. 11 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................................ 11 
6.3 
Modification of Study Intervention/Investigational Product for a Participant ............. 12 
6.4 
Accountability and Assessment of Subject Compliance with Study 
Intervention/Investigational Product ............................................................................... 13 
6.5 
Concomitant Medications/Treatments ............................................................................ 14 
6.5.1 Collection ............................................................................................................... 14 
6.5.2 Restricted Concomitant Medications ................................................................. 14 


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7 
Study Schedule 
16 
7.1 
Screening ............................................................................................................................ 16 
7.2 
Enrollment/Baseline .......................................................................................................... 16 
7.3 
Follow-up ............................................................................................................................ 16 
7.4 
Final Study Visit or Early Termination Visit ................................................................... 16 
7.5 
Unscheduled Visit .............................................................................................................. 16 
8 
Study Procedures/Evaluations 
18 
8.1 
Clinical Evaluations ........................................................................................................... 18 
8.2 
Laboratory Evaluations ..................................................................................................... 18 
8.2.1 Clinical Laboratory Evaluations .......................................................................... 18 
8.2.2 Special Assays or Procedures ........................................................................... 18 
8.3 
Quality of Life (QOL) Evaluations ................................................................................... 20 
8.3.1 Short Form 12 (SF-12) ......................................................................................... 20 
8.4 
Methods  and  Timing  for  Assessing,  Recording,  and  Analyzing  Safety 
Parameters ......................................................................................................................... 20 
8.4.1 Adverse Events ..................................................................................................... 20 
8.4.2 Serious Adverse Events ...................................................................................... 22 
8.5 
Reporting Procedures ....................................................................................................... 22 
8.5.1 Serious Adverse Events ...................................................................................... 22 
8.5.2 Regulatory Reporting ........................................................................................... 23 
8.6 
Safety Oversight (Data Review Committee) .................................................................. 24 
9 
Clinical Monitoring 
25 
9.1 
Site Monitoring Plan .......................................................................................................... 25 
10 
Statistical Considerations 
26 
10.1 
Study Hypotheses and Statistical Analyses .................................................................. 26 
10.2 
Sample Size Considerations ............................................................................................ 26 
10.3 
Study Outcomes ................................................................................................................ 26 
10.4 
Data Review Committee ................................................................................................... 27 
10.5 
Safety Review .................................................................................................................... 28 
11 
Source Documents and Access to Source Data/Documents 
29 
12 
Quality Control and Quality Assurance 
30 
13 
Ethics/Protection of Human Subjects 
31 
13.1 
Ethical Standard ................................................................................................................ 31 
13.2 
Institutional Review Board ................................................................................................ 31 
13.3 
Informed Consent Process............................................................................................... 31 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) ....................... 32 
13.5 
Subject Confidentiality ...................................................................................................... 32 
14 
Data Handling and Record Keeping 
33 
14.1 
Data Management Responsibilities ................................................................................ 33 
14.2 
Data Capture Methods ...................................................................................................... 33 
14.3 
Study Records Retention ................................................................................................. 34 
14.4 
Protocol Deviations ........................................................................................................... 34 
15 
Publication Policy 
35 


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16 
Literature References 
36 
 
Appendix A: Schedule of Events 
38 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DRC 
Data Review Committee 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IFI 
Invasive fungal infection 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NCI 
National Cancer Institute, NIH, DHHS 
NDA 
New Drug Application 
NEJM 
New England Journal of Medicine 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
SAE 
Quality of Life 
Serious Adverse Event/Serious Adverse Experience 


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SF-12 
Short Form 12 Version 2 
Standard Operating Procedure 
United States 
World Health Organization 
SOP 
US 
WHO 
 
 
 


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PROTOCOL SUMMARY 
 
Title: 
SUBA-itraconazole versus conventional itraconazole in the 
treatment of endemic mycoses:  an open-label comparative trial 
Phase: 
IIb 
Population: 
80 adults infected with one of the endemic mycoses living in the United 
States, Canada and Central/South America (Approximately: 40 
Histoplasmosis, 20 Coccidioidomycosis, 20 other endemic mycoses) 
Number of Sites: 
Approximately 20 total sites in US, Canada, and Central/South 
America 
Study Duration: 
This study is estimated to be opened for 18 months after initiation (12 
month patient accrual, 6 month treatment period). 
Subject 
Participation 
Each participant will be enrolled in the study for 180 days 


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Objectives: 
The objectives of this study are to compare PK, tolerance, safety, 
and efficacy of SUBA-Itraconazole study drug versus conventional 
itraconazole in a randomized open-label trial followed by a second 
stage of continuing open-label study drug. 
Stage I - Randomized, Open-Label, Parallel Group 
Primary Objective 
 
PK at Day 14 
 
Tolerability at Day 42 
Secondary Objective 
 
PK at Day 7 
 
PK at Day 42 
 
Efficacy by Day 42 
 
Safety by Day 42 
 
QOL (including hospital/ICU visits) Assessments by Day 42 
Stage II – Open-Label Extension 
Primary Objective 
 
Efficacy by Day 180 
 
Tolerability by Day 180 
Secondary Objective 
 
Safety by 180 
 
QOL (including hospital/ICU visits) Assessments by Day 
180 
Description of Study 
Design: 
 
 
 
 
 
 
 
 
Estimated Time to 
Complete Enrollment
This is a prospective, multi-center, randomized, open-label parallel arm 
study involving patients with proven or probable invasive endemic fungal 
infection to ascertain the pharmacokinetics, safety, efficacy, tolerability 
and health economics of oral SUBA-itraconazole compared to 
conventional itraconazole. Patients will receive randomized open-label 
study drug (SUBA-itraconazole or conventional itraconazole) over a 42 
day period and then continue therapy until Day 180 or earlier if Principal 
Investigator determines discontinuation of therapy is safe. Patients will be 
stratified based on clinically reported infection with the human 
immunodeficiency virus (HIV). 
The study sample size will be 80 evaluable patients – target enrollment 
(three groups: approximately 40 histoplasmosis, 20 coccidioidomycosis, 
20 other endemic fungal infections). 
 
12 Months 


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Schematic of Study Design: 
 
 


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1 
KEY ROLES 
MSG UAB Coordinating 
Center: (Contact for protocol 
questions, adverse events, 
deviations, randomization of 
subjects, case report forms, data 
entry and study operational 
issues) 
Principal Investigators: 
(Medical Monitors for eligibility, 
endemic mycoses, safety 
evaluations.) 
Alisa Peinhardt, MAIS, BSN, RN 
Mycoses Study Group Administrator University of 
Alabama at Birmingham, Infectious Diseases Division 
1922 7th Avenue South, Kracke Building #731 
Birmingham, AL 35233 
United States 
Phone +1-205-934-9661 
Email apeinhardt@uabmc.edu 
George R. Thompson III, M.D (Chair)  
Associate Professor of Medicine 
Department of Medical Microbiology & Immunology 
Department of Internal Medicine, Division of 
Infectious Diseases 
University of California - Davis 
One Shields Ave, Tupper Hall 
Davis, CA 95616 
United States 
Phone: +1-530-752-3545 
Email: grthompson@ucdavis.edu 
Andrej Spec, M.D., MSCI (Co-Chair) 
Assistant Professor of Medicine 
Department of Internal Medicine, Division of 
Infectious Diseases 
Washington University in St. Louis 
4523 Clayton Ave, Campus Box 8051 
St. Louis, MO 63110 
United States 
Phone: +1-314-747-1725 
Email: andrejspec@wustl.edu 
Peter G. Pappas, M.D. (Co-Chair) 
Professor of Medicine 
Principal Investigator, Mycoses Study Group 
Department of Internal Medicine, Division of 
Infectious Diseases 
University of Alabama at Birmingham 
1900 University Blvd, THT 229 
Birmingham, AL 35294-0006 
United States 
Phone: +1-205-934-9951 
Email: ppappas@uabmc.edu 


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Mayne Associate Director, Clinical 
Operations 
(Contact for Sponsor 
Administrative Issues) 
 
 
 
 
 
 
 
 
 
 
MSGERC Biostatistician and 
Data Coordinator 
(Contact for unresolved issues 
related to randomization and 
electronic case report form) 
 
Phoevos Hughes 
Director, Clinical Operations 
Mayne Pharma 
3301 Benson Drive, Suite 401  
Raleigh, NC 27609 USA  
919-573-7948 
Phoevos.Hughes@maynepharma.com 
 
 
 
 
 
Gerald McGwin, PhD 
Professor and Vice Chair, Department of 
Epidemiology, 
School of Public Health 
University of Alabama at Birmingham 
Birmingham, AL 35294USA 
Phone: +1-205-975-3036 
Email: mcgwin@uab.edu 
 
 


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BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
2.1 
Background Information 
The endemic mycoses are a diverse group of diseases that share several 
characteristics. They are able to cause disease in otherwise healthy hosts, each 
pathogen occupies a specific ecologic niche in the environment, are located within a 
specific geographic region, and exhibit temperature dimorphism – existing as yeasts 
in the host and molds in the environment [1]. 
 
These dimorphic fungi consist of numerous species, however Histoplasma, 
Coccidioides, 
Paracoccidioides, 
Blastomyces, 
Sporothrix, 
and 
Talaromyces 
(Penicillium marneffei) represent the most commonly encountered infections in clinical 
care. Histoplasma spp. are common throughout the Mississippi, Ohio, and St. 
Lawrence River valleys, the Caribbean, parts of Central and South America, Africa and 
Asia [2]; Coccidioides within the southwestern U.S., and parts of central and South 
America [3]; Paracoccidioides within Central and South America [4]; Blastomyces 
within the Mississippi and Ohio River basins, St Lawrence Seaway, and several 
Canadian provinces with sporadic cases in Africa, Central and South America [5]; 
Sporothrix schenckii is found worldwide [6]; and Talaromyces in Southeast Asia, India, 
Southern China and Hong Kong [7]. 
 
However, the range of the endemic mycoses has been recently questioned and reports 
describing these pathogens outside of their “known” endemic regions have emerged 
with increased frequency over the last few years [8-10]. These reports suggest the true 
incidence and distribution of these fungi may be far greater than previously recognized 
and thus a much larger population of patients is continually exposed to these 
pathogens. 
 
Exposure is largely unavoidable for those residing or visiting the endemic regions. 
Following inhalation these organisms are ingested by pulmonary macrophages yet 
they frequently are able to survive ingestion and escape, replicate, and thereafter 
cause disease with ensuing host morbidity and mortality. 
 
The treatment of the endemic mycoses can be difficult for both clinicians and patients. 
The majority of the endemic mycoses require long courses of antifungal treatment - 
with courses frequently requiring months to life-long suppressive therapy. Initial 
therapy for severe disease has traditionally consisted of an amphotericin B formulation 
and prolonged therapy is limited by the inherent toxicity of polyenes. Following 
improvement with an amphotericin B formulation, a triazole is prescribed for continuing 
therapy, usually for a minimum of 6-12 months, depending on the infection. 
 
Currently available agents are limited in the treatment of the endemic fungi by toxicity, 
poor oral bioavailability [11] or resistance. Fluconazole is widely available yet has 
limited activity against several of the endemic mycoses including histoplasmosis [12], 
while in others such as coccidioidomycosis treatment at high doses (> 800 mg/day) is 


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required, limiting patient tolerability. Voriconazole has been associated with cutaneous 
malignancy, photosensitivity [13], fluorosis [14], hepatotoxicity, inter-patient 
pharmacokinetic variability, and has limited activity against Sporothrix sp. Itraconazole 
exhibits variable absorption due to numerous intrinsic and extrinsic factors. In addition, 
food/acidity requirements are difficult for patients to maintain long-term. Posaconazole 
solution similarly exhibits dietary requirements and absorption concerns that limit 
patient compliance and bioavailability [15]. 
 
SUBA-itraconazole with twice-daily oral dosing options have improved 
pharmacokinetics and lack of food/acidity requirements [16]. 
 
2.2 
Rationale 
The availability of SUBA-itraconazole (65 mg capsules) with twice-daily dosing options 
with improved pharmacokinetics and lack of food/acidity requirements offers a 
substantial opportunity to improve the treatment of patients with endemic mycoses [16]. 
 
2.3 
Potential Risks and Benefits 
 
2.3.1   Potential Risks 
All medical treatments have the potential of causing undesirable effects. For this 
reason, the study is performed under carefully controlled conditions. 
 
Common side effects reported to date in patients taking conventional itraconazole 
(reported in 1-10% of the patients): 
 
 
Vomiting 
 
Headache 
 
Diarrhea 
 
Dizziness 
 
Abdominal pain 
 
Libido Decreased 
 
Anorexia 
 
Somnolence 
 
Edema 
 
Hypertension 
 
Fatigue 
 
Hypokalemia 
 
Fever 
 
Albuminuria 
 
Malaise 
 
Hepatic Function Abnormal 
 
Rash* 
 
Impotence 
 
Pruritus 
 
 
Nausea (11%) is a common side effect (reported in more than 10% of patients) 
associated with other marketed azoles that may or may not be associated with SUBA- 
Itraconazole. 
 
 
 
 


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Common side effects that were reported in less than 10% of patients taking other 
marketed azoles (fluconazole, voriconazole, itraconazole, ketoconazole, 
posaconazole, isavuconazole) were: 
 
 
 
 
 
Dizziness 
 
 
Trouble Breathing 
 
Chest pain 
 
Digestion problems 
 
Flatulence 
 
Tremors 
 
Sleeplessness 
 
Liver function test abnormalities 
 
Renal insufficiency 
 
Asthenia (weakness) 
 
Cardiovascular problems such as 
tachycardia or arrhythmia 
 
Vision disturbances 


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3 
OBJECTIVES 
 
3.1 
Study Objectives 
 
The purpose of this study is to compare safety, tolerance, PK, efficacy and cost 
effectiveness of SUBA-Itraconazole to conventional itraconazole in a randomized, 
open-label, parallel group trial followed by a second stage (open-label extension) 
where participants will continue open-label study drug. 
 
3.2 
Study Outcome Measures 
 
3.2.1 Primary and Secondary Outcome Measures – Stage I (Open-Label 
Parallel Group) 
 
Primary Outcomes 
 
PK at Day 14 
 
Tolerability at Day 42 
Secondary Outcomes 
 
PK at Day 7 
 
PK at Day 42 
 
Efficacy by Day 42 
 
Safety by Day 42 
 
QOL (including hospital/ICU visits) Assessments by Day 42 
 
 
3.2.2 Primary and Secondary Outcome Measures - Stage II (Open-Label 
Extension) 
 
Primary Outcomes 
 
Efficacy by Day 180 
 
Tolerability by Day 180 
Secondary Outcomes 
 
Safety by 180 
 
QOL (including hospital/ICU visits) Assessments by Day 180 


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4 
STUDY DESIGN 
 
This is a prospective, multi-center, randomized, open-label parallel arm study involving 
patients with proven or probable invasive endemic fungal infection to ascertain the 
pharmacokinetics, safety, efficacy, and tolerability of oral SUBA-itraconazole or 
itraconazole. Patients will receive randomized open-label study drug (either SUBA- 
itraconazole 65 mg twice daily or itraconazole 100 mg twice daily) over a 42-day period 
and then continue on their assigned open-label therapy until day 180. 
 
 
The study sample size will be 80 evaluable patients – target enrollment to include 
approximately 40 histoplasmosis, 20 coccidioidomycosis, and 20 other endemic 
fungal infections. 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
Subject Inclusion Criteria 
 
Subjects must meet all the inclusion criteria in order to be eligible to participate in the study 
as listed below: 
1. Male and female patients age > 18 years who have given written informed consent to 
participate.  
2. Patients who are unresponsive, critically ill, or requiring sedation so they are 
cognitively impaired will be considered unable to consent for themselves. A 
Legally Authorized Representative (LAR) will be approached for informed consent. 
LAR will be determined using this order: (a) legally appointed guardian, (b) health 
care proxy or authorized individual to make medical decisions in conjunction with a 
durable power of attorney, (c) spouse, (d) adult child, (e) parent, or (f) next of kin. 
Qualification of the LAR will be obtained through verbal assurance from the LAR. 
3. Patients with a proven or probable endemic mycosis (Histoplasma, Coccidioides, 
Paracoccidioides, Blastomyces, Sporothrix, Talaromyces marneffei (formerly 
Penicillium marneffei) according to current EORTC/MSG criteria, including patients 
who: 
 
Are immunosuppressed, including as a result of HIV/AIDS 
 
Have had a heart, lung or bone marrow transplant 
 
Have had chemotherapy for cancer 
 
Are otherwise normal hosts 
 
5.2 
Subject Exclusion Criteria 
 
All subjects meeting any of these listed exclusion criteria at baseline will be excluded from 
study participation: 
1. Significant liver dysfunction as evidenced by at least 5 times greater than upper limits 
of normal baseline ALT, AST, alkaline phosphatase, or total bilirubin. 
2. Use of an alternative antifungal therapy (IV or oral) for more than 14 days for this 
infection with the exception of Coccidioidomycosis. Subjects with 
Coccidioidomycosis who previously received fluconazole therapy for more than 
14 days may be included, if in the opinion of the investigator, they are having an 
inadequate response or, are intolerant of fluconazole (e.g. due to adverse 
events). Such subjects must washout from fluconazole for 7 days (~5 half-lives 
of fluconazole) before starting investigational therapy.  
3. Evidence of CNS infection. 
4. Unable to take PO medications. 
5. Female subjects who are lactating or pregnant.  


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6. Female subjects should be: 
a) Postmenopausal for 1 year, 
b) Post-hysterectomy or bilateral oophorectomy, 
c) If of child bearing potential have a negative β-HCG at screening and using 
highly effective method of birth control throughout course of study or  
remain abstinent for duration of study. 
7. Male subjects with female partner(s) of child-bearing potential, must agree to use a 
medically acceptable method of contraception during the study. If their partner is 
pregnant, males must agree to use a condom; if their partner is of child-bearing 
potential, their partner must additionally be using one of the following methods: 
hormonal contraception, intra-uterine device, diaphragm, or cervical cap. 
Spermicides alone are not an acceptable method of contraception. No sperm 
donations for 90 days post last dose of study therapy. 
8. Documented intolerance, allergy or hypersensitivity to an azole. 
9. Inability to comply with study treatment, study visits, and study procedures. 
10. Known history of congestive cardiac failure on medical treatment, fungal 
endocarditis, or other causes of ventricular dysfunction that may outweigh the benefit 
of itraconazole. 
11. Patients with active TB 
12. Concurrent use of astemizole, rifampin/rifampicin, rifabutin, ergot alkaloids, long 
acting barbiturates, carbamazepine, pimozide, quinidine, neostigmine, terfenadine, 
ketoconazole, valproic acid, or St. John’s wort in the 5 days prior to first 
administration of study drug. 
13. Any known or suspected condition of the patient that may jeopardize adherence to 
the protocol requirements or impede the accurate measurement of efficacy. 
14. Treatment with any investigational agent in the 30 days prior to study entry. 
15. Patients unlikely to survive 30 days (including severe fungal disease defined by SBP 
 
< 90mmHG; hypoxia < 60% saturation). 
16. Patients with body weight < 40 kg. 
 
5.3 
Treatment Assignment Procedures 
 
5.3.1 Randomization Procedures 
 
Stratified randomization will be used to assign qualifying participants to either 
conventional itraconazole or SUBA-itraconazole and dosed according to HIV status 
(positive or negative by clinical self-report) (Section 6.2).  
Randomization procedures are described in the Manual of Procedures. 
 
 
 
 


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5.3.2 Reasons for Withdrawal 
 
A study subject may be discontinued from participation in the study for the following 
reasons: 
 
Any clinical adverse event (AE) 
 
Withdrawn Consent 
 
Protocol Violation (e.g., violation of any exclusion criteria) 
 
Lost to Follow-Up 
 
5.3.3 Handling of Withdrawals 
 
If a subject is withdrawn prior to the end the study, the reason for withdrawal will be 
documented and entered into the eCRF and if patient is willing to return to be 
assessed, the End of Treatment (Day 180) assessments will be completed.  
Documentation of withdrawal in the source documents should include a distinction 
between participant withdrawal from the study medication regimen and withdrawal 
from the study itself. In the former case case, the study medication is stopped, but 
the participant, if willing, continues with study visit assessments; in the latter, study 
medication and study visit assessments are discontinued. 
 
 
 
5.3.4 Termination of Study 
 
This study may be prematurely terminated by the study sponsor or the 
protocol team for issues related to safety, efficacy, or other reasons (please 
see Section 5.3.2). If early termination of the study occurs, all study 
participants will have all End of Treatment (Day 180) assessments 
completed. 


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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 
6.1 
Study Product Description 
 
6.1.1 Acquisition 
 
SUBA-itraconazole and conventional itraconazole will be provided by Mayne Pharma 
for use in this study. Sites should only use product that has been sourced by Mayne 
Pharma. 
 
6.1.2 Formulation, Packaging, and Labeling 
 
SUBA-itraconazole Investigator Brochure and conventional itraconazole package 
insert are provided as separate documents. The conventional itraconazole package 
insert is also located at: 
http://www.janssen.com/us/sites/www_janssen_com_usa/files/products- 
documents/pi-sporanoxcapsules.pdf) 
 
SUBA-itraconazole study drug will consist of 65 mg capsules.  
Conventional itraconazole will consist of 100 mg capsules. 
 
Study drug will be packaged and labeled according to labeling instructions in the 
Manual of Procedures. Patients will be dispensed study drug by the site with 
sufficient amount of drug to last through the next study visit plus 5 days. 
Investigators at each site may determine if the site pharmacy may ship study 
drug to the participants’ homes when clinic visits are not recommended or 
possible.  
 
Patient initials, Study ID, and date will be recorded on dispensed study record. 
Documentation of dispensing, including identification of who dispensed the study 
drug, will be recorded in both the drug accountability log and the patient source 
documents. 
 
6.1.3 Product Storage and Stability 
 
Both SUBA-itraconazole and conventional itraconazole will be stored according to 
the guidelines provided in the investigator brochure or package insert, respectively. 
 
 


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6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Study participants will be randomized to receive either open-label SUBA-Itraconazole 
or conventional itraconazole. Each treatment arm will be dosed as follows: 
 
Arm A: Open-Label SUBA-itraconazole 65 mg Capsules – administered with 
food 
 
Stage 1 
 
Day 1 - 3: two 65 mg capsules, three times daily 
 
Day 4 - 42:  two 65 mg capsules, twice daily 
 
Stage 2: 
 
Day 43 – 180: two 65 mg capsules, twice daily. 
 
Arm B: Conventional Itraconazole 100 mg Capsules – administered with food 
Stage 1: 
 
Day 1 - 3: two 100 mg capsules, three times daily 
 
Day 4 - 42:  two 100 mg capsules, twice daily 
 
Stage 2: 
 
Day 43 – 180: two 100 mg capsules, twice daily). 
 
Based on standard of care for invasive endemic fungal infection, some participants 
will be prescribed conventional itraconazole (non-study drug) after Day 180 for up to 
a year or beyond, as prescribed by their physician. Information for discounted 
itraconazole will be provided at the end of the study to help defray costs. 
 
6.3 
Modification of Study Intervention/Investigational Product for 
a Participant 
Dose increase, reduction or cessation is permitted at the discretion of the 
investigator. Any modification to the dosing regimen will be noted in the source 
document and entered into the eCRF. 
 
The Investigator will consider a dose modification For the following combined 
drug levels (itraconazole + hydroxyitraconazole) at Day 14 and Day 42: 
 
<500ng/ml – increase dose 
 
>5000ng/ml – decrease dose 
 


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Any modification to the dosing regimen should have blood-levels re-analyzed 
every two weeks until the target therapeutic level is achieved (see schema 
below).  
 
 
 
 
 
 
 
 
The Investigator will consider dose reduction and/or dose cessation for toxicity if the 
participant: 
 
 
Develops a study drug-related, grade 4 adverse event 
 
Develops a study drug-related, serious adverse event (SAE) 
 
Develops dose-limiting study drug-related toxicity despite dose-reduction. 
 
6.4 
Accountability and Assessment of Subject Compliance with 
Study Intervention/Investigational Product 
Study drug accountability procedures will be performed by the clinical site. The site 
will maintain all product per storage guidelines highlighted in the product insert or IB. 
The clinical site will document receipt, dispensing, and any unused product. This 
documentation will be maintained throughout the conduct of the study. 
 


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Study drug compliance will be assessed at each visit (Day 7, Day 14, Day 28, Day 
42, Day 84, Day 180). Subjects will bring all containers and unused medication (if 
applicable) to each visit.  Sites will determine the total amount of product dispensed 
and compare it to returned product. This information will be collected on the source 
documents and entered into the eCRF. 
 
6.5 
Concomitant Medications/Treatments 
 
6.5.1 Collection 
 
Concomitant medications will be collected from signing of informed consent all the 
way through to the end of study visit. Any medications taken within 2 weeks of Study 
Day 1, even if prior to ICF collection date, should be noted. 
 
6.5.2 Restricted Concomitant Medications 
 
Itraconazole may affect the plasma concentration of other drugs, as it is an inhibitor 
of CYP3A4 as well as P-gp (P-glycoprotein). Sites should carefully evaluate 
concomitant medication use to ensure that possible drug interactions do not affect 
the health of the patient. 
 
Drugs that may decrease plasma concentrations of itraconazole include: 
Category 
Examples 
Anticonvulsants 
carbamazepine, phenobarbital, phenytoin 
Antimycobacterials 
isoniazid, rifabutin, rifampin 
Non-Nucleoside Reverse 
Transcriptase Inhibitors 
nevirapine 


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GI Medications 
Additionally, certain anti-acids, H2 blockers, and protein pump inhibitors are 
prohibited with conventional itraconazole. If possible, H2 blockers and protein pump 
inhibitors should be stopped 7 days prior to enrollment, at the discretion of the 
treating physician. Anti-acids may be taken 1-2 hours AFTER  oral dosing with study 
drug. 
 
Drugs that can increase plasma concentrations of itraconazole include: 
 
Category 
Examples: 
Macrolide Antibiotics 
clarithromycin, erythromycin 
Protease Inhibitors 
indinavir, ritonavir 
 
Alternative fungal medications administered for more than 14 days prior to the 
first dose of study medication are prohibited unless subject with 
coccidioidomycosis previously treated with fluconazole therapy for more than 
14 days. If in the opinion of the investigator, the subjects with 
coccidioidomycosis are having an inadequate response or, are intolerant of 
fluconazole (e.g.due to adverse events), the subjects may be included. Such 
subjects must washout from fluconazole for 7 days (~5 half-lives of fluconazole) 
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7 
STUDY SCHEDULE 
 
7.1 
Screening 
 
Patients presenting to the clinic or hospital with new onset presumed or definite endemic 
fungal infection that have not been treated with an alternative antifungal medication for 
more than 14 days prior to study drug administration; and with no known exclusion criteria 
by medical history will be given informed consent to enroll in the study. 
 
7.2 
Enrollment/Baseline 
 
Patients consenting to the study will be further evaluated for inclusion and exclusion criteria, 
medical history, physical examination, pregnancy test (blood or urine BHCG), mycologic 
assessment, antigen and antibody levels, radiography (if clinically indicated); serum 
chemistry, serum hematology. See Appendix A for study procedures per visit. 
 
7.3 
Follow-up 
 
Participants will be assessed in clinic at Day 7, Day 14, Day 28 (1 month), Day 42, Day 84 (3 
months) and Day 180 (6 months). In the opinion of the investigator, clinic visits may be 
replaced with telemedicine visits or home visits, with allowances made for blood draws at 
remote or commercial laboratories. Documentation in source documents should clearly define 
accommodations in visit locations or methods when attempting to protect participants and 
other patients from potential exposure and hazards related to COVID-19.  
The Day 7, 14 and 42 visits allow a narrow window (+/- 3 days) so that accurate PK levels 
can be drawn. 
 
The Day 84 and 180 visits will allow a window of (+/- 7 days). 
 
At each visit, blood samples will be drawn for study-specific safety and efficacy labs. In 
addition a quality of life questionnaire will be administered at Day 42. See Appendix A for 
study procedures per visit. 
 
7.4 
Final Study Visit or Early Termination Visit 
 
The final study visit will occur at Day 180 (with a window of +/-7 days). During this visit, a 
physical examination, vital signs, quality of life questionnaire, assessments of concomitant 
medications and adverse events and mycological assessments will take place. Blood and 
urine samples will be drawn for study-specific safety and efficacy labs. See Appendix A for 
study procedures per visit. 


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7.5 
Unscheduled Visit 
 
If clinically indicated, study subjects may be asked to return to clinic to further assess safety 
issues, resolution of a safety issue, evaluate treatment compliance, or other reasons as 
determined by the investigator. 


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8 
STUDY PROCEDURES/EVALUATIONS 
 
8.1 
Clinical Evaluations 
1. Medical history will be obtained by interview and if available, from medical 
records. 
2. Medications history includes medications taken within the prior 2 weeks and 
indication. Assessment of eligibility should include a review of permitted and 
prohibited medications. 
3. Physical examination will be conducted at baseline, targeted physical exams may 
occur with vital signs at each subsequent visit. At end of therapy or early 
termination, a physical examination is required. 
 
8.2 
Laboratory Evaluations 
 
Safety laboratory evaluations (Hematology, Biochemistry and Urine Pregnancy 
Tests) will be conducted by the local site laboratory as part of standard of care for 
treating patients with endemic mycoses. 
 
8.2.1 Clinical Laboratory Evaluations 
 
8.2.1.1 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with 
differential count, platelet count. 
 
8.2.1.2 
Biochemistry: creatinine, total bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST). 
 
8.2.1.3 
Blood or Urine Pregnancy test, to be done within 24 hours prior to 
study intervention and results must be available prior to 
administration of study product. 
 
8.2.1.4 
HIV: HIV Testing must be performed and resulted no more than 30 
days prior to start of study unless previous positive findings are 
documented in source documents. 
 
8.2.2 Special Assays or Procedures 
 
Antibody and antigen assays for Histoplasmosis, blastomycosis and 
coccidioidomycoses will be performed at study sites using instructions for specimen 
handling and processing found in the Manual of Procedures. 
 


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Pharmacokinetic assessments to quantify plasma concentrations of itraconazole and 
hydroxyitraconazole will be performed by a Central Laboratory. Instructions for 
specimen handling, storage, and shipping are found in the Manual of Procedures. 


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8.3 
Quality of Life (QOL) Evaluations 
 
8.3.1 
Short Form 12 Version 2  (SF-12v2) 
 
The SF-12v2 is a 12-question multipurpose survey instrument derived from the 
larger, SF-36 [17]. The SF-12v2 has been used in numerous healthcare settings and 
disease types to help determine the patient’s overall state of wellbeing and health-
related QOL by means of assessing both physical and mental status at the time of 
the survey. The 8 domains of the survey are: physical functioning (PF), role-physical 
(RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role- 
emotional (RE), and mental health (MH). Subjects will be administered the SF-12PK 
at Day 1, Day 42, and Day 180. Version 2 of the SF-12 (Optum) will be used for this 
study. 
 
8.4 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
 
8.4.1 Adverse Events 
 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product regardless of its causal 
relationship to the study treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of medicinal (investigational) product. The 
occurrence of an AE may come to the attention of study personnel during study visits 
and interviews of a study recipient presenting for medical care, or upon review by a 
study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for “serious 
adverse events” should be captured on the appropriate CRF. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority 
to make a diagnosis, which would include MD, PA, Nurse Practitioner, DO, or DDS), 
and time of resolution/stabilization of the event.  All AEs occurring while on study 
must be documented appropriately regardless of relationship.  All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the patient is screened should 
be considered as baseline and not reported as an AE. However, if it deteriorates at 
any time during the study, it should be recorded as an AE. 
 
All AEs must be graded for severity and relationship to study product. 


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FDA defines an AE as any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. 
 
Severity of Event: All AEs will be assessed by the clinician using a protocol defined 
grading system. For events not included in the protocol defined grading system, than 
the following guidelines will be used to quantify intensity. 
 
Mild: events require minimal or no treatment and do not interfere with the 
patient’s daily activities. 
 
Moderate: events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
 
Severe: events interrupt a patient’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
 
Life threatening: any adverse drug experience that places the patient or subject, 
in the view of the investigator, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that had it occurred in a more severe 
form, might have caused death. 
 
Changes in the severity of an AE should be documented to allow an assessment of 
the duration of the event at each level of intensity to be performed. Adverse events 
characterized as intermittent require documentation of onset and duration of each 
episode. 
 
Relationship to Study Products: The clinician’s assessment of an AE's 
relationship to test article (study drug) is part of the documentation process, but it is 
not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study product assessed using the terms: 
related or not related. In a clinical trial, the study product must always be suspect.  
To help assess, the following guidelines are used. 
 
 
Related – There is a reasonable possibility that the study product caused the 
adverse event. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study product and the adverse event. 
 
 
Not Related – There is not a reasonable possibility that the administration of the 
study product caused the event. 
 
 
 
 


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8.4.2 Serious Adverse Events 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
 
 
Death, 
 
 
a life-threatening adverse event*, 
 
 
inpatient hospitalization or prolongation of existing hospitalization, 
 
 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
 
 
a congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
* Life-threatening adverse event: an adverse event is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event, had it occurred in a 
more severe form, might have caused death. 
 
All SAEs will be: 
 
recorded on the appropriate SAE CRF 
 
followed through resolution by a study clinician 
 
reviewed and evaluated by a study clinician 
 
8.5 
Reporting Procedures 
 
8.5.1 Serious Adverse Events 
AEs will be followed until resolution even if this extends beyond the study-reporting 
period. Resolution of an AE is defined as the return to pretreatment status or 
stabilization of the condition with the expectation that it will remain chronic. 


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Any AE that meets a protocol-defined serious criterion must be submitted 
immediately (within 24 hours of site awareness) on an SAE form (located in the 
Manual of Procedures) to the MSG Coordinating Center at the University of 
Alabama in Birmingham. 
 
Contact:  
Alisa Peinhardt 
Mycoses Study Group Administrator 
University of Alabama at Birmingham, Infectious Diseases Division 
1922 7th Avenue South, Kracke Building #731 
Birmingham, AL 35233 
Phone 205-934-9661 
Fax 205-975-9901 
Email apeinhardt@uabmc.edu 
 
Other supporting documentation of the event should be provided immediately or as soon 
as possible. 
 
The Study Principal Investigator will be notified of the SAE by the MSG Coordinating 
Center and will review and assess the SAE for regulatory reporting and potential impact 
on study subject safety and protocol conduct. 
 
At any time after completion of the study, if the investigator becomes aware of an SAE 
that is suspected as being related to study product, the investigator will report the event 
to the MSG Coordinating Center who will notify Mayne Pharma. 
 
8.5.2 Regulatory Reporting 
 
The MSG Coordinating Center, will report any suspected adverse reaction that is both 
serious and unexpected. The MSG Coordinating Center will report an adverse event as 
a suspected adverse reaction only if there is evidence to suggest a causal relationship 
between the drug and the adverse event. The MSG Coordinating Center will notify FDA, 
Mayne Pharma, and all participating investigators (i.e., all investigators to whom the 
sponsor is providing drug under the IND) in an IND safety report of potential serious 
risks from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for 
reporting as specified in 21 CFR Part 312.32. The MSG Coordinating Center will also 
notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as 
soon as possible but in no case later than 7 calendar days after the sponsor’s initial 
receipt of the information. Relevant follow up information to an IND safety report will be 
submitted as soon as the information is available. Upon request from FDA, the MSG 
Coordinating Center will submit to FDA any additional data or information that the 


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agency deems necessary, as soon as possible, but in no case later than 15 calendar 
days after receiving the request. 
 
All serious events designated as “not related” to study product(s), will be reported to the 
FDA at least annually in a summary format. 
 
8.6 
Safety Oversight (Data Review Committee) 
 
Safety oversight will be under the direction of the study designated Data Review 
Committee (DRC). The DRC will meet to assess safety and efficacy data on each arm 
of the study. The DRC will review aggregate safety data for increased rate of 
occurrence of serious suspected adverse reactions. The DRC will operate under the 
rules of a charter that will be written at the organizational meeting of the DRC. At this 
time, each data element that the DRC needs to assess will be clearly defined. The DRC 
will advise the study team of its findings. 


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9 
CLINICAL MONITORING 
 
9.1 
Site Monitoring Plan 
Trial monitoring is an integral component of trial quality assurance and critical for ICH GCP 
fulfillment. According to the International Council for Harmonisation E6 Good Clinical 
Practice (R2), and the FDA Title 21 CFR, Part 312, Subpart D, Responsibilities of the 
Sponsor. The sponsor should determine the appropriate extent and nature of monitoring 
based on the study objectives, purpose, design, complexity, blinding, size and endpoints. 
ICH states that naturally, there is a need for on-site monitoring, but there are 
circumstances when remote or central monitoring may be permitted. These regulations 
incorporated risk-based monitoring in the most recent revision encouraging the sponsor 
to rationalize the blend of monitoring (on-site, combination of on-site and centralized 
monitoring, or only remote monitoring). 
Risk-based monitoring is defined by the FDA Guidance for Industry Oversight of Clinical 
Investigations — A Risk-Based Approach to Monitoring, as focused sponsor oversight 
activities on preventing or mitigating important and likely risks to data quality and 
processes critical to human subject protection and trial integrity. The approach the sponsor 
has approved for this study is a hybrid of on-site and centralized monitoring. Qualification 
visit will be performed on-site with all the assigned study staff present and facilities 
inspected. Site Initiation and Training can be performed remotely or on-site, based on the 
availability of the site staff. 
Routine monitoring activities will be performed both on-site periodically, as is possible and 
safe related to the ongoing COVID-19 precautions, with the primary process being remote 
monitoring of the regulatory files and electronic case report forms to identify potential 
issues. 
A site monitor will be appointed as an unbiased and independent party to perform various 
study visits to evaluate the site’s capabilities and monitor the ongoing progress of a clinical 
study. Over the course of the study, the role of the site monitor is to verify the following on 
behalf of the study team at the appointed site: 
• 
The rights, well-being, and safety of human subjects are protected. 
• 
Reported trial data are accurate, complete, and verifiable from source documents. 
• 
The conduct of the trial is in compliance with the currently approved Protocol, GCP, 
and applicable regulatory requirements. 


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10 
STATISTICAL CONSIDERATIONS 
 
10.1 Study Hypotheses and Statistical Analyses 
 
For the primary outcomes of Stage I, t- and chi-square tests will be used to test whether 
the treatment group experiences superior PK at Day 14 and Tolerability at Day 42, 
respectively. If it is determined that the assumptions of the t-test are not met by the data, 
non-parametric statistical tests will be employed; Fisher’s exact test will be used as 
deemed necessary. In the unusual occurrence that the study groups are not in equipoise 
with respect to the measured baseline demographic, behavioral and clinical 
characteristics, linear and logistic regression models will be used to compare the 
treatment groups, adjusted for any observed differences. The same aforementioned 
statistics techniques will be used for the secondary outcomes of Stage I as well as the 
primary and secondary outcomes of Stage II. 
 
10.2 Sample Size Considerations 
 
The study will randomize 80 adults infected with one of the endemic mycoses living in the 
United States, Canada and Central/South America (40 Histo, 20 Cocci, 20 other endemic 
mycoses). This sample size provides adequate power (77%) to reject the null hypothesis 
of equal pharmacokinetic means when the population mean difference is μ1 - μ2 = 231.7 
- 291.7 = -60.0 with standard deviations of 94.0 and 101.8 for the study groups, and with 
a significance level (alpha) of 0.050 using a two-sided two-sample unequal-variance t- 
test. 
 
10.3 Study Outcomes 
 
Stage I- Randomized Open-Label, Parallel Group 
Primary Endpoints 
1. Pharmacokinetic superiority at Day 14 
a) Inter- and intra- patient variability: Time to attain therapeutic plasma 
concentrations of itraconazole (> 500 mcg/L) 
b) Interpatient variability as calculated by co-efficient of variation 
 
Trough (pre-morning dose) sample will be collected at Days 14 and 42. 
Using validated LC-MS/MS methods, blood samples will be analyzed to quantify 
plasma concentrations of itraconazole and hydroxyitraconazole. 
 
Participants should arrive to the trial site having not taken their morning dose of 
study drug. 


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Note: site investigators are discouraged from drawing independent PK laboratories 
to check itraconazole levels outside of the designated timepoints (Day 14) 
 
2. Tolerability - ability to remain on study drug at Day 42 with less than a 7-day 
interruption of therapy 
 
Secondary Endpoints 
 
1. PK at day 7 – plasma concentrations of itraconazole- (comparative trough, steady 
state plasma itraconazole concentrations of SUBA-itraconazole 65mg capsules 
with food to  itraconazole 100mg capsules with food over 7 days) 
2. PK at day 42 - plasma concentrations of itraconazole- (comparative trough, steady 
state plasma itraconazole concentrations of SUBA-itraconazole 65mg capsules 
with food to  itraconazole 100mg capsules with food over 42 days) 
3. Efficacy: clinical outcomes (time to relief of fungal signs and symptoms) at days 
14, 28, and 42 
4. Safety- defined as: adverse events that occurred in each study arm by Day 42 
5. Tolerability - ability to remain on study drug at Days 14 & 28 
6. Days of Hospitalization and ICU stays at Day 42 
7. Other health economic endpoints: 
1. Number of unscheduled procedures (i.e., labs, scans, etc.) at Day 42 
2. Total number of capsules taken at Day 42 
3. SF-20 (QOL) assessments at Day 42 
 
Stage II- Open-Label, Extension 
Primary Endpoint 
1. Efficacy- Free from proven or probable invasive endemic fungal infection at Day 
180 
2. Tolerability- ability to stay on study drugs at Days 43 - 180. 
 
Secondary Endpoints 
 
1. Safety- Adverse events that occurred in each study arm between Days 43 - 180 
or end of therapy 
2. Days of Hospitalization (Days 1 - 180) defined as days of hospitalization and ICU 
stays from randomization to Day 180 or end of therapy) 
 
10.4 Data Review Committee 
 
In addition to discrete laboratory parameters for PK, laboratory reports, days of hospitalization, 
ER and ICU stays, and safety reports; a data review committee (DRC) consisting of a DRC 
chair and 3 additional mycology experts will review data to determine safety and efficacy 
parameters as follows: 


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Success 

Resolution of all attributable clinical symptoms, physical findings 
and radiography 

Partial resolution of attributable clinical symptoms, physical findings 
and/or radiography 
Success 

Eradication 

Presumed eradication 
 
DRC-Assessments of Clinical Response (Baseline, Days 14, 28, 42, 84, 180) 
Outcome 
DRC-Assessed Clinical Response 
 
 
 
 
 
 
 
 
Failure 
   No resolution and/or worsening of attributable clinical symptoms, 
physical findings, and/or radiography 
 
 
DRC-Assessments of Mycological Response (Days Baseline, Days 14, 28, 42, 84, 180) 
Outcome 
DRC-Assessed Mycological Response 
 
 
 
 
 
Failure 
   Persistence 
 
 Presumed persistence 
 
 
10.5 Safety Review 
 
A comparison of adverse events reported per study arm will be quantified and compared. 
Not applicable 

No attributable signs and symptoms present at baseline and no 
symptoms attributable to IFD developed post-baseline 
Not applicable 
   No mycological evidence available at baseline 


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11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
 
Each participating site will maintain appropriate medical and research records for this 
trial, in compliance with ICH E6, Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in 
this study, each site will permit authorized representatives of the sponsor(s), MSG, and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits, and evaluation of the 
study safety and progress. 
 
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Examples of these original documents and data records include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
memory aid or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial. It is acceptable to use 
CRFs as source documents. If this is the case, it should be stated what data will be 
collected on CRFs and what data will be collected from other sources. ECRFs must be 
completed in their entirety regardless of the site’s use of alternate source documents. 
 
Refer to: (http://www.fda.gov/downloads/Drugs/Guidance/ucm073122.pdf). 


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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
This section will address the plans for local quality assurance and quality control. 
(http://www.fda.gov/downloads/Drugs/Guidance/ucm073122.pdf). 
 
All sites conducting research are required to have a plan in place for assuring the quality 
of the research being conducted. 
 
Each site should have standard operating procedures (SOPs) for quality management 
which describe: 
 
How data will be evaluated for compliance with the protocol and for accuracy in 
relation to source documents. 
 
The documents to be reviewed (e.g., informed consents, eCRFs, clinic notes, 
product accountability), who is responsible, and the frequency for reviews should be 
identified, either in a formal quality management plan or in site SOPs. 
 
Methods of training for staff should be specified. 
 
 
Additional information about site quality control are found in the Manual of Procedures 


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13 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
13.1 Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research of the US National Commission for the 
Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) 
and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 
(1997). 
 
If the study is conducted at international sites, compliance with the Declaration of 
Helsinki, CIOMS, and International Ethical Guidelines for Biomedical Research Involving 
Human Subjects (2002), or another country’s ethical policy statement, whichever 
provides the most protection to human subjects. 
 
13.2 Institutional Review Board 
 
Each participating institution must provide for the review and approval of this protocol 
and the associated informed consent documents and recruitment material by an 
appropriate independent ethics committee (IEC) or IRB. Any amendments to the 
protocol or consent materials must also be approved before they are placed into use. 
 
13.3 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continuing throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
subjects and their families. Consent forms describing in detail the study 
interventions/products, study procedures, and risks are given to the subject and written 
documentation of informed consent is required prior to starting intervention/administering 
study product. Consent forms will be IRB-approved and the subject will be asked to read 
and review the document. Upon reviewing the document, the investigator will explain the 
research study to the subject and answer any questions that may arise. The subjects will 
sign the informed consent document prior to any procedures being done specifically for 
the study. The subjects should have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. The subjects may withdraw 
consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the subjects for their records. The rights and welfare of the 
subjects will be protected by emphasizing to them that the quality of their medical care 
will not be adversely affected if they decline to participate in this study. 


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A model informed consent form for subject participation is provided in the Manual of 
Procedures. Each institution should place the informed consent document in its own 
template. Each institution may add but not remove anything from the model consent 
form. 
 
13.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
Study participants will consist of males or females, age 18 or greater, who meet eligibility 
requirements. Women who are pregnant will be excluded from participation because of 
potential side effects of the study drugs on the fetus. There are no exclusion criteria 
based on race or ethnicity. 
 
13.5 Subject Confidentiality 
 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participating subjects. 
 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence. No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the sponsor. 
 
The study monitor or other authorized representatives of the sponsor may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
subjects in this study. The clinical study site will permit access to such records. 


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14 
DATA HANDLING AND RECORD KEEPING 
 
14.1 Data Management Responsibilities 
 
The investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data. Black ink is required to ensure 
clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Data reported in the eCRF derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
 
The MSG Coordinating Center and/or its designee will provide guidance to investigators 
on making corrections to the source documents and eCRF. 
 
All source documents and laboratory reports must be reviewed by the clinical team and 
data entry staff at the site, who will ensure that they are accurate and complete. 
Adverse events must be graded, assessed for severity and causality, and reviewed by 
the site PI or designee. 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. During the study, the investigator must maintain complete and 
accurate documentation for the study. 
 
The MSGERC Statistical and Data Coordinating Center for this study will be responsible 
for data management, quality review, analysis, and reporting of the study data under the 
direction of the study statistician. 
 
14.2 Data Capture Methods 
 
Clinical data (including AEs, concomitant medications, and clinical assessments) and 
clinical laboratory data will be entered into a 21 CFR Part 11-compliant Internet Data 
Entry System (IDES) provided by The MSG Statistical and Data Coordinating Center. 
The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 


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14.3 Study Records Retention 
 
Study documents should be retained for a minimum of 2 years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by local regulations. No 
records will be destroyed without the written consent of the sponsor, if applicable. It is 
the responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained. 
 
14.4 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical 
Practice (GCP), or Manual of Procedure’s requirements. The noncompliance may be 
either on the part of the subject, the investigator, or the study site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
 
 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
 
 
Quality Assurance and Quality Control, section 5.1.1 
 
 
Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or 
within 5 working days of the scheduled protocol-required activity. All deviations 
must be promptly reported to the MSG Coordinating Center by Email or fax. 
 
All deviations from the protocol must be addressed in study subject source documents. 
A completed copy of the MSG Protocol Deviation Form must be maintained in the 
regulatory file, as well as in the subject’s source document. Protocol deviations must be 
sent to the local IRB/IEC per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to their IRB/IEC requirements. 


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15 
PUBLICATION POLICY 
 
Following completion of the study, the investigator is expected to publish the results of 
this research in a scientific journal. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a trials-registration policy as a condition 
for publication. This policy requires that all clinical trials be registered in a public trials 
registry such as ClinicalTrials.gov*, which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. The MSG 
Coordinating Center will register this study in ClinicalTrials.gov. Any clinical trial 
starting enrollment after 01 July 2005 must be registered on or before patient 
enrollment. For trials that began enrollment prior to this date, the ICMJE member 
journals will require registration by 13 September 2005, before considering the results of 
the trial for publication. 
 
The ICMJE defines a clinical trial as any research project that prospectively assigns 
human subjects to intervention or comparison groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome. Studies designed for 
other purposes, such as to study pharmacokinetics or major toxicity (e.g., Phase I trials), 
would be exempt from this policy. 
 
 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial registration: a statement 
from the International Committee of Medical Journal Editors. N Engl J Med. 2004;351:1250-1. 


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16 
LITERATURE REFERENCES 
 
1. 
Kauffman CA. Endemic mycoses: blastomycosis, histoplasmosis, and sporotrichosis. 
Infectious disease clinics of North America 2006; 20(3): 645-62, vii. 
2. 
Cano MV, Hajjeh RA. The epidemiology of histoplasmosis: a review. Semin Respir Infect 
2001; 16(2): 109-18. 
3. 
Brown J, Benedict K, Park BJ, Thompson GR, 3rd. Coccidioidomycosis: epidemiology. 
Clinical epidemiology 2013; 5: 185-97. 
4. 
San-Blas G, Nino-Vega G, Iturriaga T. Paracoccidioides brasiliensis and 
paracoccidioidomycosis: molecular approaches to morphogenesis, diagnosis, 
epidemiology, taxonomy and genetics. Medical mycology : official publication of the 
International Society for Human and Animal Mycology 2002; 40(3): 225-42. 
5. 
Bariola JR, Vyas KS. Pulmonary blastomycosis. Seminars in respiratory and critical care 
medicine 2011; 32(6): 745-53. 
6. 
Lopez-Romero E, Reyes-Montes Mdel R, Perez-Torres A, et al. Sporothrix schenckii 
complex and sporotrichosis, an emerging health problem. Future microbiology 2011; 
6(1): 85-102. 
7. 
Vanittanakom N, Cooper CR, Jr., Fisher MC, Sirisanthana T. Penicillium marneffei 
infection and recent advances in the epidemiology and molecular biology aspects. Clin 
Microbiol Rev 2006; 19(1): 95-110. 
8. 
Marsden-Haug N, Goldoft M, Ralston C, et al. Coccidioidomycosis acquired in 
Washington State. Clin Infect Dis 2013; 56(6): 847-50. 
9. 
Centers for Disease C, Prevention. Histoplasmosis in a state where it is not known to be 
endemic--Montana, 2012-2013. MMWR Morb Mortal Wkly Rep 2013; 62(42): 834-7. 
10. 
Baddley JW, Winthrop KL, Patkar NM, et al. Geographic distribution of endemic fungal 
infections among older persons, United States. Emerging infectious diseases 2011; 
17(9): 1664-9. 
11. 
Wiederhold NP, Pennick GJ, Dorsey SA, et al. Clinically Achievable Voriconazole, 
Posaconazole, and Itraconazole Concentrations within the Bloodstream and Cerebral 
Spinal Fluid: A Reference Laboratory Experience. Antimicrob Agents Chemother 2013. 
12. 
Wheat J, MaWhinney S, Hafner R, et al. Treatment of histoplasmosis with fluconazole in 
patients with acquired immunodeficiency syndrome. National Institute of Allergy and 
Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and 
Mycoses Study Group. The American journal of medicine 1997; 103(3): 223-32. 
13. 
Zwald FO, Spratt M, Lemos BD, et al. Duration of voriconazole exposure: an 
independent risk factor for skin cancer after lung transplantation. Dermatologic surgery : 
official publication for American Society for Dermatologic Surgery [et al] 2012; 38(8): 
1369-74. 
14. 
Wermers RA, Cooper K, Razonable RR, et al. Fluoride excess and periostitis in 
transplant patients receiving long-term voriconazole therapy. Clin Infect Dis 2011; 52(5): 
604-11. 
15. 
Thompson GR, 3rd, Rinaldi MG, Pennick G, Dorsey SA, Patterson TF, Lewis JS, 2nd. 
Posaconazole therapeutic drug monitoring: a reference laboratory experience. 
Antimicrob Agents Chemother 2009; 53(5): 2223-4. 
16. 
Abuhelwa AY, Foster DJ, Mudge S, Hayes D, Upton RN. Population pharmacokinetic 
modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and 
sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob 
Agents Chemother 2015; 59(9): 5681-96. 


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17. 
Ware, J.E., Kosinski, M. and Keller, S.D. (1996) A 12-Item Short-Form Health Survey: 
Construction of Scales and Preliminary Tests of Reliability and Validity. Medical Care, 
34, 220-233. 


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APPENDIX A: SCHEDULE OF EVENTS 
Activities 
Day 1g 
(Baseline) 
Day 7 
(1 wk) 
+/- 3 
days 
Day 14 
(2 wks) 
+/- 3 
days 
Day 28 
(4wks)
+/- 7 
days 
Day 42 
(6 wks) 
+/- 3 
days 
Day 84 
(3 mos) 
+/- 7 
days 
Day 180 
(6 mos) 
+/- 7 
days 
Informed Consent 
X 
Review of 
Inclusion/Exclusion Criteria 
X 
Randomization 
X 
Medical History 
X 
Clinical Assessment: vital 
signs, PEa, & radiographsb; 
X 
X 
X 
X 
X 
X 
X 
Participant Administered 
SF-12 Quality of Life 
Survey 
X 
X 
X 
Tolerability 
X 
X 
X 
X 
βHCG - pregnancy testc 
X 
Mycologic Assessment: 
clinical, urine and serum 
quantitative antigen levelsd & 
serum antibodiese,f 
X 
X 
X 
X 
X 
X 
Serum and Urine for future 
use: blood, urine, saliva, 
sputume 
X 
X 
X 
X 
X 
X 
Plasma PKf 
X 
X 
X 
Chemistry: Creatinine, AST 
and Alkaline Phosphatase, 
Total Bilirubinf 
X 
X 
X 
X 
X 
X 
Hematology: CBC with 
Differentialf 
X 
X 
X 
X 
HIV Status: Documentation 
of any positive test; 
Documentation of Negative 
test 30 days or less prior to 
start of study drug. 
X 
 
 
 
 
 
 
Antifungal Therapy (Pre- and 
during study) 
X 
X 
X 
X 
X 
X 
X 
Dose Modifications 
 
X 
X 
X 
X 
Study Drug Dosing & 
Accountability 
X 
X 
X 
X 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Days of Hospitalization, ICU 
X 
X 
X 
X 
X 
X 
X 
 
a Complete physical exam on baseline; targeted physical exams for all other visits. 
b Radiograph results that were performed as standard of care to diagnose or assess the fungal infection. 
c Urine or Serum pregnancy test is acceptable. 
d Histoplasma and Coccidioides urine and serum quantitative antigen. 
e Collection of sputum, if associated with the IFI and available. 
fChemistry and hematology will be processed at the site for safety evaluations; PK samples will be sent to a central lab for processing; see Manual of Procedures for specimen handling 
procedures; 


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gBaseline Visit: Study drug is be started on Day 1. Visit windows for Day 7, 14 and 42 will be a +/-3 day window. All other visits have a +/- 7 day window.