Randomized, Double-blind, Phase III Study of the Efficacy and Safety of Miconazole Oil, Active Versus Placebo in the Treatment of Otomycosis
Phase: PHASE3
Conditions: Otomycosis
Sponsor: Hill Dermaceuticals, Inc.

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
Page 1 of 50 
 
CLINICAL TRIAL PROTOCOL 
 
Study Title: 
Randomized, Double-blind, Phase III Study of the Efficacy 
and Safety of Miconazole Oil, Active versus Placebo in the 
Treatment of Otomycosis 
Study Number: 
MZ-1015-ESP3-054 
Study Drug: 
Miconazole oil 
Sponsor: 
Hill Dermaceuticals, Inc. 
2650 S. Mellonville Ave 
Sanford, FL 32773 
Protocol Date/Version: 
December 16, 2022  
Original 
NCT Number 
NCT05660382 
 
The information contained in this document is confidential and proprietary property of  
Hill Dermaceuticals, Inc. 

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
Page 2 of 50 
 
PROTOCOL APPROVAL 
The following individuals approve the December 16, 2022 version of the MZ-1015-ESP3-054 
protocol. All changes to this version of the protocol must have prior written approval and require 
an amendment or administrative letter. 
 
Company: 
Hill Dermaceuticals, Inc. 
Name: 
Rosario G. Ramirez, MD 
Title: 
Medical Officer 
Address: 
2650 South Mellonville Avenue 
 
Sanford, FL 32773 
 
 
 
 
 
Signature                                                      Date 
 

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
Page 3 of 50 
 
STUDY ACKNOWLEDGEMENT 
Protocol number: MZ-1015-ESP3-054 
I have read this protocol and commit to conduct the study as outlined herein in accordance with 
current Good Clinical Practices (cGCPs) and all applicable law. 
I agree that I or my designee will completely inform all subjects in this study and their legal 
representative(s) concerning the pertinent details and purpose of the study prior to their 
agreement to participate in the study in accordance with cGCPs and regulatory authority 
requirements. 
I will be responsible for maintaining the informed consent form signed by each subject or 
subject’s legal representative(s), as applicable, and the assent form signed by each subject, as 
applicable, and for providing each subject or each subject’s legal representative with a signed 
copy of these forms. 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
________________________________________  
_____________________ 
Investigator’s signature 
 
 
 
 
 
Date 
________________________________________ 
Investigator’s printed name 
 

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
Page 4 of 50 
 
SYNOPSIS 
Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
Study Title: 
Randomized, Double-blind, Phase III Study of the Efficacy and Safety of Miconazole Oil, 
Active versus Placebo in the Treatment of Otomycosis 
Study Number: MZ-1015-ESP3-054 
Study Center(s): Up to 8 study centers in the United States (US) 
Number of Subjects Planned:  
Approximately 110 
Study Period: 
The study duration for each subject will be up to approximately 24 days, which includes 14 
days of treatment and a follow-up visit 7 days after the end of treatment (Test of Cure) visit, 
including the visit window of 3 additional days after the protocol-specified day to complete the 
final Test of Cure visit.  
Phase of Development: 3 
Objectives: 
 Confirm the efficacy of miconazole oil (active) compared with mineral oil (placebo) over a 
14-day treatment duration in subjects with clinical otomycosis 
 Assess the safety of miconazole oil over a 14-day treatment duration in subjects with 
clinical otomycosis  
Design and Methodology: 
This study is a randomized, double-blind, parallel-group study to be conducted at up to 8 
study centers in the US. Approximately 110 male or female subjects with otomycosis will 
receive study drug.  Subjects will be randomly assigned in a 1:1 ratio within site to receive 
miconazole oil [administered as 5 drops per ear at ~30 mg per drop instilled into the external 
ear canal of the ear(s) affected by otomycosis] or mineral oil, for 14 days. Both the subject 
and the investigator as well as study staff will be blinded as to the contents of the study drug.  
At Screening/Baseline (Day 1), potentially eligible subjects will provide informed consent, and 
subjects will undergo screening evaluations to include a condensed physical examination, an 
assessment of the signs and symptoms of otomycosis (pruritus, debris, visual examination for 
presence of fungal elements, and aural fullness), and an evaluation of medical history. Urine 
will be obtained for pregnancy screening in female subjects of childbearing potential. Prior 
and concomitant medications will be reported. Subjects with positive signs and symptoms of 
otomycosis and who meet all other eligibility criteria will be entered into the study. A fungal 
culture of the affected ear(s) will be taken, then debris will be cleaned from the affected ear(s) 
following the site’s normal procedures.  The subject will then begin treatment with study drug. 
The subject or caregiver will instill the first dose of study drug at the site, under the 
supervision of the investigator or site personnel. Adverse events (AEs) will  be assessed. The 
subject will then leave the clinic and continue to administer the study drug twice per day as 
instructed. Subjects will be instructed to avoid getting water in the ear, to consider drying 
excessive water in the ear by using a blow dryer, and to place a Vaseline-impregnated cotton 
ball over the affected ear(s) to help keep water out of the ear while bathing or showering. 

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
Subjects will continue to administer the study drug twice per day, up through Day 14, 
following the same instructions as provided at the Screening/Baseline Visit on Day 1. 
Subjects will return to the clinic on Day 15 for the End of Treatment Visit, at which time a 
clinical evaluation of the signs and symptoms of otomycosis will be performed. AEs and 
concomitant medications will also be assessed, and the subject will return all unused study 
drug.  
Subjects will return to the clinic on Day 22 for the Test of Cure Visit, at which time a clinical 
evaluation of the signs and symptoms of otomycosis and a fungal culture of the affected 
ear(s) will be performed. AEs and concomitant medications will also be assessed. A urine 
pregnancy test will be performed in women of childbearing potential. 
Study Visits: 
Screening/Baseline (1 visit); End of Treatment (1 visit); Test of Cure (1 visit) 
Efficacy Evaluations: 
 Clinical signs and symptoms of otomycosis (pruritus; debris; presence of fungal elements; 
aural fullness) 
Safety Evaluations: 
 AEs 
Key Inclusion Criteria: 
Male or non-pregnant, non-lactating females with a clinical diagnosis of uncomplicated 
otomycosis of the external ear only, with an intact tympanic membrane, who are in general 
good health as determined by medical examination and medical history, and who are free of 
clinically significant disease, including diabetes mellitus, that is not well-controlled or that 
could interfere with the study, will be included in the study.  In each ear to be treated with 
study drug, subjects must have a visual presence of fungal elements and must also have the 
following signs or symptoms of otomycosis: pruritus ≥2; debris ≥2; and aural fullness ≥2. 
Key Exclusion Criteria: 
Subjects with any other dermatoses or conditions of the ear that may interfere with the 
evaluation of otomycosis, including concomitant otic infections (including bacterial infection) 
that require antimicrobial treatment, disease that has spread beyond the external ear(s), or 
pre-existing skin atrophy of the affected ear(s); tympanostomy tube or perforated tympanic 
membrane in the ear(s) that will be treated with study drug; history of prior surgery directly 
affecting and compromising the external auditory canal and/or tympanic membrane of the 
ear(s) that will be treated with study drug, except for prior tympanostomy tube(s) that have 
already been removed and completely healed; use of any topical medicated treatments for 
otomycosis within 14 days of study entry; use of any systemic antifungal therapy within 28 
days of study entry, warfarin within 28 days of study entry, immunosuppressive or immune-
stimulating drugs within 28 days of study entry, or systemic steroids within 3 months of study 
entry; fever of ≥100°F at study entry; recurrent otomycosis that has been unresponsive to 
previous antifungal treatment; known hypersensitivity to any of the components in the test 
formulation; and/or participation in another investigative trial within 28 days of study entry will 
be excluded from the study. 
Test Product, Dose and Mode of Administration: 
Miconazole oil 

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
Page 6 of 50 
 
Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
Active ingredient: 2% miconazole 
Other ingredients: refined peanut oil, mineral oil, oleth-2, and isopropyl myristate 
Mode of administration: subjects will be seated and then instructed to tilt their heads so that 
the affected ear is facing up. The subject or caregiver will then gently pull the ear lobe 
backward and upward and apply 5 drops of miconazole oil into the ear. The subject will be 
instructed to keep the head tilted with the ear facing up for approximately 3 to 5 minutes to 
allow the miconazole oil to penetrate lower into the ear canal. If both ears are being treated, 
the process will then be repeated for the other ear after a 5-minute wait.  
Placebo, Dose and Mode of Administration: 
Mineral oil 
Active ingredient: none (placebo group) 
Other ingredients: mineral oil 
Mode of administration: same as described for the active test product.  
Endpoints: 
Primary Efficacy Endpoint 
 
Percentage of subjects with “Clinical Cure,” defined as the score of 0 for fungal 
elements, and score of 0 for signs and symptoms of otomycosis (pruritus, debris, and 
aural fullness). 
Safety Endpoint 
 
Percentage of subjects with treatment-emergent adverse events (TEAEs). 

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
Statistical Analyses: 
Descriptive statistics will be presented for the percentages of subjects by treatment group 
with Clinical Cure in the study ear at each evaluation. Descriptive statistics will also be 
presented for the percentages of subjects by treatment group with each sign or symptom of 
otomycosis in the study ear at each evaluation. Descriptive statistics will include the number 
and percentage of subjects in each category. 
In cases of bilateral otomycosis, the ear with the worse infection at Screening/Baseline, as 
assessed by the investigator based on clinical signs and symptoms, will be used as the study 
ear for efficacy analyses. If both ears are determined by the investigator to have the same 
degree of infection at Screening/Baseline, the left ear will be used as the study ear for the 
purposes of efficacy analyses. 
For the primary efficacy endpoint, percentages of subjects with Clinical Cure at the Test of 
Cure Visit will be compared using a Cochran-Mantel-Haenszel (CMH) exact test stratified by 
clinical site with a 2-sided significance level of 0.05. Comparisons will be conducted in a 
similar manner between the miconazole oil and mineral oil (placebo)  groups for the 
secondary endpoints. Missing data will be imputed as treatment failures for the primary and 
secondary efficacy analyses; missing data otherwise will not be imputed. 
The primary population for all efficacy analyses will be the ITT population, defined as all 
subjects who were randomized, dispensed study drug, and with a clinical diagnosis of 
otomycosis. 
The primary population for all safety analyses will be the safety population, defined as all 
randomized subjects who received at least one dose of study drug and had at least one post-
Baseline safety assessment. 
All AEs occurring during the study will be recorded and classified using terminology from the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported treatment-emergent 
adverse events (TEAEs), defined as any AE with an onset on or after the date of first study 
drug application, will be summarized by treatment group. Summaries will provide the number 
of subjects reporting TEAEs, system organ class, preferred term, severity, and relationship to 
study drug. When summarizing TEAEs by severity or relationship to study drug, each subject 
will be counted only once within a system organ class or a preferred term using the event 
with the greatest severity or causality, respectively, within each category. All reported SAEs 
will be summarized by the number of subjects reporting the event, system organ class, 
preferred term, severity, and relationship to study drug. Descriptive statistics will be 
presented for all safety data. 
Sample Size: 
Approximately 110 subjects (~55 in each group) are required to provide 80% power, using a 
Fisher’s Exact test with a 2-sided significance level of 0.05, assuming a response rate for the 
primary efficacy endpoint of 35% in the miconazole oil group and 10% in the mineral oil 
group.   
  

Hill Dermaceuticals, Inc. 
 
Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
CONFIDENTIAL 
Page 8 of 50 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................................ 12 
1.1 
Background .................................................................................................................. 12 
1.2 
Study Purpose .............................................................................................................. 17 
1.3 
Inclusion of Subjects with Peanut Allergy ..................................................................... 18 
1.4 
Compliance with Good Clinical Practice ....................................................................... 18 
2 
STUDY OBJECTIVES AND endpoints ............................................................................ 18 
3 
STUDY DESIGN ................................................................................................................ 20 
3.1 
Number of Subjects ...................................................................................................... 21 
3.2 
Investigators ................................................................................................................. 21 
3.3 
Study Duration ............................................................................................................. 21 
4 
STUDY SUBJECTS ........................................................................................................... 22 
4.1 
Inclusion Criteria .......................................................................................................... 22 
4.2 
Exclusion Criteria ......................................................................................................... 23 
4.3 
Subject Completion ...................................................................................................... 23 
4.4 
Subject Discontinuation ................................................................................................ 23 
4.5 
Subjects Lost to Follow-up ........................................................................................... 24 
5 
CONCOMITANT THERAPIES ........................................................................................... 25 
5.1 
Permitted Medications .................................................................................................. 25 
5.2 
Prohibited Medications ................................................................................................. 25 
6 
STUDY SCHEDULE .......................................................................................................... 26 
6.1 
Study Flow Chart .......................................................................................................... 26 
6.2 
Study Visits .................................................................................................................. 27 
6.2.1 
Screening / Baseline (Day 1) .................................................................................. 27 
6.2.2 
End of Treatment  (Day 15) .................................................................................... 27 
6.3 
Test of Cure (Day 22) ................................................................................................... 28 
6.4 
Unscheduled Study Visits............................................................................................. 28 
6.5 
Post-study Follow-up .................................................................................................... 28 
6.6 
Missed Visits ................................................................................................................ 29 
6.7 
Subject Completion ...................................................................................................... 29 
6.8 
Early Study Termination ............................................................................................... 29 
7 
STUDY PROCEDURES ..................................................................................................... 30 
7.1 
Medical/Medication History .......................................................................................... 30 
7.2 
Condensed Physical Examination ................................................................................ 30 
7.3 
Urine Pregnancy Test................................................................................................... 30 
7.4 
Otomycosis Signs and Symptoms ................................................................................ 30 
7.4.1 
Pruritus ................................................................................................................... 30 
7.4.2 
Debris ..................................................................................................................... 31 
7.4.3 
Presence of Fungal Elements ................................................................................ 32 
7.4.4 
Aural Fullness ......................................................................................................... 32 
7.5 
Adverse Event Evaluations .......................................................................................... 33 
7.6 
Randomization ............................................................................................................. 33 
7.7 
Study Drug Administration............................................................................................ 33 
7.8 
Photography of the Ear ................................................................................................ 33 
7.9 
Treatment Compliance ................................................................................................. 34 
7.10 
Protocol Deviations ...................................................................................................... 34 
8 
ADVERSE EVENTS .......................................................................................................... 35 
8.1 
Definition of an Adverse Event ..................................................................................... 35 

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December 16, 2022 
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8.1.1 
Definition of a Serious Adverse Event .................................................................... 35 
8.2 
Severity of Adverse Events .......................................................................................... 36 
8.3 
Relationship of Adverse Events to Study Drug ............................................................ 36 
8.4 
Documentation of Adverse Events ............................................................................... 37 
8.4.1 
Additional Reporting Requirements for Serious Adverse Events ........................... 37 
8.5 
Pregnancy .................................................................................................................... 38 
8.6 
Study Contacts ............................................................................................................. 38 
9 
STUDY TREATMENTS ..................................................................................................... 39 
9.1 
Description of Study Drug ............................................................................................ 39 
9.1.1 
Administration ......................................................................................................... 39 
9.2 
Randomization ............................................................................................................. 39 
9.3 
Blinding/Unblinding ...................................................................................................... 39 
9.4 
Study Drug Handling and Dispensing .......................................................................... 40 
9.4.1 
Packaging and Labeling ......................................................................................... 40 
9.4.2 
Storage ................................................................................................................... 40 
9.5 
Accountability ............................................................................................................... 41 
9.6 
Return and Destruction ................................................................................................ 41 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 42 
10.1 
Study Endpoints ........................................................................................................... 42 
10.1.1 
Primary Efficacy Endpoint ...................................................................................... 42 
10.1.2 
Secondary Efficacy Endpoints ................................................................................ 42 
10.1.3 
Safety Endpoint ...................................................................................................... 42 
10.2 
Hypotheses .................................................................................................................. 42 
10.3 
Sample Size ................................................................................................................. 43 
10.4 
Study Populations ........................................................................................................ 43 
10.4.1 
Intent-to-treat Population ........................................................................................ 43 
10.4.2 
Per Protocol Population .......................................................................................... 43 
10.4.3 
Safety Population ................................................................................................... 44 
10.5 
Statistical Methods ....................................................................................................... 44 
10.5.1 
Efficacy Analyses ................................................................................................... 44 
10.5.2 
Safety Analyses ...................................................................................................... 45 
10.5.3 
Subject Demographics and Baseline Characteristics ............................................. 45 
10.5.4 
Missing Data ........................................................................................................... 45 
11 
ADMINISTRATIVE CONSIDERATIONS ........................................................................... 46 
11.1 
Institutional Review Board ............................................................................................ 46 
11.2 
Ethics ........................................................................................................................... 46 
11.3 
Informed Consent and Assent ...................................................................................... 46 
11.4 
Confidentiality of Subject Information ........................................................................... 47 
11.5 
Study Monitoring .......................................................................................................... 47 
11.6 
Case Report Form Requirements ................................................................................ 48 
11.7 
Quality Assurance Audits ............................................................................................. 49 
11.8 
Records Retention........................................................................................................ 49 
11.9 
Publication of Results ................................................................................................... 49 
12 
REFERENCES ................................................................................................................... 50 

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Protocol MZ-1015-ESP3-054 
 
 
December 16, 2022 
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LIST OF TABLES 
Table 1 
Treatment-emergent Adverse Event Preferred Terms Reported in >1 Patient in 
the Safety Population of Hill Dermaceuticals, Inc. Study HD-MCZ-PHII-
DRF062016 ............................................................................................................ 13 
Table 2 
Treatment-emergent Adverse Event Leading to Permanent Withdrawal of Study 
Drug and/or Early Discontinuation from the Study in the Safety Population of Hill 
Dermaceuticals, Inc. Study HD-MCZ-PHII-DRF062016 ......................................... 14 
Table 3 
Phase 3 Study - Summary of Treatment-Emergent Adverse Events 
Characteristics (Randomization Safety Population and Open-label Safety 
Population) ............................................................................................................. 16 
Table 4 
Phase 3 Study - Summary of Treatment-Emergent Adverse Events Leading to 
Permanent Withdrawal of Study Drug and/or Early Discontinuation From Study 
(Randomization Period Safety Population and Open-label Safety Population) ...... 17 
Table 5 
Study Schedule ...................................................................................................... 26 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
CMH 
Cochran-Mantel-Haenszel 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
HDPE 
Good Clinical Practice 
High density polyethylene 
ICH 
International Conference on Harmonisation 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent-to-treat 
NSAID 
Non-steroidal anti-inflammatory drug 
OLE 
Open-Label Extension 
OTC 
Over the counter 
PP 
Per protocol 
RP 
Randomization Period 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 
US 
United States 
 

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Protocol MZ-1015-ESP3-054 
 
 
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1 
INTRODUCTION 
1.1 
Background 
Miconazole is an imidazole antifungal agent that has been available by prescription and over the 
counter (OTC), in different formulations, for many years. It is commonly used for different types 
of fungal skin infections, such as Candida, ringworm, jock itch, athlete’s foot, nail fungus, 
vaginal yeast infections, and oropharyngeal candidiasis. Formulations containing up to 4% 
miconazole nitrate have been approved for OTC use as topical antifungal agents in cream, 
ointment, powder, or gel dosage forms. The 2% formulation is commonly used for 
dermatophytic infections. 
While antifungal agents including miconazole are used in practice for the treatment of fungal 
otitis externa (also called otomycosis), there are currently no treatments approved by the United 
States (US) Food and Drug Administration (FDA) for this indication in humans. Miconazole is 
currently FDA-approved as a component of two veterinary combination products (Surolan and 
Easotic) administered otically to dogs for the treatment of canine otitis externa caused by 
susceptible strains of yeast and bacteria. Each veterinary product contains miconazole in 
combination with an antibacterial agent and a corticosteroid. The concentration of miconazole 
present in Surolan (23 mg/mL miconazole nitrate) is similar to the 2% concentration of 
miconazole planned for use in humans in this study. The concentration of miconazole present in 
Easotic is 15.1 mg/mL miconazole nitrate, which equates to approximately 1.5% miconazole. 
While the causative organism of canine otitis externa, Malassezia pachydermatis, is not typically 
associated with human otomycosis in the US, it is expected that human otomycosis, which is 
most commonly associated with organisms from the Candida and Aspergillus genera, would 
respond to concentrations of miconazole similar to those used in dogs. 
The mechanisms of action of miconazole when used topically for the treatment of fungal 
infections involve its actions against the fungal organisms, rather than their human host. 
Miconazole targets the cytochrome P450-dependent enzyme 14-α-sterol demethylase, an enzyme 
that is also involved in mammalian cholesterol synthesis, resulting in inhibition of ergosterol 
biosynthesis in the cell membrane. Because ergosterol is an important component of the cell 
membrane, inhibition of its synthesis inhibits fungal cell growth [Vandenbosch 2012]. In 
addition to its activity toward the enzyme 14-α-sterol demethylase, miconazole also leads to 
increased reactive oxygen species in fungal organisms, which appears to result in fungicidal 
activity [Vandenbosch 2010; Musaji 2010]. 
Clinical studies of 2% miconazole conducted outside of the United States also suggest the 
efficacy of miconazole in the treatment of human otomycosis [Kiakojuri 2007; Vennewald 2010; 
Navaneethan 2015]. In vitro studies of miconazole have also demonstrated activity of 
miconazole against some clinical isolates of fungi associated with human otomycosis in the US 
[Bassiouny 1986; Stern 1988].  
The mechanisms of action of miconazole against fungi in general appear to be applicable to 
fungi associated with otomycosis. Data from the completed Phase 2 study of the investigational 
product (2% miconazole oil; Hill Dermaceuticals, Inc. Study HD-MCZ-PHII-DRF062016) 
demonstrated 25.0% of subjects with Therapeutic Cure, defined as a negative fungal culture plus 

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December 16, 2022 
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the absence of each of the otomycosis signs and symptoms of pruritus, debris, fungal elements, 
and pain, compared with 7.1% of subjects treated with control product (vehicle oil), at the final 
test of cure study visit, following a 14-day treatment regimen. The percentage of subjects with 
therapeutic cure following a 7-day treatment regimen was 8.3%, supporting the 14-day treatment 
duration for miconazole. 
In the recently completed Phase 3 study (Hill Dermaceuticals, Inc. Study HD-MZ-0120-ESP3-
052), 14 of 67 subjects (20.9%) in the Miconazole Oil group achieved the primary endpoint of  
Therapeutic Cure (both negative fungal culture and no signs or symptoms of otomycosis) at Test 
of Cure visit, compared to 11 of 64 subjects (17.2%) in the Vehicle Oil group, (p = 0.589). 
Differences between groups in favor of the Miconazole Oil group were greater for the secondary 
endpoints than for the primary endpoint. For the secondary endpoint of Clinical Cure (score of 0 
for visual presence of fungal elements, pruritus, debris and aural fullness) at the Test of Cure 
visit, an approximately 1.5-fold greater percentage of subjects achieved this endpoint in the 
Miconazole Oil group (22 of 67 subjects, 32.8%) relative to the Vehicle Oil group (14 of 64 
subjects, 21.9%); and for the secondary endpoint of Mycological Cure (negative fungal culture) 
at the Test of Cure visit, an approximately 1.5-fold greater percentage of subjects achieved this 
endpoint in the Miconazole Oil group (4 of 67 subjects, 35.8%) relative to the Vehicle Oil group 
(15 of 64 subjects, 23.4%).  
Adverse event (AE) data from the completed Phase 2 and Phase 3 of the investigational studies 
support the acceptable safety of miconazole oil and generally demonstrated a lower percentage 
of patients with treatment-emergent AEs (TEAEs) in each of the miconazole oil groups.  
The most frequently reported TEAEs in the 14-day miconazole oil group in the Phase 2 study 
were application site pruritus, application site pain, and ear infection fungal (Table 1). In each 
case except for ear infection fungal, a higher percentage of subjects in the 14-day vehicle oil 
group compared with the 14-day miconazole oil group reported the TEAE. Similar results were 
observed for the 7-day miconazole oil group, although a higher percentage of subjects in the 7-
day miconazole oil group had the TEAE of application site infection compared with the 14-day 
miconazole oil and 14-day vehicle oil groups. 
Table 1 
Treatment-emergent Adverse Event Preferred Terms Reported in >1 Patient 
in the Safety Population of Hill Dermaceuticals, Inc. Study HD-MCZ-PHII-
DRF062016  
System Organ Class 
Preferred Term 
Study Group 
7-Day 
Miconazole Oil 
(N=23) 
n (%) 
14-Day 
Miconazole Oil 
(N=22) 
n (%) 
14-Day 
Vehicle Oil 
(N=20) 
n (%) 
Ear and labyrinth disorders 
0 (0.0) 
0 (0.0) 
4 (20.0) 
Ear pain 
0 (0.0) 
0 (0.0) 
2 (10.0) 
Tympanic membrane perforation 
0 (0.0) 
0 (0.0) 
2 (10.0) 
General disorders and 
administration site conditions 
4 (17.4) 
6 (27.3) 
9 (45.0) 
Application site pain 
1 (4.3) 
2 (9.1) 
5 (25.0) 
Application site pruritus 
3 (13.0) 
4 (18.2) 
6 (30.0) 

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System Organ Class 
Preferred Term 
Study Group 
7-Day 
Miconazole Oil 
(N=23) 
n (%) 
14-Day 
Miconazole Oil 
(N=22) 
n (%) 
14-Day 
Vehicle Oil 
(N=20) 
n (%) 
Infections and infestations 
4 (17.4) 
3 (13.6) 
2 (10.0) 
Application site infection 
2 (8.7) 
0 (0.0) 
0 (0.0) 
Ear infection fungal 
1 (4.3) 
2 (9.1) 
1 (5.0) 
Source: Study HD-MCZ-PHII-DRF062016 Clinical Study Report Table 18 
No serious AEs (SAEs) were reported in the Phase 2 study. AEs leading to discontinuation in the 
Phase 2 study were observed in a higher percentage of subjects in the 14-day vehicle oil group 
compared with either the 14-day miconazole oil or 7-day miconazole oil group, providing further 
evidence of an acceptable safety profile for miconazole oil (Table 2). 
Table 2 
Treatment-emergent Adverse Event Leading to Permanent Withdrawal of 
Study Drug and/or Early Discontinuation from the Study in the Safety 
Population of Hill Dermaceuticals, Inc. Study HD-MCZ-PHII-DRF062016 
Preferred Term 
Study Group 
7-Day 
Miconazole Oil 
(N=23) 
n (%) 
14-Day 
Miconazole Oil 
(N=22) 
n (%) 
14-Day 
Vehicle Oil 
(N=20) 
n (%) 
Application site discharge 
0 (0.0) 
0 (0.0) 
1 (5.0) 
Application site erosion 
0 (0.0) 
1 (4.5) 
0 (0.0) 
Application site infection 
1 (4.3) 
0 (0.0) 
0 (0.0) 
Application site pain 
0 (0.0) 
1 (4.5) 
3 (15.0) 
Application site pruritus 
1 (4.3) 
1 (4.5) 
1 (5.0) 
Dysgeusia 
0 (0.0) 
1 (4.5) 
0 (0.0) 
Ear pain 
0 (0.0) 
0 (0.0) 
1 (5.0) 
Nausea 
0 (0.0) 
0 (0.0) 
1 (5.0) 
Tympanic membrane perforation 
0 (0.0) 
0 (0.0) 
2 (10.0) 
Source: Study HD-MCZ-PHII-DRF062016 Clinical Study Report Table 19 
 
In the Phase 3 study, the percentages of subjects who experienced 1 or more TEAEs in the 
Miconazole Oil group was lower (41 subjects [46.6%]) compared with the Vehicle Oil group (49 
subjects [55.1%]) during the Randomization Period (RP; Table 3). During Open Label Extension 
(OLE) treatment (which consisted of an optional 2 weeks of treatment with miconazole oil in 
patients who had completed the RP), a total of 1 (3.6%) and 7 (16.7%) subjects who had received 
prior miconazole oil or who had received prior treatment with vehicle oil, respectively, 
experienced at least 1 TEAE. In Enrollment B, during which generally healthy subjects who 
were not required to have otomycosis were treated with open-label miconazole oil for 2 weeks, 
13 (6.4%) subjects reported at least 1 TEAE (Table 3). Severe TEAEs were experienced by 3 
subjects (3.4%) in the Miconazole Oil group during the Randomization Period and 1 subject 
(0.5%) in Enrollment B. The number of subjects who experienced 1 or more TEAEs suspected 
by the investigator to be study drug related were 2 (2.3%), 1 (1.1%), and 8 (3.9%) subjects in the 
Miconazole Oil, Vehicle Oil, and Enrollment B groups, respectively. 

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No deaths occurred after the initiation of study drug use. One subject in the Miconazole Oil 
group experienced SAEs of acute kidney injury and hypotension but completed the study.  
Overall, 11 subjects discontinued study drug due to TEAEs, including 4 subjects (4.5%) in the 
Miconazole Oil group, 6 subjects (6.7%) in the Vehicle Oil group, and 1 subject (0.5%) in the 
Enrollment B portion of the study. The most common TEAEs leading to early discontinuation 
were the disease under study (fungal ear infection) and application site pain (Table 4).  Two 
additional subjects were discontinued, 1 subject withdrew consent as the primary reason for 
discontinuation and 1 subject completed the Enrollment A treatment and Randomization Period 
but discontinued study drug during the OLE.  

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Table 3 
Phase 3 Study - Summary of Treatment-Emergent Adverse Events 
Characteristics (Randomization Safety Population and Open-label Safety 
Population) 
 
Enrollment A 
 
 
Subjects Randomized to Miconazole Oil 
Subjects Randomized to Vehicle Oil 
 
 
RP 
(N=88) 
OLE 
Miconazole Oil 
(N=28) 
Total 
(N=88) 
RP 
(N=89) 
OLE 
Miconazole Oil 
(N=42) 
Total 
(N=89) 
Enrollment B 
Miconazole Oil 
(N=203) 
 
 
 
 
 
 
 
 
Subjects (%) Reporting At 
Least One Adverse Event 
41 (46.6%) 
1 (3.6%) 
41 (46.6%) 
49 (55.1%) 
7 (16.7%) 
51 (57.3%) 
13 (6.4%) 
Subjects (%) Reporting At 
Least One Serious Adverse 
Event 
1 (1.1%) 
0 (0.0%) 
1 (1.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Subjects (%) Who Died 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Subjects (%) Who 
Discontinued Study Drug Due 
to Adverse Event 
4 (4.5%) 
0 (0.0%) 
4 (4.5%) 
6 (6.7%) 
0 (0.0%) 
6 (6.7%) 
1 (0.5%) 
By Subject 
 
 
 
 
 
 
 
Maximum Severity 
 
 
 
 
 
 
 
Mild 
31 (35.2%) 
0 (0.0%) 
31 (35.2%) 
37 (41.6%) 
4 (9.5%) 
37 (41.6%) 
12 (5.9%) 
Moderate 
7 (8.0%) 
1 (3.6%) 
7 (8.0%) 
12 (13.5%) 
3 (7.1%) 
14 (15.7%) 
0 (0.0%) 
Severe 
3 (3.4%) 
0 (0.0%) 
3 (3.4%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (0.5%) 
Strongest Relationship to 
Study Drug 
 
 
 
 
 
 
 
Not Suspected 
39 (44.3%) 
1 (3.6%) 
39 (44.3%) 
48 (53.9%) 
7 (16.7%) 
50 (56.2%) 
5 (2.5%) 
Suspected 
2 (2.3%) 
0 (0.0%) 
2 (2.3%) 
1 (1.1%) 
0 (0.0%) 
1 (1.1%) 
8 (3.9%) 
OLE = Open-label Extension; RP = Randomization Period. 
Treatment-emergent adverse events are those with an onset on or after the date of first study drug application in the 
Randomization Period of Enrollment A or in Enrollment B or an onset after the date of first study drug application 
in the Open-label Extension for Enrollment A. 
 

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Table 4 
Phase 3 Study - Summary of Treatment-Emergent Adverse Events Leading 
to Permanent Withdrawal of Study Drug and/or Early Discontinuation From 
Study (Randomization Period Safety Population and Open-label Safety 
Population) 
 
Enrollment A 
 
 
Subjects Randomized to Miconazole Oil 
Subjects Randomized to Vehicle Oil 
 
 Organ Classa 
  Preferred Term 
RP 
(N=88) 
OLE 
Miconazole 
Oil 
(N=28) 
Total 
(N=88) 
RP 
(N=89) 
OLE 
Miconazole 
Oil 
(N=42) 
Total 
(N=89) 
Enrollment B 
Miconazole 
Oil 
(N=203) 
Ear and labyrinth  
disorders 
 
0 
 
0 
 
0 
 
1 (1.1%) 
 
0 
 
1 (1.1%) 
 
0 
 Tympanic membrane  
 perforation 
 
0 
 
0 
 
0 
 
1 (1.1%) 
 
0 
 
1 (1.1%) 
 
0 
General disorders and  
administration site  
conditions 
 
 
3 (3.4%) 
 
 
0 
 
 
3 (3.4%) 
 
 
1 (1.1%) 
 
 
0 
 
 
1 (1.1%) 
 
 
0 
 Application site 
    irritation 
1 (1.1%) 
0 
1 (1.1%) 
0 
0 
0 
0 
 Application site pain 
2 (2.3%) 
0 
2 (2.3%) 
1 (1.1%) 
0 
1 (1.1%) 
0 
Infections and infestations 
2 (2.3%) 
0 
2 (2.3%) 
7 (7.9%) 
0 
7 (7.9%) 
0 
 Ear infection fungal 
2 (2.3%) 
0 
2 (2.3%) 
6 (6.7%) 
0 
6 (6.7%) 
0 
 Otitis externa bacterial 
0 
0 
0 
1 (1.1%) 
0 
1 (1.1%) 
0 
Nervous system disorders 
0 
0 
0 
0 
0 
0 
1 (0.5%) 
 Headache 
0 
0 
0 
0 
0 
0 
1 (0.5%) 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; OLE = Optional Open-label Extension; RP = 
Randomization Period 
aCounts reflect numbers of subjects reporting one or more adverse events that map to MedDRA. At each level of summarization 
(System Organ Class or Preferred Term) subjects are counted once. 
Treatment-emergent adverse events are those with an onset on or after the date of first study drug application in the 
Randomization Period of Enrollment A or in Enrollment B or an onset after the date of first study drug application in the 
Open-label Extension for Enrollment A. 
MedDRA dictionary (23.0). 
1.2 
Study Purpose 
The purpose of this study is to gather confirmatory data on the efficacy and safety of 2% 
miconazole oil after topical otic administration in subjects with otomycosis, and to fully establish 
evidence of efficacy for miconazole oil compared to the placebo (mineral oil). A 14-day regimen 
of twice-daily administration of 2% miconazole oil will be compared with the same treatment 
regimen using the placebo, mineral oil.  

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1.3 
Inclusion of Subjects with Peanut Allergy 
Miconazole oil contains refined peanut oil. Inclusion in this study of subjects with peanut allergy 
is justified by studies and publications documenting safe use of the refined peanut oil, as well as 
the FDA approved products containing the refined peanut oil (such as DermOtic, which is the 
same product as the Derma-Smoothe/FS for which two safety studies were performed in subjects 
with known hypersensitivity to peanuts) [Yunginger 2001; Paller 2003]. Reports also exist of 
subjects with known peanut allergy who have continued to safely use products such as Derma-
Smoothe/FS even after an anaphylactic reaction to peanuts [Paller 2003]. The refined peanut oil 
used in the Derma-Smoothe/FS, DermOtic, and miconazole oil products, undergoes refining 
process to remove the peanut proteins which are generally responsible for allergic reactions to 
peanuts. Thus, the inclusion of subjects with peanut allergy in this study is not expected to pose 
an excessive risk to these subjects. 
1.4 
Compliance with Good Clinical Practice 
The investigator and all study staff will conduct the study in compliance with this protocol and 
FDA regulations, all applicable federal, state, and local laws, rules and regulations relating to the 
conduct of a clinical study, the ethical principles of the Declaration of Helsinki, and the current 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines.  
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The objectives of the study are to: 
 Confirm the efficacy of miconazole oil compared with mineral oil over a 14-day treatment 
duration in subjects with otomycosis 
 Further assess the safety of miconazole oil over a 14-day treatment duration in subjects with 
otomycosis 
2.2 
Endpoints 
The primary efficacy endpoint is: 
 Clinical Cure, defined as score of 0 for fungal elements, and 0 for each of the 
signs/symptoms of pruritus, aural fullness and debris, at the Test of Cure visit. 
The secondary efficacy endpoints are: 
 Clinical Cure at the End of Treatment visit with Clinical Cure defined as score = 0 for 
fungal elements, and score = 0 for each signs/symptoms of otomycosis (debris, pruritus 
and aural fullness) 

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 Clinical Clearance at Test of Cure visit with Clinical Clearance defined as score = 0 for 
fungal elements, and score = 0 or 1 for each signs/symptoms of otomycosis (debris, 
pruritus and aural fullness) 
 Clinical Clearance at End of Treatment visit with Clinical Clearance defined as score = 0 
for fungal elements, and score = 0 or 1 for each signs/symptoms of otomycosis (debris, 
pruritus and aural fullness) 
 Modified Clinical Cure at the Test of Cure visit with Modified Clinical Cure defined as 
score = 0 for fungal elements, and score = 0 or 1 for each of debris and aural fullness 
 Modified Clinical Cure at the End of Treatment visit with Modified Clinical Cure defined 
as score = 0 for fungal elements, and score = 0 or 1 for each debris and aural fullness 
The exploratory efficacy endpoint is: 
 Mycological culture results through time 
2.3 
Primary Estimand 
The primary estimand will address the following clinical question of interest:  
 To establish the efficacy of miconazole oil when taken over a 14-day treatment duration 
compared with mineral oil in subjects with uncomplicated otomycosis of the external ear 
only. 
This primary estimand is defined as follows: 
 Target population: all randomized subjects as defined by the study inclusion / exclusion 
criteria who are dispensed study drug (ITT population). 
 Variable of interest (primary efficacy endpoint): the proportion of subjects who achieve 
Clinical Cure, defined as score of 0 for fungal elements, and 0 for each of the 
signs/symptoms of pruritus, aural fullness and debris at the Test of Cure visit 
 Intercurrent events (IcE) 
1. Discontinuation of study treatment due to AE unrelated to study drug 
2. Discontinuation of study treatment due to AE related to study drug 
3. Discontinuation of study treatment due to lack of efficacy  
4. Use of rescue medication prior to the Test of Cure visit 
For each above IcE, a composite strategy will be taken where subjects with any of the above 
IcEs will be considered to have not achieved Clinical Cure.  
 Population-level summary: the difference in proportions in Clinical Cure at the Test of Cure 
visit between the miconazole group and the mineral oil group. 
 
 

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3 
STUDY DESIGN 
This study is a randomized, double-blind, parallel-group study to be conducted at up to 8 study 
centers in the US. An estimated 110 male or female subjects with otomycosis will receive study 
drug. Subjects will be randomly assigned in a 1:1 ratio within study site to receive miconazole 
oil or mineral oil for 14 days [administered as 5 drops per ear at ~30 mg per drop instilled into 
the external ear canal of the ear(s) affected by otomycosis]. Both the subject and the investigator 
and study staff will be blinded as to the contents of the study drug.  
At Screening/Baseline (Day 1), potentially eligible subjects will provide informed consent, and 
subjects will undergo screening evaluations to include a condensed physical examination, an 
assessment of the signs and symptoms of otomycosis (pruritus, debris, visual examination for 
presence of fungal elements, and aural fullness), and an evaluation of medical history. Urine will 
be obtained for pregnancy screening in female subjects of childbearing potential. Prior and 
concomitant medications will be reported. Subjects with positive signs and symptoms of 
otomycosis and who meet all other eligibility criteria will be entered into the study. A fungal 
culture of the affected ear(s) will be taken, then debris will be cleaned from the affected ear(s) 
following the site’s normal procedures. The subject will then begin treatment with study drug. 
The subject or caregiver will instill the first dose of study drug at the site, under the supervision 
of the investigator or site personnel. Adverse events (AEs) will be assessed. The subject will then 
leave the clinic and continue to administer the study drug twice per day as instructed. Subjects 
will be instructed to avoid getting water in the ear, to consider drying excessive water in the ear 
by using a blow dryer, and to place a Vaseline-impregnated cotton ball over the affected ear(s) to 
help keep water out of the ear while bathing or showering. 
Subjects will continue to administer the study drug twice per day, up through Day 14, following 
the same instructions as provided at the Screening/Baseline Visit on Day 1.  Subjects will then 
return to the clinic on Day 15 for the End of Treatment Visit, at which time a clinical evaluation 
of the signs and symptoms of otomycosis will be performed. AEs and concomitant medications 
will also be assessed, and the subject will return all unused study drug.  
Subjects will return to the clinic on Day 22 for the Test of Cure Visit, at which time an 
assessment of clinical signs and symptoms of otomycosis and fungal culture of the affected 
ear(s) will be performed. AEs and concomitant medications will also be assessed. A urine 
pregnancy test will be performed in women of childbearing potential.  Results from the fungal 
culture will not be used to assess primary or secondary efficacy endpoints. All fungal results will 
be summarized.   
Efficacy assessments will include assessments of clinical signs and symptoms of otomycosis. In 
cases of bilateral otomycosis, both ears will be treated and evaluated by the investigator, but only 
one ear will be used as the study ear for efficacy analyses, the designation of which will be 
performed at the end of the study in accordance with the following: (1) If only one ear has 
clinical signs/symptoms at Screening/Baseline, that ear will be used as the study ear for efficacy 
analyses;  (2) If both ears have clinical signs/symptoms at Screening/Baseline, the ear with the 
worse infection at Screening/Baseline as assessed by the investigator, will be used as the study 
ear for efficacy analyses; (3) If both ears are determined by the investigator to have the same 

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degree of infection at Screening/Baseline, the left ear will be used as the study ear for the 
purposes of efficacy analyses. 
Safety assessments will include AEs. 
For subjects who did not improve or had received the placebo, optional rescue treatment may be 
provided at the end of the study. 
3.1 
Number of Subjects 
An estimated 110 eligible patients are planned to be enrolled and included in the ITT population, 
defined as those who were randomized, dispensed study drug, and with a clinical diagnosis of 
otomycosis. 
3.2 
Investigators 
The study will be conducted at up to 8 study centers located in the US. 
The study will be conducted by investigators who are determined by the sponsor to be suitably 
qualified by training and experience to conduct this study in compliance with all applicable GCP 
and FDA federal regulations or local regulations. Sub-investigators will be identified on the 
Form FDA 1572. 
3.3 
Study Duration 
The total duration of the study for a subject from screening until the last visit will be up to 25 
days (including the visit window of up to 3 additional days after the protocol-specified day to 
complete the final Test of Cure visit). 

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4 
STUDY SUBJECTS 
4.1 
Inclusion Criteria 
In order to be eligible for the study, subjects must meet all of the following criteria: 
1. Male or non-pregnant, non-lactating females 
2. Diagnosis of uncomplicated otomycosis of the external ear only, in the ear(s) that will be 
treated with study drug, with a score for fungal elements of 1 in each ear to be treated with 
study drug (see Section 7.4 for definitions of the scores for each of the otomycosis signs and 
symptoms). Subjects must also have the following signs and symptoms of otomycosis in the 
study ear: pruritus ≥2; debris ≥2; and aural fullness ≥2. 
3. General good health as determined by medical examination and medical history, and who are 
free of clinically significant disease, including diabetes mellitus that is not well-controlled or 
that could interfere with the study 
4. Females of childbearing potential must have had a negative urine pregnancy test at 
Screening/Baseline and must agree to use an effective method of contraception (as defined in 
Section 8.5) from Screening/Baseline up through the End of Treatment visit  (see Section 6). 
Females of childbearing potential include any female who has experienced menarche and 
who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation 
or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive 
months). Females who are using oral, implanted, or injectable contraceptive hormones, an 
intrauterine device (IUD), barrier methods (diaphragm, condoms, spermicide) to prevent 
pregnancy, practicing abstinence or where partner is sterile (e.g., vasectomy), should be 
considered to be of childbearing potential 
5. Subjects and/or their caregivers (as appropriate for the age of the subject) must have full 
legal capacity to volunteer 
6. Subjects and/or their caregivers must have completed an appropriately administered 
institutional review board (IRB)-approved informed consent and assent (as applicable) prior 
to any study related procedures 
7. Subjects and their caregivers (as applicable) must agree to comply with all requirements of 
the protocol 
8. For subjects with only one ear meeting all study eligibility criteria, the subject will be eligible 
for the study, and the ear meeting all eligibility criteria will be treated with study drug and 
considered to be the study ear for the purposes of study evaluations. In case of bilateral 
otomycosis in which at least one ear meet all study eligibility criteria, the subject will be 
eligible for the study, both ears may be treated with study drug provided that both ears have a 
score of 1 for fungal elements, and the worse ear will be considered to be the study ear for 
the purposes of study evaluations. If both ears meet study eligibility criteria and are 
determined by the investigator to have the same degree of infection at Screening/Baseline, 
the left ear will be considered to be the study ear for the purposes of study evaluations. 

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4.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will not be eligible for the study: 
1. Any other dermatoses or conditions of the ear that may interfere with the evaluation of 
otomycosis, including concomitant otic infections (including bacterial infection) that require 
antimicrobial treatment, disease that has spread beyond the external ear(s), or pre-existing 
skin atrophy of the affected ear(s) that will be treated with study drug 
2. Tympanostomy tube or perforated tympanic membrane in the ear(s) that will be treated with 
study drug 
3. History of prior surgery directly affecting and compromising the external auditory canal 
and/or tympanic membrane of the ear(s) that will be treated with study drug, except for prior 
tympanostomy tube(s) that have already been removed and completely healed 
4. Use of any topical medicated treatments for otomycosis within 14 days of study entry for the 
ear(s) that will be treated with study drug 
5. Use of any systemic antifungal therapy within 28 days of study entry, warfarin within 28 
days of study entry, immunosuppressive or immune-stimulating drugs within 28 days of 
study entry, or systemic steroids within 3 months of study entry 
6. Fever of ≥100°F at study entry 
7. Recurrent otomycosis that has been unresponsive to previous antifungal treatment within the 
last 12 months 
8. Known hypersensitivity to any of the components in the test formulation 
9. Participation in another investigative trial within 28 days of study entry. 
4.3 
Subject Completion 
The subject has completed the study when the Test of Cure Visit is completed. Subjects who 
require further follow-up for an AE will be followed according to Section 8.4. 
4.4 
Subject Discontinuation 
A subject MAY be withdrawn from the study (at the discretion of the investigator, sponsor, 
and/or IRB) prior to study completion for any of the following reasons, including, but not limited 
to: 
 A serious adverse event (SAE) occurring during the course of the study which precludes 
continued follow-up 
 Intercurrent illness which may, in the investigator’s opinion, significantly affect study 
assessments 
 Failure to follow required study procedures 
A subject MUST be discontinued prior to the final study visit for any of the following reasons: 
 Whenever the subject decides it is in his/her best interest to withdraw 

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 Whenever the investigator decides it is in the subject’s best interest to be withdrawn 
Prior to discontinuing a subject, every effort should be made to contact the subject, schedule a 
final study visit, and obtain as much follow-up data as possible. If possible, the assessment 
schedule for the Test of Cure Visit should be performed, and an effort should be made to collect 
all study drug. 
Subject discontinuations will be documented clearly on the applicable electronic case report form 
(eCRF).  
4.5 
Subjects Lost to Follow-up 
An effort must be made to contact subjects who do not return for scheduled visits, to schedule 
the visit and/or obtain as much follow-up data as possible. At least three telephone calls and one 
certified letter must be placed to the subject after the first missed visit, to attempt to get the 
subject to complete the visit and to gather as much follow-up data as possible, before a subject 
may be considered lost to follow-up and discontinued from the study. Subjects who miss a visit 
may still be scheduled for a subsequent visit. 
All follow-up attempts will be documented and kept with the subject’s source documentation, 
and the applicable eCRFs will be completed. The date a subject will be considered lost to follow-
up will be the date of the last non-missing visit. 

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5 
CONCOMITANT THERAPIES 
All concomitant therapies must be recorded on the eCRF. All therapies within 3 months prior to 
Day 1 must also be recorded on the eCRF. 
Every effort should be made to keep concomitant therapy and dosing constant during the study. 
Any changes in concomitant therapies during the study must be recorded on the eCRF at each 
visit. The reason for any change in concomitant therapies should be reported as, or in 
conjunction with, an AE except as noted below:  
 Prophylactic therapies, such as vaccines or prophylactic analgesics, must be recorded on the 
eCRF but should not be reported as AEs.  
 Changes in therapy for pre-existing conditions that are not related to a worsening of the 
condition must be reported on the eCRF but should not be reported as AEs. The condition 
must be reported on the eCRF as part of the subject’s medical history.  
5.1 
Permitted Medications 
Therapies (medication and non-medication therapies) not restricted by the protocol may be used 
during the study for the treatment or prevention of disease or to maintain good health. Vitamins 
and mineral supplements are permitted at dosages considered by the investigator as reasonable 
for maintaining good health. Non-prohibited chronic therapies being used at Screening/Baseline 
may be continued. 
Oral analgesic medications such as non-steroidal anti-inflammatory drugs (NSAIDs) or 
acetaminophen are permitted. Such medications may be helpful for the management of pain 
caused by otomycosis and/or study procedures such as ear cleaning and administration of study 
drug. 
5.2 
Prohibited Medications 
Other than the study drug, no other topical medications are allowed to be used in any ear that is 
being treated with study drug. Other prohibited treatments during the study include systemic 
antifungal therapy, warfarin, immunosuppressive or immune-stimulating drugs, antibiotics, and 
systemic steroids. 

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6 
STUDY SCHEDULE 
6.1 
Study Flow Chart 
The study schedule is presented in Table 5. 
Table 5 
Study Schedule 
Evaluations and Procedures: 
Screening/ 
Baseline 
Day 1 
End of 
Treatment a 
Day 15 
Test of Cure 
Day 22 b, c  
Informed consent/assent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Medical/medication history 
X 
 
 
Condensed physical examination 
X 
 
 
Otomycosis signs and symptoms 
X 
X 
X 
Fungal Culture 
X 
 
X 
Photographs of eard 
Xe 
X 
X 
Urine pregnancy test f 
X 
 
X 
Randomization 
X 
 
 
Dispensation of study drug 
X 
 
 
Ear cleaning prior to administration of study drug 
X 
 
 
Administration of study drug at site 
X 
 
 
Weighing of study drug 
X 
X 
 
Collection of study drug 
 
X 
 
AE evaluations 
X 
X 
X 
Concomitant medications review 
X 
X 
X 
a. This visit may occur up to 3 days later than the specified day. 
b. This visit may occur up to 1 day sooner or up to 3 days later than the specified day.  
c. In case of early termination, the assessments planned for the Test of Cure Visit should be performed if possible. 
d. Only applicable to designated site(s).  
e.    Prior to ear cleaning at this visit.   
f. Females of childbearing potential only. 
 

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6.2 
Study Visits 
Prior to the signing of informed consent and assent (as applicable), the investigator or designee 
will explain the purpose of the study, procedures, and subject responsibilities to the potential 
study subject and/or caregiver (as applicable). The subject’s (and caregiver’s, as appropriate) 
willingness and ability to meet the follow-up requirements of the study will be determined. 
The schedule of visits is presented in Table 5. Details about study procedures and how they are 
to be performed are presented in Section 7. 
6.2.1 
Screening / Baseline (Day 1) 
Screening procedures will occur prior to randomization and will include: 
 Informed consent and assent (as applicable) 
 Medical history 
 Prior and concomitant medications 
 Condensed physical examination 
 Urine pregnancy test (in female subjects of childbearing potential only) 
 Otomycosis signs and symptoms 
 Determination of subject eligibility for the study 
Subjects who are eligible for the study will undergo the following additional procedures, in the 
order listed: 
 Photography of the affected ear(s) prior to ear cleaning and culture.  Photography will be 
limited to designated site(s). 
 Fungal culture of the affected ear(s) prior to ear cleaning 
 Ear cleaning prior to study drug administration 
 Randomization 
 Weighing of study drug, followed by dispensation of study drug to subject 
 Administration of the first dose by the subject or caregiver under the supervision of the 
investigator or other study personnel 
 Collection of AE information, with the time of AEs to be reported as occurring either 
before or after the first dose of study drug 
 Subjects will be instructed to continue administering study drug twice daily and to bring 
their bottle of study drug to the site for their next visit 
6.2.2 
End of Treatment  (Day 15) 
This visit may occur up to 3 days later than the specified day, in the order listed.  

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The following procedures and evaluations will occur during this visit: 
 Photography of the affected ear(s).  Photography will be limited to designated site(s). 
 Otomycosis signs and symptoms 
 AE evaluation 
 Review of concomitant medications 
 Collection/weighing of study drug  
6.3 
Test of Cure (Day 22) 
This visit may occur up to 1 day sooner or up to 3 days later than the specified day. 
The following procedures and evaluations will occur during this visit, in the order listed: 
 Photography of the affected ear(s) prior to fungal culture.  Photography will be limited to 
designated site(s). 
 Otomycosis signs and symptoms 
 Fungal culture of the affected ear(s) 
 AE evaluation 
 Review of concomitant medications 
 Urine pregnancy test (in female subjects of childbearing potential only) 
In case of early termination, the procedures planned for the Test of Cure Visit should be 
performed if possible. 
6.4 
Unscheduled Study Visits 
Additional visits may be scheduled, as necessary, to ensure the safety and well-being of subjects. 
All additional examinations should be fully documented in the source files and eCRFs, as 
appropriate. Visits that fall outside the designated scheduled visit window but that are intended 
to fulfill scheduled visit requirements will be collected and transcribed to the appropriate 
scheduled visit eCRF. 
If a subject is seen for multiple visits during a given visit time frame, the data from the visit(s) 
that are intended to meet the protocol requirements for the scheduled visit should be captured on 
the visit eCRF. Any other data from any additional visits within a scheduled visit interval will be 
captured elsewhere on the eCRF. 
6.5 
Post-study Follow-up 
If a subject requires further follow-up of AEs upon discontinuation or completion of the study, 
the investigator should schedule post-study follow-up visits, as necessary.  

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6.6 
Missed Visits 
If a subject misses any scheduled follow-up visit and cannot be seen prior to the start of the visit 
range for the next scheduled follow-up visit, the visit is considered missed. 
6.7 
Subject Completion 
The subject has completed the study when the Test of Cure Visit is completed. Subjects who 
require further follow-up for an AE will be followed according to Section 6.5. 
6.8 
Early Study Termination 
The sponsor reserves the right to terminate this study prematurely. If during the study it becomes 
evident to the sponsor that the study should be stopped prematurely, the study will be terminated 
and appropriate notification will be given to the investigator, IRB, and FDA, as applicable. The 
sponsor or designee will instruct the investigator to stop randomizing subjects, to bring all 
subjects who remain in the study (for example, subjects who are currently receiving treatment or 
who have completed treatment but have not yet completed the Test of Cure Visit) in for a Test of 
Cure Visit as soon as possible, and to arrange for study closeout at the site. 

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7 
STUDY PROCEDURES 
The required study procedures are detailed in this section. The timeline for these procedures is 
presented in Section 6. 
7.1 
Medical/Medication History 
At Screening/Baseline, the investigator or designee will interview each subject and obtain a 
complete medical and medication history, including a history of all surgeries and past medical 
procedures. The subject must not require any treatment or medication for concurrent illnesses as 
specified by the inclusion and exclusion criteria or anticipate the need for any excluded 
concomitant medications. 
7.2 
Condensed Physical Examination 
At Screening/Baseline, the investigator or designee will perform a physical examination to 
include the following: general appearance; head, eyes, ears, nose, throat; neck; cardiovascular; 
lungs; abdomen; lymph nodes; extremities; neurological; skin; musculoskeletal; and body 
temperature. 
7.3 
Urine Pregnancy Test 
The urine pregnancy test (performed in females of childbearing potential only) must have a 
minimum sensitivity of 25 mIU of β-hCG/mL of urine. 
7.4 
Otomycosis Signs and Symptoms 
The signs and symptoms of otomycosis will be assessed according to the scales for pruritus (see 
Section 7.4.1), debris (see Section 7.4.2), presence of fungal elements (see Section 7.4.3), and 
aural fullness (see Section 7.4.4). The same evaluator should assess each subject for signs and 
symptoms of otomycosis at each visit throughout the subject’s participation in the study, if 
possible. 
7.4.1 
Pruritus 
Subjects or their caregivers (as appropriate, based on the age of the subject) will be asked by the 
investigator (or designee) about the severity of itching present in each ear being treated with 
study drug. Questions such as the following will be used in order to gather information for this 
assessment, with careful consideration given to distinguish between a nonspecific occasional itch 
and itching from the infection: 
“Over the last 24 hours, have you had itching in your ear?” 
“Over the last 24 hours, did itching interfere with your daily activities?” 
“Over the last 24 hours, has your itching been bad enough to keep you awake?” 
“Over the last 24 hours, would you describe your itching as intolerable or constant?” 

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The investigator will then score the symptom of pruritus for each ear being treated with study 
drug, taking into consideration the subject’s and/or caregiver’s answers and the investigator’s 
observations of the subject. Scores will be according to the following scale: 
Score 
Category 
Description 
0 
None 
No itching; occasional nonspecific itch 
1 
Mild 
Occasional itching, not interfering with daily activities 
2 
Moderate 
Fairly persistent itching, partially tolerated; sleep is not interrupted 
3 
Severe 
Intolerable, constant itching; sleep is interrupted 
7.4.2 
Debris 
Upon otoscopic examination, the investigator will score the amount of debris present in each ear 
being treated with study drug.  Debris would consist of earwax, fungal elements or 
microorganisms, skin cells, and sometimes exudates.  Scores will be according to the following 
scale: 
Score 
Category 
Description 
0 
None/Normal No debris, normal earwax present 
1 
Scant 
Debris minimally present, but with no notable occlusion of external 
ear canal 
2 
Moderate 
Debris present with partial occlusion of external ear canal; 
tympanic membrane can be visualized 
3 
Heavy 
Complete occlusion of ear canal; tympanic membrane cannot be 
visualized 

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7.4.3 
Presence of Fungal Elements 
Upon otoscopic examination, the investigator will assess the presence of fungal elements in each 
ear being treated with study drug.  Visual inspection of the ear canal with otoscope may show 
presence of white filaments in debris; black, gray, bluish, yellow, or white discharge; white 
debris with hyphae; or moist white plugs with black debris; or other observations that in the 
investigator’s judgment are indicative of macroscopic fungal presence.  
Scores will be according to the following scale: 
Score 
Category 
Description 
0 
Absent 
No fungal elements present on visual inspection with otoscope 
1 
Present 
Fungal elements present on visual inspection with otoscope, such as 
visualization of white filaments in debris; black, gray, bluish, 
yellow, or white discharge; white debris with hyphae; or moist 
white plugs with black debris; or other observations that in the 
investigator’s judgment are indicative of the presence of fungus 
 
7.4.4 
Aural Fullness 
Subjects or their caregivers (as appropriate, based on the age of the subject) will be asked by the 
investigator (or designee) whether aural fullness is present in each ear being treated with study 
drug.  Aural fullness can be defined as a sensation of blockage in the ear, or sound is muffled.  
Questions such as the following will be used in order to gather information for this assessment: 
“Over the last 24 hours, have you had a feeling of fullness in your ear?” 
“Over the last 24 hours, has a feeling of fullness in your ear interfered with your daily 
activities?” 
“Over the last 24 hours, has a feeling of fullness in your ear been bad enough to keep you 
awake?” 
“Over the last 24 hours, would you describe a feeling of fullness in your ear as intolerable?” 
The investigator will then score the symptom of aural fullness for each ear being treated with 
study drug, taking into consideration the subject’s and/or caregiver’s answers and the 
investigator’s observations of the subject. Scores will be according to the following scale: 

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Score 
Category 
Description 
0 
None 
Not present 
1 
Mild 
Present but not affecting daily activities 
2 
Moderate 
Present and affecting daily activities but tolerable 
3 
Severe 
Intolerable and severely disrupting daily activities; sleep is 
interrupted 
 
7.5 
Fungal Culture 
At designated visits, the investigator or designee will obtain a sample from the external ear to be 
sent to a central laboratory for fungal culture.  Techniques for obtaining and handling the sample 
and sending it to the laboratory will be described in a separate laboratory manual.  If both ears 
will be treated with the study drug, both ears will be cultured. 
The central laboratory will grow and identify fungal organisms from the sample provided by the 
investigator.  Susceptibility testing will not be performed. 
The results of fungal cultures will not be blinded as they do not affect the primary efficacy 
endpoint analysis.  
7.6 
Ear Cleaning 
There will be only one ear cleaning which will occur at Screening/Baseline after the fungal 
culture has been taken and prior to the first application of the study drug.  No other ear cleaning 
will be done during the study. 
7.7 
Adverse Event Evaluations 
See Section 8. 
7.8 
Randomization 
See Section 9.2. 
7.9 
Study Drug Administration 
See Section 9.1.1. 
7.10 Photography of the Ear 
Designated site(s) will be provided with, and trained on, photography equipment appropriate for 
use in capturing images of the ear canal.  Alternatively, site may use existing equipment that is 
approved by the sponsor.  Investigators may take as many images of each affected ear as they 

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deem appropriate to reflect the condition of the ear. Missing photography of an ear or a visit, will 
not constitute a protocol deviation.  
7.11 Treatment Compliance 
Subjects or their caregivers (as appropriate) will be given the study drug. Additionally, each 
bottle of study drug will be weighed by the investigator or designee before dispensing to the 
subject and at the last visit in which the used bottle is brought to the site. 
7.12 Protocol Deviations 
The IRB-approved protocol must be followed except in the case of a change that is intended to 
eliminate an immediate risk to subjects. 
The date of, nature of, and reason for deviations, will be documented and explained by the 
investigator in all cases. Significant or major protocol deviations impacting the safety of the 
subject or the integrity of the study must be reported by the investigator to the sponsor and/or its 
designee and to the IRB immediately. Reporting of all other protocol deviations must adhere to 
the requirements of the governing IRB. 
All changes to the protocol will be made by the sponsor or designee as an approved amendment 
to the protocol, submitted to the FDA, and approved by the IRB prior to implementation. New or 
altered consent forms required by the IRB due to a protocol revision must be signed by all 
subjects currently enrolled in the study and must be used for any subsequent subject enrollment. 

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8 
ADVERSE EVENTS 
8.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a study drug and which does not necessarily have a causal relationship with the 
study drug. An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational or marketed study drug, whether or not 
considered related to the investigational or marketed study drug. AEs include any illness, sign, or 
symptom that has appeared or worsened during the course of the clinical trial, regardless of 
causal relationship to the study drug. Study drug includes the investigational drug under 
evaluation and the comparator placebo. 
Medical conditions/diseases present before signing the informed consent form are only 
considered AEs if they worsen after the informed consent form is signed.  
AEs may be either spontaneously reported or elicited during questioning and examination of a 
subject. At each examination or visit, study personnel will ask each subject the following 
question, “Have you had any problems since we last spoke?” If known, the investigator should 
report the diagnosis of the underlying illness or disorder, rather than its individual symptoms. 
The worsening or reoccurrence as compared to any previous visit in a subject of any symptom of 
otomycosis (including any increase in numerical score for pruritus and/or aural fullness 
according to the scales presented in Section 7.4, and/or any other symptom of otomycosis that 
worsens but is not captured in the scales presented in Section 7.4) should be reported as an AE. 
The diagnosis of the underlying disease or disorder should be reported as the AE, if known. For 
example, if the worsening symptom is believed to be due to otomycosis, the AE should be 
reported as “worsening of disease under study.” If the worsening symptom is believed to be due 
to some other cause (such as bacterial infection), that underlying illness or disorder should be 
reported as the AE. 
Debris and fungal elements are considered signs (manifestations) of otomycosis and minor 
changes are expected as a natural progression of the disease; therefore, minor changes in debris 
and fungal elements scores may not necessarily be captured as AEs if the changes are not 
clinically significant in the judgment of the investigator. If, however, in the investigator’s 
judgment there is a clinically significant worsening of debris and/or fungal elements, an AE of 
“worsening of disease under study” should be recorded. 
8.1.1 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence occurring at any dose that results in any of the 
following outcomes: 
 Results in death 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 

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 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment may jeopardize the patient/subject or may require medical or 
surgical intervention to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include but are not limited to: allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasia or 
convulsions that do not result in inpatient hospitalization; the development of drug 
dependency or drug abuse.  
Treatment on an outpatient emergency basis that does not result in hospital admission, or a 
hospitalization that is elective or is a preplanned treatment for a pre-existing condition that has 
not worsened since the start of the study, is not considered an SAE. 
8.2 
Severity of Adverse Events 
The severity of an AE will be determined by the investigator according to the following 
definitions: 
 Mild: Awareness of event, but easily tolerated and does not disrupt usual activity 
 Moderate: Discomfort sufficient to cause interference with usual activity 
 Severe: Incapacitating, with inability to perform usual activities 
8.3 
Relationship of Adverse Events to Study Drug 
The relationship of AEs to the study drug will be assessed by the investigator according to the 
following definitions: 
 Not suspected: The temporal relationship of the event to the study drug makes a causal 
relationship unlikely, or, other drugs, therapeutic interventions or underlying conditions 
provide a sufficient explanation for the observed event. 
 Suspected: The temporal relationship of the event to the study drug makes a causal 
relationship possible or other drugs, therapeutic interventions or underlying conditions do 
not provide a sufficient explanation for the observed event. 
A temporal relationship is the timing between a factor and an outcome which can be used to 
assign causality to a relationship. 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the study drug and the occurrence of the AE, then the AE should be 
considered “suspected.” 

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If the relationship between the AE and the study drug is determined by the sponsor to be 
“suspected,” the event will be considered to be related to the study drug for the purposes of 
expedited regulatory reporting. 
8.4 
Documentation of Adverse Events 
All AEs must be completely recorded on the Adverse Events section of the eCRF. The collection 
of AE information should begin after the subject has signed informed consent and continue up 
through the Test of Cure Visit. Subjects experiencing AEs that cause interruption or 
discontinuation of study drug, or those experiencing AEs that are present at the end of their 
participation in the study or that resulted in permanent discontinuation will receive follow-up as 
appropriate until the AEs have either resolved or have stabilized. 
For each AE, the Investigator will evaluate and report the following: 
 Onset (date); 
 Resolution (date); 
 Severity grade (mild, moderate, severe); 
 Relationship to study drug (not suspected, suspected); 
 Action taken (none, study drug temporarily interrupted, study drug permanently 
discontinued, concomitant medication taken, hospitalization/prolonged hospitalization, 
other); 
 Serious (yes/no); 
 Whether the AE occurred at the study drug application site (yes/no); 
 For AEs of the ear, which ear (left, right, or both) was affected. 
8.4.1 
Additional Reporting Requirements for Serious Adverse Events 
All SAEs that occur from the time the subject has signed the informed consent until the Test of 
Cure Visit will be reported. Additionally, any SAEs “suspected” to be related to the study drug 
and discovered by the investigator at any time after the study should be reported. Each of these 
SAEs must be reported to the sponsor’s designee within 24 hours of the occurrence of the SAE, 
or within 24 hours of learning of the SAE. Information on recurrent episodes, complications, or 
progression of the initial SAE must also be reported within 24 hours of the investigator receiving 
the information.  
Reporting may be by telephone, confirmed facsimile transmission, or confirmed email to the 
medical monitor. The investigator must assess the relationship of the SAE to study drug and 
must complete the SAE form. If only limited information is initially available, follow-up reports 
are required. Follow-up information (e.g., discharge summary) will be retained in the subject’s 
chart and a copy (with the subject’s personal information removed and with the subject identified 
only by subject number) will be sent by confirmed facsimile transmission or confirmed email to 
the medical monitor. In the event of death, if an autopsy is performed, a copy of the report (with 
the subject’s personal information removed and with the subject identified only by subject 
number) should be sent to the medical monitor. 

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As required and after the sponsor’s review and determination of causality, the sponsor and/or 
designee will notify investigators of all AEs that are serious, unexpected, and considered by the 
investigator to have a suspected relationship to the study drug. This notification will be in the 
form of an update to the Investigator’s Brochure (i.e., “15-day letter”). An AE, whether serious 
or non-serious, is designated unexpected (unlabeled) if it is not reported in the clinical safety 
section of the Investigator’s Brochure or if the event is of greater frequency, specificity or 
severity.  
Upon receiving such notices, the investigator must review and retain the notice with the 
Investigator’s Brochure and immediately submit a copy of this information to the responsible 
IRB according to local regulations. The investigator and IRB will determine if the informed 
consent requires revision. The investigator should also comply with the IRB procedures for 
reporting any other safety information. Follow-up reports should be submitted when requested or 
when pertinent information becomes available. 
The sponsor will report all SAEs to the US FDA on the appropriate schedule depending on the 
event’s expectedness and relationship to study drug based on the available information as 
presented in the Investigator’s Brochure.  
Any SAE occurring after the Test of Cure Visit and which is not considered to be of “suspected” 
relationship to study drug does not need to be reported. 
8.5 
Pregnancy 
Females of childbearing potential, as defined in Section 4.1, must use an effective method of 
contraception from screening up through the Test of Cure Visit. Acceptable methods include the 
use of at least one of the following: 1) IUD; 2) hormonal contraceptives (oral, injectable, 
implant, or ring); 3) barrier contraceptives (condom or diaphragm) with spermicide; or 4) 
abstinence. 
Should a pregnancy occur, it must be reported and recorded on the pregnancy form and sent by 
confirmed facsimile or confirmed email to the medical monitor, as well as documented in the 
eCRF. Pregnancy in itself is not regarded as an AE unless there is a suspicion that the study drug 
product may have interfered with the effectiveness of a contraceptive medication. 
In the event of pregnancy that is detected during treatment with study drug, the subject must be 
withdrawn from further treatment with study drug. The subject may continue to participate in the 
study on a case-by-case basis after discussion between the investigator and the sponsor and/or 
the sponsor’s designee. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study and/or study drug. 
8.6 
Study Contacts 
Study contacts will be provided in a separate document. 

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9 
STUDY TREATMENTS 
9.1 
Description of Study Drug 
Miconazole oil contains the active ingredient, 2% miconazole, formulated in an oil vehicle 
containing refined peanut oil, light mineral oil, oleth-2, and isopropyl myristate. For subjects 
randomized to the placebo group, the placebo is plain mineral oil. 
Study drug will be supplied in bottles containing ~20 grams (20 mL) of product. The dispensing 
tip will deliver approximately 30 mg of product per drop. 
9.1.1 
Administration  
Subjects will be seated or lying on one side with the head positioned so the ear being treated is 
facing up. If both ears are being treated, the ear that appears to have less severe disease will be 
treated first. The subject or caregiver will gently pull the ear lobe backward and upward and 
apply 5 drops of study drug into the ear. The subject will be instructed to keep the head 
positioned with the ear facing up for approximately 3 to 5 minutes to allow the oil to coat the ear 
canal. After this time, the subject can then straighten his/her head, and excess material dripping 
out of the ear can be gently patted using a clean cotton ball. 
If both ears are being treated, the subject will then wait at least 5 minutes, then repeat this 
procedure for the second ear. 
While on study treatment, subjects will be instructed to avoid getting water in the ear, to consider 
drying excessive water in the ear by using a blow dryer, and to place a Vaseline-impregnated 
cotton ball over the affected ear(s) to help keep water out of the ear(s) while bathing or 
showering. Subjects will be asked to avoid bathing or showering for at least 30 minutes after 
applying study drug. 
9.2 
Randomization 
Subjects will be randomized in a 1:1 ratio to one of two groups: 1) 14-day treatment with 
miconazole oil; or 2) 14-day treatment with mineral oil. 
Randomization will be by site. 
9.3 
Blinding/Unblinding 
The contents of the study drug (miconazole oil versus mineral oil) will be blinded to both the 
investigator (and all study staff) and the subject. Randomized study drug will be packaged in 
identical bottles and will be labeled with a randomization number rather than the contents of the 
bottle. 
If it becomes necessary to unblind a subject’s treatment assignment in case of emergency, the 
investigator should contact the sponsor. A person at the sponsor organization who is not 
otherwise involved with the study will maintain a randomization list that will enable that person 
to inform the investigator of the subject’s treatment allocation. The treatment allocation is to be 

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obtained only if a medical emergency exists and knowledge of the medication being taken will 
influence the medical management of the subject. 
9.4 
Study Drug Handling and Dispensing 
9.4.1 
Packaging and Labeling 
The miconazole oil and the mineral oil will be processed and labeled by Hill Dermaceuticals, 
Inc. It will be packaged in dropper bottles, each of which will contain ~20 grams (20 mL) of 
study drug. The dropper bottle will dispense approximately 30 mg per drop. 
The active drug and mineral oil will be packaged in a 1 ounce HDPE bottle with a dispensing tip 
and provided in identical study drug kits. Each kit will contain the investigational drug product 
(or placebo product), reserve identical drug product (or placebo product), bag of cotton balls, and 
Vaseline jelly. The subject will be dispensed the kit (minus the reserve product) at Baseline only. 
The dropper bottles will be weighed with the cap on prior to dispensing. If the subject loses a 
bottle (lost or damaged), the reserve bottle will be dispensed using a replacement process as 
defined in the randomization plan. Each drug kit dispensed will be documented on the drug 
accountability log. Labels on the drug kit will contain the following information: 
 Protocol number 
 Subject number  
 Space for entry of the subject initials 
 Space for entry of date dispensed 
 A statement reading, “For otic use only. Avoid contact with eyes and lips” 
 A statement reading, “Store at controlled room temperature 20°C to 25°C (68°F to 77°F) 
with excursions permitted between 15°C to 30°C (59°F to 86°F)”  
 A statement indicating the sponsor, Hill Dermaceuticals 
 A statement indicating the quantity of product (20 g/ 20 mL) 
 A statement reading, “Caution: New Drug - Limited by Federal Law to Investigational 
Use” 
 A statement reading, “Keep out of Reach of Children” 
9.4.2 
Storage 
The study drug is to be stored at room temperature (20°C to 25°C, or 68°F to 77°F), with 
excursions permitted between 15°C and 30°C (59°F and 86°F). All investigational study drug 
must be stored in a secure facility, with access limited to the investigator and authorized staff. 

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9.5 
Accountability 
The investigator or designee (e.g., study coordinator or pharmacist) is responsible for ensuring 
storage as per the label on the study drug and adequate accountability of all used and unused 
study drug. Adequate accountability includes acknowledgment of receipt of each shipment of 
study drug (quantity and condition), records of administration (including container number, date 
administered, subject number, and the initials of the person administering the drug), and 
documentation of quantities returned to the sponsor (or designee). 
At time points during the course of the study and/or upon completion of the study, the sponsor or 
designee will review and verify the investigator's accountability records.  
9.6 
Return and Destruction 
At the completion of the study, following verification of the investigator’s accountability records 
by the sponsor and/or designee, all study drug must be returned to the sponsor or designee. This 
would include study drug returned by the subjects at the completion of the study, and reserve 
products that were not used. 

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10 STATISTICAL CONSIDERATIONS 
10.1 Study Endpoints 
10.1.1 
Primary Efficacy Endpoint   
The primary efficacy endpoint will be the percentage of subjects at the Test of Cure Visit with 
Clinical Cure defined as score of 0 for fungal elements, and 0 for each of the signs/symptoms of 
otomycosis (debris, pruritus and aural fullness) based on investigator assessment according to the 
scales for each individual sign or symptom. See Section 7.4 for the scales for each otomycosis 
sign and symptom. 
10.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will consist of the following: 
a) Clinical Cure at the End of Treatment visit with Clinical Cure defined as score = 0 for 
fungal elements, and score = 0 for each signs/symptoms of otomycosis (debris, pruritus 
and aural fullness) 
b) Clinical Clearance at Test of Cure visit with Clinical Clearance defined as score = 0 for 
fungal elements, and score = 0 or 1 for each signs/symptoms of otomycosis (debris, 
pruritus and aural fullness) 
c) Clinical Clearance at End of Treatment visit with Clinical Clearance defined as score = 0 
for fungal elements, and score = 0 or 1 for each signs/symptoms of otomycosis (debris, 
pruritus and aural fullness) 
d) Modified Clinical Cure at the Test of Cure visit with Modified Clinical Cure defined as 
score = 0 for fungal elements, and score = 0 or 1 for each of debris and aural fullness 
e) Modified Clinical Cure at the End of Treatment visit with Modified Clinical Cure defined 
as score = 0 for fungal elements, and score = 0 or 1 for each debris and aural fullness 
10.1.3 
Exploratory Endpoints 
The results of the mycological cultures will be summarized over time. 
10.1.4 
Safety Endpoints 
A safety endpoint will be the percentage of subjects with treatment-emergent AEs (TEAEs), with 
treatment-emergent defined as occurring upon or after administration of the first dose of study 
drug. 
10.2 Hypotheses 
The primary efficacy endpoint of the study is percentage of subjects at the Test of Cure Visit 
with “clinical cure”, defined as score of 0 for fungal elements, and 0 for signs/symptoms of 

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otomycosis based on investigator assessment according to the scales for each individual sign or 
symptom.  
Analysis is based on the following hypothesis:  
H0: pT – pP = 0  
H1: pT - pP ≠ 0.  
where H0 is the null hypothesis, H1 the alternative hypotheses, and pT and pP are percentage of 
subjects with success in the Treatment (miconazole oil) and Placebo (mineral oil) groups, 
respectively. Comparisons between groups for the difference in the percentage of subjects 
achieving the primary endpoint of clinical improvement will be conducted using a Cochran-
Mantel-Haenszel (CMH) exact test stratified by clinical site with a 2-sided significance level of 
0.05. 
10.3 Sample Size 
Approximately 110 subjects (~55 in each group) provide 80% power, using a Fisher’s Exact test 
chi-square test with a 2-sided significance level of 0.05, assuming a response rate for the primary 
efficacy endpoint of 35% in the miconazole oil group and 10% in the mineral oil group. These 
assumptions are consistent with the findings from the first Phase 3 study for the miconazole oil 
group, and with conservative assumptions for the mineral oil group. 
10.4 Study Populations 
10.4.1 
Intent-to-treat Population 
The intent-to-treat (ITT) population will be defined as all subjects who were randomized and 
dispensed study medication.  The ITT population will be the primary population to assess 
efficacy. 
10.4.2 
Per Protocol Population 
The per protocol (PP) population will be a subset of the ITT population and will include all subjects 
who complete the Test of Cure visit without any major protocol violations. The PP population will 
exclude subjects from the ITT population that met any of the following criteria: 
 Violated the inclusion/exclusion criteria 
 Used an interfering concomitant medication 
 Did not attend the Test of Cure visit 
 Did not attend the End of Treatment visit 
 Have not been compliant with the dosing regimen (i.e., subjects must have received 
80%-120% of the expected applications of study medication in the study ear during 
participation in the study) 
 Out of visit window at the Test of Cure Visit (-1/+8 days) 

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Subjects who discontinue from the study due to an adverse event related to study treatment, 
documented lack of treatment effect, or worsening of condition will be included in the PP 
population. Prior to breaking the blind, other additional criteria may be added to the list to 
accommodate for unforeseen events that occurred during the conduct of the trial that result in 
noteworthy study protocol violations. 
All efficacy analyses will be performed using the PP population in a supportive manner. 
10.4.3 
Safety Population 
The safety population will include all randomized subjects who received at least one dose of 
study drug and had at least one post-Baseline safety assessment.  
All safety analyses will be performed using the safety population. 
10.5 Statistical Methods 
All statistical processing will be performed using Statistical Analysis System (SAS®) Version 9.4 
or higher. Except where noted, all statistical tests will be two-sided and will be performed at the 
0.05 level of significance. 
Descriptive statistics will be used to provide an overview of the efficacy and safety results. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. For continuous parameters, descriptive statistics will include n (number of subjects), 
mean, and standard deviation, median, minimum, and maximum. 
Full details of statistical analyses will be provided in a separate statistical analysis plan. 
10.5.1 
Efficacy Analyses 
The primary population for the primary estimand analysis and all efficacy analyses will be the 
ITT population (see Section 10.4). Efficacy analyses will also be performed for the PP 
population and will be considered supportive. 
The number and percent of subjects who demonstrate a positive outcome for the primary efficacy 
outcome will be presented. 
The primary endpoint, defined as the percentage of subjects at the Test of Cure Visit with 
“Clinical Cure”, will be compared between groups using a Cochran-Mantel-Haenszel (CMH) 
exact test stratified by analysis center with a 2-sided significance level of 0.05. 
Secondary endpoints will be analyzed analogously to the primary endpoint. 
The exploratory endpoint will be summarized by visit. 
In cases of bilateral otomycosis, if only 1 ear has clinical signs/symptoms of otomycosis at 
Screening/Baseline, that ear will be used as the study ear for efficacy analyses. If both ears have 
clinical otomycosis at Screening/Baseline, the ear with the worse infection at 

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Screening/Baseline, as assessed by the investigator, will be used as the study ear for efficacy 
analyses. If both ears are determined by the investigator to have the same degree of infection at 
Screening/Baseline, the left ear will be used as the study ear for the purposes of efficacy 
analyses. 
Descriptive statistics will be provided for otomycosis signs and symptoms. 
10.5.2 
Safety Analyses 
Safety summaries will be conducted using the safety population (see Section 10.4.3). All AEs 
occurring during the study will be recorded and classified using terminology from the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported treatment-emergent adverse events 
(TEAEs), defined as any AE with an onset on or after the date of first study drug application, 
will be summarized by treatment group. Summaries will provide the number of subjects 
reporting TEAEs, system organ class, preferred term, severity, and relationship to study drug. 
When summarizing TEAEs by severity or relationship to study drug, each subject will be 
counted only once within a system organ class or a preferred term using the event with the 
greatest severity or causality, respectively, within each category. All reported SAEs will be 
summarized by the number of subjects reporting the event, system organ class, preferred term, 
severity, and relationship to study drug. 
All information pertaining to AEs noted during the study will be listed by treatment group and 
subject and will include a verbatim description of the event as reported by the investigator, as 
well as the preferred term, system organ class, start date, stop date (if stopped), seriousness, 
severity, action taken regarding the study drug, corrective treatment, outcome, and relationship to 
the study drug. In addition, a listing of subjects who prematurely discontinue from the study due 
to AEs will be provided as well as a listing of subjects who report an SAE. 
10.5.3 
Subject Demographics and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized descriptively for the ITT, 
PP, and safety populations and will be supported with individual subject data listings. 
10.5.4 
Missing Data 
If a subject has missing efficacy data at the Test of Cure visit, the subject will be considered as a 
treatment failure for the primary and secondary efficacy analyses. 
Missing data otherwise will not be imputed. 
10.5.5 
Pooling of Sites 
The study is intended to be conducted in a manner such that a minimum of 5 Subjects will be 
enrolled in each treatment arm for any Investigator. In the event that there are too few Subjects in 
a treatment arm for an Investigator, then this Investigator's data will be combined to achieve the 
desired sample size minimum per arm. The combining of Investigator's data will be 
accomplished by taking the Investigator with the smallest enrollment and combining it with the 
Investigator with the largest enrollment. If there is a further need to combine data, then the data 

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of the Investigator with the second smallest enrollment will be combined with the Investigator's 
data which had the second largest enrollment and so on. This process will continue for all 
Investigators who did not have a minimum of 5 Subjects per treatment arm. The process of 
combining Investigator data that have insufficient Subjects per treatment arm will result in 
redefining the groups of Investigators for the purposes of statistical analyses. These combined 
groups will be referred to as "analysis centers" in the statistical analyses. 
 
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Institutional Review Board 
The protocol, informed consent documents including photography consent, any information 
provided to subjects, recruitment advertisements and any amendments to these items will have 
IRB approval prior to their use in the study.  
Before study initiation, this protocol, the miconazole oil Investigator’s Brochure, the informed 
consent form, any other written information given to subjects, and any advertisement for subject 
recruitment must have IRB approval. Documentation of IRB approval must be sent to the 
sponsor or designee before study drug will be shipped to the site. The investigator should also 
provide the miconazole oil Investigator’s Brochure to the IRB. 
The investigator must provide the IRB with reports, updates, and other information (e.g., safety 
updates, protocol amendments, and administrative letters) according to regulatory requirements 
and Institution procedures. The IRB must be notified of completion or termination of the study. 
Copies of all correspondence with the IRB regarding this study must be sent to the sponsor or its 
designee. Additionally, the clinical site must maintain an accurate and complete record of all 
reports, documents, and other submissions made to the IRB concerning this protocol. 
11.2 Ethics 
The investigator and all study staff will conduct the study in compliance with this protocol and 
compliance with FDA regulations, all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical study, the ethical principles of the Declaration 
of Helsinki, and the current ICH GCP guidelines. 
The rights, safety, and wellbeing of the study subjects are the most important considerations and 
prevail over the interests of science and society. 
All personnel involved in the conduct of this study must be qualified by education, training 
and/or experience to perform their assigned responsibilities. 
11.3 Informed Consent and Assent 
Voluntary informed consent and assent (as applicable) will be given by every subject and/or the 
subject’s legal representative (as applicable) prior to the initiation of any study related 

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procedures. The IRB-approved consent and assent forms must include all elements required by 
FDA, state, and local regulations, and may include appropriate additional elements. Sample 
informed consent and assent forms containing the required elements of informed consent or 
assent (as applicable) will be provided by the sponsor or designee. Any changes made to this 
sample must be approved by the sponsor or its designee prior to submission to the IRB. After 
approval by the sponsor or its designee, the informed consent and assent forms must be 
submitted to and approved by the IRB. 
The informed consent and assent forms must be written in a language in which the subject is 
fluent. Regulations require that foreign language informed consent and assent forms be 
submitted to the IRB for approval. The foreign language translation is required to contain a 
statement of certification of the translation. The investigator must forward a copy of the consent 
form, the certified foreign language translation, and an IRB approval letter to the sponsor. 
The investigator/designee will explain the study to each potential subject and/or the subject’s 
legal representative (as applicable) prior to the screening evaluation, and the subject and/or the 
subject’s legal representative (as applicable) must indicate voluntary consent by signing and 
dating the approved informed consent form. The consent process will be conducted prior to the 
start of any study-related procedure. The investigator must retain the original and provide the 
subject and/or the subject’s legal representative (as applicable) with a copy of the consent 
form(s). 
The investigator will maintain documentation that informed consent and assent (as applicable) 
was obtained prior to the initiation of any study-related procedures. 
11.4 Confidentiality of Subject Information 
Subject data recorded on eCRFs during the study will be documented in a coded fashion, and all 
communications and reports regarding this study will identify subjects only by their subject 
numbers. Complete subject identification will be kept by the investigator for purposes of long-
term follow-up, if needed. This information, as well as all medical information resulting from a 
subject’s participation in this study, will be treated with strict adherence to professional standards 
of confidentiality. Confidentiality of subject records must be maintained to ensure adherence to 
applicable local privacy regulations. 
Data generated for the study should be stored in a limited-access file area and be accessible only 
to the investigator and authorized personnel, the sponsor and its designee(s), the IRB, and FDA 
or other relevant regulatory authorities. Medical information resulting from a subject’s 
participation in this study may be given to the subject’s personal physician or to the appropriate 
medical personnel responsible for the subject’s welfare, but no information that can be related to 
a specific individual subject will be released or used in any fashion without the signed written 
consent of that subject. 
11.5 Study Monitoring 
Representatives of the sponsor and designee(s) must be allowed to visit all study sites, to review 
study records and to directly compare them with source documents (including, but not limited to 
patient and hospital records), to discuss the study conduct with the investigator and study staff 

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and to verify that the investigator, study staff and facilities remain acceptable for the conduct of 
the study. Representatives of government regulatory authorities (i.e. FDA) may also evaluate the 
study records, source documents, investigator, study staff and facilities. All data generated 
during this study and the medical records/documents from which they originated are subject to 
inspection by the sponsor, its designee(s), the FDA, and other regulatory agencies. 
Prior to the start of the study, the sponsor and/or its designee will review the protocol, eCRF, 
regulatory obligations, and other material or equipment relevant to the conduct of the study with 
the investigator and relevant study site personnel.  
Monitoring visits and telephone consultations will occur as necessary, during the course of the 
investigation to verify the following: 
 the rights and well-being of subjects are protected 
 the conduct of the investigation is in compliance with the currently approved 
protocol/amendment, ICH GCPs, and IRB requirements 
 the integrity of the data, including adequate study documentation 
 the facilities remain acceptable 
 the investigator and site personnel remain qualified and able to conduct the study 
 study drug accountability 
The investigator must immediately notify the sponsor of any audits by any regulatory agency, 
and must promptly provide copies of any audit reports. 
11.6 Case Report Form Requirements 
Paper source documents will be created and retained at the clinical site.  
Electronic case report forms (eCRFs) will be used to record subject data during the course of the 
study. The investigator and study site personnel will be responsible for completing the eCRFs. 
The investigator is required to verify that all of the requested information is accurately recorded 
in the eCRFs. All information requested in the eCRFs needs to be entered, including subject 
identification, date(s), assessment values, etc. Any omission or discrepancy will require 
explanation. 
The sponsor or designee will review the data recorded in the eCRFs utilizing original source 
documentation, as applicable. Discrepant findings will be queried within the electronic data 
capture (EDC) system. The investigator and study site personnel will be responsible for 
answering all queries.  
A copy of the eCRFs or archive of eCRFs will be retained by the investigator, who must ensure 
that it is stored in a secure place. 

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11.7 Quality Assurance Audits 
Representatives from the sponsor and/or a third party selected by the sponsor or designee may 
conduct a quality assurance audit of this study at any time during or after completion of the 
study. The Investigator will be given adequate notice if he/she is selected for an audit. During the 
audit, the investigator must provide the auditor with direct access to all relevant documents and 
discuss any findings with the auditor. 
In the event of an inspection by the FDA or other regulatory authority, the investigator must give 
the inspector direct access to relevant documents and discuss any findings with the inspector. If 
an inspection is requested by a regulatory authority and/or IRB, the investigator must inform the 
sponsor immediately that this request has been made. 
11.8 Records Retention 
The investigator must retain all study-related records for at least 2 years after a marketing 
application is approved for the drug. If an application is not approved for the drug, the 
investigator must retain all study-related records until at least 2 years after shipment and delivery 
of the drug for investigational use is discontinued, and FDA or regulatory agencies have been so 
notified. 
The investigator must contact the sponsor prior to destroying any records associated with this 
study.  
If the location of the study files changes from the address noted on the Form FDA 1572, written 
notification of the new location must be given to the sponsor. In the event the investigator 
withdraws from participation in the study, study records will be transferred to a mutually agreed 
upon designee. The investigator must provide written notice to the sponsor of such transfer. 
11.9 Publication of Results 
All information concerning miconazole oil including study data and sponsor operations including 
but not limited to formulation information, manufacturing processes, basic scientific data, and 
patent applications will be regarded as confidential and will remain the sole property of the 
sponsor. The investigator agrees to use this information solely for the purposes of accomplishing 
this study and agrees not to use it for any other purposes without the written consent of the 
sponsor. 
Study-related information must not be published or presented by the investigator without prior 
consultation with and written agreement from the sponsor. 

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Vandenbosch D, Braeckmans K, Nelis HJ, Coenye T. Fungicidal activity of miconazole against 
Candida spp. biofilms. J Antimicrob Chemother. 2010 Apr;65(4):694-700. 
Vennewald I, Klemm E. Otomycosis: Diagnosis and treatment. Clin Dermatol. 2010 Mar 
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Yunginger JW, Calobrisi SD. Investigation of the allergenicity of a refined peanut oil-containing 
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