Conditions: Otomycosis
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 382
Healthy volunteers: yes

Brief summary:
This study involves two portions, a randomized, double-blind portion and an open-label portion, to evaluate the efficacy and safety of Miconazole oil 2% versus its Vehicle in the treatment of fungal infection of the outer ear canal (Otomycosis). The subjects randomized in the first portion of the study will have active fungal infection of the ear(s) and will be treated with either Miconazole Oil or the Vehicle for 14 days twice daily, 5 drops into the affected ear(s) per dose. The subjects enrolled in the open-label portion of the study may or may not have active fungal infection of the ear(s), and will be given the Miconazole Oil active drug following the same application of 5 drops into the ear(s) twice daily for 14 days.

The intention of the study is to evaluate the efficacy of Miconazole Oil on fungal infection of the ears when applied using 5 drops into the ear(s) twice daily for 14 days continuously. This study also intends to show safety of Miconazole Oil 5 drops into each ear twice a day for 14 consecutive days.

Detailed description:
This study will be conducted in 2 portions:

1. Enrollment A, which will consist of 2 treatment periods as follows and will be conducted in subjects with otomycosis:

   1. A randomized, double-blind, parallel-group treatment period. This treatment period will be referred to as the "Randomization Period" and will be followed by:
   2. An optional, open-label treatment period with miconazole oil. This treatment period will be referred to as the "Optional Open-label Extension."
2. Enrollment B will consist of open-label treatment with miconazole oil in subjects who will not be required to have signs and symptoms of otomycosis.

The study will start with Enrollment A, with an estimated 220 male or female subjects with otomycosis. Subjects will be randomly assigned in a 1:1 ratio to receive miconazole oil or vehicle (placebo), for 14 days. The study drug will be administered as 5 drops per ear at \~30 mg per drop instilled into the external ear canal of the ear(s) affected by otomycosis.

In the Randomization Period, both the subject and the investigator and study staff are blinded to the contents of the study drug.

At Screening/Baseline (Day 1), assessment of the signs and symptoms of otomycosis (pruritus, debris, visual examination for presence of fungal elements, and aural fullness), evaluation of medical history, pregnancy screening in female of childbearing potential, and, prior and concomitant medications, will be collected. Subjects with positive signs and symptoms of otomycosis and who meet all eligibility criteria will enter the study. Fungal culture of affected ear(s) will be taken, debris will be cleaned from the affected ear(s), and subject will be randomized and study drug dispensed. Treatment will be for 14 days. Day 8 On Treatment Visit will include clinical evaluation of otomycosis, cleaning of ear(s), and assessment of Adverse Events (AEs) and concomitant medications, and continue treatment up to Day 14. Day 15 End of Treatment Visit will include clinical evaluation of otomycosis and fungal culture, adverse events including Treatment emergent adverse events (TEAEs) and concomitant medications assessed. Day 22 Test of Cure Visit is an assessment of clinical signs and symptoms of otomycosis and fungal culture, AEs and concomitant medications assessed, and urine pregnancy test performed in women of childbearing potential.

Only the subjects that had positive fungal (mycological) culture at Baseline will be evaluated for efficacy. This is the Modified intent-to-treat (MITT) population.

The Optional Open-label Extension period will allow subjects to get miconazole oil for 14 days. No unblinding of the subject's treatment in the Randomization Period will occur at this time.

For Enrollment B, male or female subjects will be enrolled to receive miconazole oil to use for 14 days and will be evaluated for safety.

Intent-to-Treat (ITT) population are all subjects enrolled and randomized to treatment. Modified Intent-to-Treat (MITT) population are subjects in the ITT population with a clinical diagnosis of otomycosis confirmed by positive fungal culture at Baseline.

Arms:
arm 1: Treatment with miconazole 2% oil, 5 drops into each ear twice daily for 14 consecutive days arm 2: Treatment with the vehicle oil, placebo, 5 drops into each ear twice daily for 14 consecutive days arm 3: Application of miconazole 2% oil, 5 drops into each ear twice daily for 14 consecutive days

Interventions: intervention 1: miconazole 2% oil intervention 2: vehicle oil
Intervention descriptions: intervention 1: Drug treatment of otomycosis for 14 days intervention 2: Placebo treatment of otomycosis for 14 days

Protocol document:
Prot_SAP_001.pdf: 
Hill Dermaceuticals, Inc. 
 
Protocol MZ-0120-ESP3-052 
 
 
14 Sep 2020 / Version 4 
Page 1 of 88 
CLINICAL TRIAL PROTOCOL 
 
Study Title: 
Randomized, Double-blind, Phase III Study of the Efficacy 
and Safety of Miconazole Oil versus Vehicle Oil in the 
Treatment of Otomycosis, Followed by an Open-label Safety 
Evaluation 
Study Number: 
MZ-0120-ESP3-052 
Study Drug: 
Miconazole oil 
Sponsor: 
Hill Dermaceuticals, Inc. 
2650 S. Mellonville Ave 
Sanford, FL 32773 
Protocol Date/Version: 
14 September 2020 / Version 4 
Previous versions: 
28 January 2020 / Version 1 (internal only) 
04 February 2020 / Version 2 
18 May 2020 / Version 3 
The information contained in this document is confidential and proprietary property of Hill 
Dermaceuticals, Inc. 


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PROTOCOL APPROVAL 
The following individuals approve the 14 September 2020 version of the MZ-0120-ESP3-052 
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 Director, Research & Development 
Address: 
2650 South Mellonville Avenue 
 
Sanford, FL 32773 
 
 
 
 
 
Signature                                                      Date 
 
Rosario Ramirez
Digitally signed by Rosario Ramirez 
DN: c=US, st=FL, l=Sanford, o=Hill Dermaceuticals, Inc, cn=Rosario 
Ramirez, email=nini.ramirez@hillderm.com 
Reason: I am approving this document 
Date: 2020.09.14 09:13:42 -04'00'


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STUDY ACKNOWLEDGEMENT 
Protocol number: MZ-0120-ESP3-052 Version 4 
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 
 


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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 
versus Vehicle Oil in the Treatment of Otomycosis, Followed by an Open-label Safety 
Evaluation 
Study Number: MZ-0120-ESP3-052 
Study Center(s): Up to 20 study centers in the United States (US) 
Number of Subjects Planned:  
Approximately 390 (estimated); the actual number enrolled will be the number needed to 
achieve at least 128 subjects eligible to be included in the modified intent-to-treat (MITT) 
population, defined as all subjects who were randomized with a positive fungal culture at 
Screening/Baseline, and to achieve at least 300 subjects exposed to miconazole oil for 14 
days who are evaluable for safety. Thus, a higher or lower number than estimated may be 
enrolled, with enrollment continuing until the required numbers of subjects have been 
achieved. 
Phase of Development: 3 
Objectives: 
• Confirm the efficacy of miconazole oil compared with vehicle over a 14-day treatment 
duration in subjects with otomycosis 
• Assess the safety of miconazole oil over a 14-day treatment duration  
Design and Methodology: 
This study will be conducted in 2 portions: 
1. Enrollment A, which will consist of 2 treatment periods as follows and will be conducted in 
subjects with otomycosis: 
a. A randomized, double-blind, parallel-group treatment period. This treatment period will 
be referred to as the “Randomization Period” and will be followed by: 
b. An optional, open-label treatment period with miconazole oil. This treatment period will 
be referred to as the “Optional Open-label Extension.” 
2. Enrollment B, which will consist of open-label treatment with miconazole oil in subjects who 
will not be required to have signs and symptoms of otomycosis. 
Enrollment A 
The study will start with Enrollment A, in which an estimated 220 male or female subjects with 
otomycosis will receive study drug, although this number may be higher or lower depending on 
the percentage of subjects eligible to be included in the MITT population. Subjects will be 
randomly assigned in a 1:1 ratio to receive miconazole oil or vehicle, for 14 days. The study 
drug will be administered as 5 drops per ear at ~30 mg per drop instilled into the external ear 
canal of the ear(s) affected by otomycosis. 
Randomization Period 
During the Randomization Period, both the subject and the investigator and study staff will be 
blinded as to the contents of the study drug. 


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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
At Screening/Baseline (Day 1), potentially eligible subjects will provide informed consent, and 
subjects will undergo screening evaluations to include a 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 be randomized, and study drug will be 
weighed and dispensed to the subject along with a subject diary. 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 then 
be assessed. The subject will then leave the clinic and continue to administer the study drug 
and to complete the subject diary 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 return to the clinic on Day 8 for the On Treatment Visit, at which time a clinical 
evaluation of the signs and symptoms of otomycosis, a cleaning of the affected ear(s) 
(following the site’s normal procedures), a review of the subject diary, and an assessment of 
AEs and concomitant medications will be performed. Subjects will continue to administer the 
study drug and to complete the subject diary 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 and a fungal culture of the 
affected ear(s) will be performed; however, a fungal culture will not be required at this visit for 
subjects known to have a negative fungal culture at Screening/Baseline, as assessed after at 
least 14 days of incubation by the clinical laboratory performing the fungal culture. AEs and 
concomitant medications will also be assessed, and the subject will return all unused study 
drug along with the completed subject diary.  
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 a fungal culture of the affected 
ear(s) will be performed; however, a fungal culture will not be required at this visit for subjects 
known to have a negative fungal culture at Screening/Baseline, as assessed after at least 14 
days of incubation by the clinical laboratory performing the fungal culture. AEs and 
concomitant medications will also be assessed. A urine pregnancy test will be performed in 
women of childbearing potential. 
Optional Open-label Extension 
Subjects who either complete the Randomization Period of the study (up through the Test of 
Cure Visit), or who are prematurely discontinued from study treatment during the 
Randomization Period due to worsening of signs and/or symptoms of otomycosis in the 
judgment of the investigator, will be offered the opportunity to participate in an optional open-
label extension, if they have a visual presence of fungal elements in at least one ear treated 
during the Randomization Period. Only the ear(s) that were treated in the Randomization 


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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
Period will be potentially eligible for treatment during the Optional Open-label Extension. 
All subjects in the Optional Open-label Extension will receive miconazole oil for 14 days. No 
unblinding of the subject’s treatment in the Randomization Period will occur at this time. 
Before a subject enters the Optional Open-label Extension, all procedures for the Test of Cure 
Visit will be completed for that subject; however, a fungal culture will not be required at this 
visit for subjects known to have a negative fungal culture at Screening/Baseline, as assessed 
after at least 14 days of incubation by the clinical laboratory performing the fungal culture.  
At the first visit of the Optional Open-label Extension (Day OLE1, which will occur while the 
subject is already onsite for the Test of Cure or Early Termination Visit from the 
Randomization Period), study drug (miconazole oil) will be weighed and dispensed to the 
subject along with a subject diary. Subjects or their caregivers will administer the first dose of 
miconazole oil at the site. AEs and concomitant medications will then be assessed. Subjects 
will then continue to administer miconazole oil and to complete the subject diary twice per day 
for a total of 14 days, following the same instructions as provided at the Screening/Baseline 
Visit on Day 1. 
Subjects will return to the clinic on Day OLE15 for the End of Treatment Visit, at which time a 
clinical evaluation of the signs and symptoms of otomycosis will be performed, as well as an 
assessment of AEs and concomitant medications. A urine pregnancy test will be performed in 
women of childbearing potential. The subject will return all unused miconazole oil along with 
the completed subject diary.  
Data for Enrollment A will be unblinded after all subjects planned for Enrollment A have 
completed both the Randomization Period and the Optional Open-label Extension, so that 
analyses from Enrollment A can be conducted even if Enrollment B is still ongoing (i.e., before 
the conclusion of Enrollment B). 
Enrollment B 
Enrollment B may be initiated while Enrollment A is still actively enrolling subjects. An 
estimated 170 male or female subjects will receive study drug (miconazole oil) in Enrollment B, 
although this number may be higher or lower depending on the total number of subjects 
needed to achieve at least 300 subjects who are exposed to miconazole oil for 14 days in the 
study overall who are evaluable for safety.  
At Screening/Baseline (Day B1), potentially eligible subjects will provide informed consent, and 
subjects will undergo screening evaluations to include a physical examination 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 
who meet all eligibility criteria will be entered into the study. Study drug will be weighed and 
dispensed to the subject along with a subject diary. The subject will then begin treatment with 
miconazole oil. In subjects who do not have otomycosis, treatment will be in the left ear if both 
ears are otherwise eligible; if only one ear is eligible, treatment will be in that ear. In subjects 
who have otomycosis (i.e., any signs and/or symptoms consistent with a clinical diagnosis of 
otomycosis in the judgment of the investigator), treatment will preferably be in the ear(s) with 
otomycosis, provided the ear(s) meet all eligibility criteria. If both ears are judged by the 
investigator to have otomycosis and both meet all eligibility criteria, both ears may be treated. 
The subject or caregiver will instill the first dose of miconazole oil at the site, under the 


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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
supervision of the investigator or site personnel. AEs will then be assessed. The subject will 
then leave the clinic and continue to administer miconazole oil and to complete the subject 
diary twice per day, following the same instructions for miconazole oil administration as in 
Enrollment A. 
Subjects will return to the clinic on Day B15 for the End of Treatment Visit, at which time AEs 
and concomitant medications will be assessed. Subjects will return all unused miconazole oil 
along with the completed subject diary. A urine pregnancy test will be performed in women of 
childbearing potential. 
Timing of Subject Recruitment Into Enrollment A and Enrollment B 
The study will start with Enrollment A, which will continue until the sponsor determines that a 
sufficient number of subjects (see Sample Size below) has been recruited to conduct the 
planned analyses for Enrollment A, at which time the sponsor (or designee) will notify all study 
sites to terminate further enrollment into the Enrollment A portion of the study. 
Recruitment of subjects into Enrollment B will begin when the sponsor (or designee) notifies 
sites to begin recruiting subjects into Enrollment B, and will end when the sponsor (or 
designee) notifies study sites to pause or permanently terminate recruitment of subjects into 
Enrollment B. Enrollment B may occur over one or multiple time periods, each of which will 
begin and then pause (or permanently end) upon sponsor (or designee) notification to the 
study sites. The purpose of this mechanism is to allow concurrent enrollment of Enrollment A 
and Enrollment B at times (such as during the wintertime) when recruitment into Enrollment A 
is likely to be diminished due to a lower expected incidence of otomycosis, while also allowing 
the sponsor the flexibility to pause or permanently terminate recruitment into Enrollment B for 
reasons including (but not limited to) time periods during which a higher incidence of 
otomycosis is expected (at which times the sponsor may wish for the focus of the study to be 
on recruitment of subjects into Enrollment A), or evaluation by the sponsor of the number of 
subjects still needed for Enrollment B (see Sample Size below).  
At times when Enrollment A and Enrollment B are concurrently ongoing, if a subject is found to 
be eligible for both Enrollment A and Enrollment B, the subject should be enrolled into 
Enrollment A whenever possible. 
Study Visits: 
Enrollment A 
Randomization Period: 
• 
Day 1: Screening/Baseline (1 visit); 
• 
Day 8: On Treatment (1 visit); 
• 
Day 15: End of Treatment (1 visit); 
• 
Day 22: Test of Cure (1 visit) 
Optional Open-label Extension: 
• 
Day OLE1 (which will occur while the subject is already onsite for the Test of Cure 
or Early Termination Visit for the Randomization Period); 
• 
Day OLE15 (1 visit) 


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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
Enrollment B 
• 
Day B1: Screening/Baseline (1 visit); 
• 
Day B15: End of Treatment (1 visit) 
Study Duration: 
Enrollment A 
During Enrollment A, the study duration for each subject who participates only in the 
Randomization Period will be up to approximately 31 days, which includes up to 1 day for 
screening (if screening procedures need to be initiated the day before treatment), 14 days of 
treatment, and 8 days of follow-up, plus a visit window of up to 8 additional days after the 
scheduled day for the follow-up (Test of Cure) Visit. 
The study duration for each subject who participates in both the Randomization Period and the 
Optional Open-label Extension will be up to approximately 48 days, which includes up to 31 
days for the Randomization Period followed by up to 17 days for the Optional Open-label 
Extension (which includes a visit window of up to 3 additional days after the 14-day treatment 
to complete the final study visit). This study duration takes into account that the Day OLE1 
procedures will occur while the subject is already onsite for the Test of Cure or Early 
Termination Visit for the Randomization Period. 
Enrollment B 
In Enrollment B, the study duration for each subject will be up to 19 days, which includes up to 
1 day for screening (if screening procedures need to be initiated the day before treatment), 14 
days of treatment, and a 1-day final study visit after the 14-day treatment (which has a visit 
window of up to 3 additional days). 
Efficacy Evaluations: 
• Clinical signs and symptoms of otomycosis (pruritus; debris; presence of fungal elements; 
aural fullness) 
• Fungal culture 
Safety Evaluations: 
• AEs 
Key Inclusion Criteria: 
Enrollment A 
Male or non-pregnant, non-lactating females with a clinical diagnosis of uncomplicated 
otomycosis of the external ear only, with an intact tympanic membrane in the ear(s) to be 
treated with study drug, 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. 
Enrollment B 
Male or non-pregnant, non-lactating females with an intact tympanic membrane in the ear(s) to 
be treated with study drug, who are in general good health as determined by medical 
examination and medical history, and who are free of clinically significant disease, including 


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Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
diabetes mellitus, that is not well-controlled or that could interfere with the study, will be 
included in the study. 
Key Exclusion Criteria: 
Enrollment A 
Subjects with any other dermatoses or conditions of the ear that may interfere with the 
evaluation of otomycosis or with safety evaluations, 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, in the 
ear(s) that will be treated with study drug, 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; 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. 
Enrollment B 
Subjects with any other dermatoses or conditions of the ear that may interfere with safety 
evaluations, 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; systemic antifungal therapy or warfarin within 28 days of 
study entry; fever of ≥100°F at study entry; 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 
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.  


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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
Reference Product, Dose, and Mode of Administration (Enrollment A Only): 
Vehicle oil 
Active ingredient: none (vehicle group) 
Other ingredients: refined peanut oil, mineral oil, oleth-2, and isopropyl myristate 
Mode of administration: same as described for the test product.  
Endpoints: 
Primary Efficacy Endpoint 
• 
Percentage of subjects with “therapeutic cure,” defined as “mycological cure” plus 
“clinical cure” at the Test of Cure Visit. Mycological cure is defined as a negative 
mycological culture, and clinical cure is defined as the absence of all otomycosis signs 
and symptoms according to the scales for each individual sign or symptom. 
Secondary Efficacy Endpoints 
• 
Percentage of subjects with mycological cure at the Test of Cure Visit. 
• 
Percentage of subjects with clinical cure at the Test of Cure Visit. 
Tertiary Efficacy Endpoints 
• 
Percentage of subjects with “modified therapeutic cure” at the Test of Cure Visit, 
defined as mycological cure plus a score of 0 for the clinical sign of fungal elements 
plus a score of 0 or 1 for each of the clinical signs and symptoms of pruritus, debris, 
and aural fullness. 
• 
Percentage of subjects with “therapeutic improvement” at the Test of Cure Visit, 
defined as mycological cure plus a score of 0 or 1 for each of the clinical signs and 
symptoms of fungal elements, pruritus, debris, and aural fullness. 
Safety Endpoint 
• 
Percentage of subjects with treatment-emergent adverse events (TEAEs). 
Statistical Analyses: 
Descriptive statistics will be presented for the percentages of subjects by treatment group with 
therapeutic cure, mycological cure, and clinical cure in the study ear at each evaluation. 
Descriptive statistics will also be presented for the percentages of subjects by treatment group 
with success at each secondary and tertiary endpoint, and for 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 Enrollment A in cases of bilateral otomycosis, the ear with the worse infection at 
Screening/Baseline, as assessed by the investigator by taking into account both clinical signs 
and symptoms and fungal culture results, 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 therapeutic cure at the Test of 
Cure Visit will be compared using a chi-square test with a 2-sided significance level of 0.05. 
Comparisons will be conducted in a similar manner between the miconazole oil and vehicle oil 


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Name of Sponsor/Company: Hill Dermaceuticals, Inc. 
Name of Finished Product: Miconazole oil 
Name of Active Ingredient: 2% miconazole 
groups for the secondary endpoints of clinical cure and mycological cure. 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 efficacy analyses will be the MITT population, defined as all 
subjects who were randomized with a positive fungal culture at Screening/Baseline. 
Two safety populations will be used for safety analyses. The first will be the Randomization 
Period safety population, defined as all subjects who received at least one dose of study drug 
and had at least one post-Baseline safety assessment during the Randomization Period; this 
population will be used for safety data for the Randomization Period. The second will be the 
Open Label safety population, defined as all subjects who received at least one dose of 
miconazole oil and had at least one post-Baseline safety assessment during the Optional 
Open-label Extension or Enrollment B; this population will be used for safety data for the 
Optional Open-label Extension and Enrollment B. 
All AEs occurring during the study will be recorded and classified using terminology from the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported TEAEs, defined as any AE 
with an onset on or after the date of first study drug application, will be summarized. 
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 serious AEs (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: 
For the Randomization Period of Enrollment A, approximately 128 subjects (~64 in each 
group) are required to provide 80% power, using a chi-square test with a 2-sided significance 
level of 0.05, assuming a response rate for the primary efficacy endpoint of 25.0% in the 
miconazole oil group and 7.1% in the vehicle oil group.  
The sample size of 220 subjects for Enrollment A assumes that ~58% of subjects enrolled into 
Enrollment A will have a positive fungal culture at Screening/Baseline and will therefore be 
included in the MITT population. This number may be higher or lower depending on the 
percentage of subjects eligible to be included in the MITT population. 
The overall study sample size of ~390 subjects is the total number of study subjects estimated 
to achieve at least 300 subjects exposed to miconazole oil for 14 days who are evaluable for 
safety. A higher or lower number of total subjects may be enrolled in order to achieve the 
required total numbers of subjects for each of Enrollment A and Enrollment B. 


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TABLE OF CONTENTS 
1 
INTRODUCTION .............................................................................................................. 17 
1.1 
Background ................................................................................................................ 17 
1.2 
Study Purpose ............................................................................................................ 19 
1.3 
Inclusion of Subjects with Peanut Allergy.................................................................... 19 
1.4 
Compliance with Good Clinical Practice ..................................................................... 20 
2 
STUDY OBJECTIVES...................................................................................................... 20 
3 
STUDY DESIGN .............................................................................................................. 20 
3.1 
Enrollment A ............................................................................................................... 21 
3.1.1 
Randomization Period ........................................................................................... 22 
3.1.2 
Optional Open-label Extension ............................................................................. 23 
3.1.3 
Timing of Analysis for Enrollment A ...................................................................... 24 
3.2 
Enrollment B ............................................................................................................... 24 
3.3 
Timing of Subject Recruitment Into Enrollment A and Enrollment B ............................ 24 
3.4 
Number of Subjects .................................................................................................... 25 
3.4.1 
Enrollment A ......................................................................................................... 25 
3.4.2 
Enrollment B ......................................................................................................... 25 
3.5 
Investigators ............................................................................................................... 26 
3.6 
Study Duration ............................................................................................................ 26 
3.6.1 
Enrollment A ......................................................................................................... 26 
3.6.2 
Enrollment B ......................................................................................................... 28 
4 
STUDY SUBJECTS ......................................................................................................... 29 
4.1 
Enrollment A ............................................................................................................... 29 
4.1.1 
Inclusion Criteria ................................................................................................... 29 
4.1.2 
Exclusion Criteria .................................................................................................. 30 
4.2 
Enrollment B ............................................................................................................... 31 
4.2.1 
Inclusion Criteria ................................................................................................... 31 
4.2.2 
Exclusion Criteria .................................................................................................. 32 
4.3 
Subject Discontinuation .............................................................................................. 33 
4.4 
Subjects Lost to Follow-up .......................................................................................... 34 
5 
CONCOMITANT THERAPIES ......................................................................................... 34 
5.1 
Enrollment A ............................................................................................................... 34 
5.1.1 
Permitted Medications .......................................................................................... 34 
5.1.2 
Prohibited Medications .......................................................................................... 35 
5.2 
Enrollment B ............................................................................................................... 35 
5.2.1 
Permitted Medications .......................................................................................... 35 
5.2.2 
Prohibited Medications .......................................................................................... 35 
6 
STUDY SCHEDULE ........................................................................................................ 35 
6.1 
Enrollment A ............................................................................................................... 35 
6.1.1 
Study Flow Chart .................................................................................................. 35 
6.1.2 
Study Visits for the Randomization Period ............................................................ 36 
6.1.2.1 
Screening / Baseline (Day 1) ........................................................................... 37 
6.1.2.2 
On Treatment (Day 8) ..................................................................................... 37 
6.1.2.3 
End of Treatment (Day 15) .............................................................................. 38 
6.1.2.4 
Test of Cure (Day 22) ...................................................................................... 38 
6.1.3 
Study Visits for the Optional Open-label Extension ............................................... 39 
6.1.3.1 
Start of Treatment (Day OLE1) ....................................................................... 39 
6.1.3.2 
End of Treatment (Day OLE15) ....................................................................... 39 
6.2 
Enrollment B ............................................................................................................... 39 


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6.2.1 
Study Flow Chart .................................................................................................. 39 
6.2.2 
Study Visits ........................................................................................................... 40 
6.2.2.1 
Screening / Baseline (Day B1) ........................................................................ 40 
6.2.2.2 
End of Treatment (Day B15) ........................................................................... 41 
6.3 
Screen Failures .......................................................................................................... 41 
6.4 
Unscheduled Study Visits ........................................................................................... 41 
6.5 
Post-study Follow-up .................................................................................................. 42 
6.6 
Missed Visits .............................................................................................................. 42 
6.7 
Subject Completion .................................................................................................... 42 
6.8 
Early Study Termination ............................................................................................. 42 
7 
STUDY PROCEDURES ................................................................................................... 42 
7.1 
Medical/Medication History ......................................................................................... 42 
7.2 
Physical Examination.................................................................................................. 43 
7.3 
Urine Pregnancy Test ................................................................................................. 43 
7.4 
Otomycosis Signs and Symptoms .............................................................................. 43 
7.4.1 
Pruritus ................................................................................................................. 43 
7.4.2 
Debris ................................................................................................................... 44 
7.4.3 
Presence of Fungal Elements ............................................................................... 44 
7.4.4 
Aural Fullness ....................................................................................................... 44 
7.5 
Fungal Culture ............................................................................................................ 45 
7.6 
Ear Cleaning ............................................................................................................... 45 
7.7 
Adverse Event Evaluations ......................................................................................... 45 
7.8 
Randomization ........................................................................................................... 45 
7.9 
Study Drug Administration .......................................................................................... 46 
7.10 
Treatment Compliance ............................................................................................... 46 
7.11 
Protocol Deviations ..................................................................................................... 46 
8 
ADVERSE EVENTS ......................................................................................................... 46 
8.1 
Definition of an Adverse Event .................................................................................... 46 
8.1.1 
Definition of a Serious Adverse Event ................................................................... 47 
8.2 
Severity of Adverse Events ......................................................................................... 47 
8.3 
Relationship of Adverse Events to Study Drug ........................................................... 48 
8.4 
Documentation of Adverse Events .............................................................................. 48 
8.4.1 
Additional Reporting Requirements for Serious Adverse Events ........................... 49 
8.5 
Pregnancy .................................................................................................................. 50 
8.6 
Study Contacts ........................................................................................................... 50 
9 
STUDY TREATMENTS .................................................................................................... 50 
9.1 
Description of Study Drug ........................................................................................... 50 
9.1.1 
Administration ....................................................................................................... 50 
9.2 
Randomization ........................................................................................................... 51 
9.3 
Blinding/Unblinding ..................................................................................................... 51 
9.4 
Study Drug Handling and Dispensing ......................................................................... 51 
9.4.1 
Packaging and Labeling ........................................................................................ 51 
9.4.2 
Storage ................................................................................................................. 52 
9.5 
Accountability ............................................................................................................. 52 
9.6 
Return and Destruction ............................................................................................... 53 
10 
STATISTICAL CONSIDERATIONS ................................................................................. 53 
10.1 
Study Endpoints ......................................................................................................... 53 
10.1.1 
Primary Efficacy Endpoint ..................................................................................... 53 
10.1.2 
Secondary Efficacy Endpoints .............................................................................. 53 


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10.1.3 
Tertiary Efficacy Endpoints ................................................................................... 53 
10.1.4 
Safety Endpoint .................................................................................................... 54 
10.2 
Hypotheses ................................................................................................................ 54 
10.3 
Sample Size ............................................................................................................... 54 
10.4 
Study Populations ....................................................................................................... 55 
10.4.1 
Intent-to-treat Population ...................................................................................... 55 
10.4.2 
Modified Intent-to-treat Population ........................................................................ 55 
10.4.3 
Per Protocol Population ........................................................................................ 55 
10.4.4 
Safety Population .................................................................................................. 55 
10.5 
Statistical Methods ..................................................................................................... 56 
10.5.1 
Efficacy Analyses .................................................................................................. 56 
10.5.1.1 
Multiple Comparison/Multiplicity ...................................................................... 56 
10.5.2 
Safety Analyses .................................................................................................... 57 
10.5.3 
Subject Demographics and Baseline Characteristics ............................................ 57 
10.5.4 
Missing Data ......................................................................................................... 57 
10.5.5 
Sensitivity Analyses .............................................................................................. 58 
10.5.6 
Subgroup Analyses ............................................................................................... 58 
11 
ADMINISTRATIVE CONSIDERATIONS .......................................................................... 58 
11.1 
Institutional Review Board .......................................................................................... 58 
11.2 
Ethics ......................................................................................................................... 58 
11.3 
Informed Consent and Assent .................................................................................... 59 
11.4 
Confidentiality of Subject Information .......................................................................... 59 
11.5 
Study Monitoring ......................................................................................................... 60 
11.6 
Case Report Form Requirements ............................................................................... 60 
11.7 
Quality Assurance Audits ............................................................................................ 61 
11.8 
Records Retention ...................................................................................................... 61 
11.9 
Publication of Results ................................................................................................. 61 
12 
REFERENCES ................................................................................................................. 62 
13 
SUMMARY OF PROTOCOL AMENDMENTS ................................................................. 63 
13.1 
Amendment 1 Version 2 04 February 2020 ................................................................ 63 
13.2 
Amendment 2 Version 3 18 May 2020 ........................................................................ 63 
13.3 
Amendment 3 Version 4 14 September 2020 ............................................................. 84 


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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 .......................................................................................................... 18 
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 ............. 19 
Table 3 
Study Schedule: Enrollment A .............................................................................. 36 
Table 4: 
Study Schedule: Enrollment B .............................................................................. 40 
 
LIST OF FIGURES 
Figure 1: 
Diagram of Study Design ...................................................................................... 21 
Figure 2: 
Diagram of Study Duration for Enrollment A ......................................................... 28 
Figure 3: 
Diagram of Study Duration for Enrollment B ......................................................... 29 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
MITT 
Modified intent-to-treat 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over the counter 
PP 
Per protocol 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 
US 
United States 
 


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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]. 
The mechanisms of action of miconazole against fungi in general appear to be applicable to 
fungi associated with otomycosis. Data from a recently-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 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. 


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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].  
Adverse event (AE) data from the recently-completed Phase 2 study of the investigational study 
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 (which 
were treated for either 7 or 14 days) compared with the vehicle oil group (which was treated for 
14 days). 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) 
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). 


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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 
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. During the 
Randomization Period of the Enrollment A portion of the study, a 14-day regimen of twice-daily 
administration of 2% miconazole oil will be compared with the same treatment regimen using 
the product vehicle. During the Optional Open-label Extension of the Enrollment A portion and 
the Enrollment B portion of the study, a 14-day regimen of twice-daily administration of 2% 
miconazole oil will be administered in an open-label fashion in order to gather safety information 
in additional subjects. 
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 
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 has been treated 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. 


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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 
The objectives of the study are to: 
• Confirm the efficacy of miconazole oil compared with vehicle over a 14-day treatment 
duration in subjects with otomycosis 
• Assess the safety of miconazole oil over a 14-day treatment duration  
3 
STUDY DESIGN 
This study will be conducted in 2 portions (see also Figure 1 for a schematic diagram of the 
study design): 
1. Enrollment A, which will consist of 2 treatment periods as follows and will be conducted in 
subjects with otomycosis: 
a. A randomized, double-blind, parallel-group treatment period. This treatment period will 
be referred to as the "Randomization Period" and will be followed by: 
b. An optional, open-label treatment period with miconazole oil. This treatment period will 
be referred to as the "Optional Open-label Extension." 
2. Enrollment B, which will consist of open-label treatment with miconazole oil in subjects who 
will not be required to have signs and symptoms of otomycosis. 


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Figure 1: 
Diagram of Study Design 
 
 
a. 
Subjects must meet all eligibility criteria in Section 4.1 to be randomized in Enrollment A. 
b. 
Subject must have a visual presence of fungal elements to be enrolled in the Optional Open-label Extension. 
c. 
Subject must meet all eligibility criteria in Section 4.2 to receive treatment with miconazole oil in Enrollment B. 
3.1 
Enrollment A 
The study will start with Enrollment A, in which an estimated 220 male or female subjects with 
otomycosis will receive study drug, although this number may be higher or lower depending on 
the percentage of subjects eligible to be included in the modified intent-to-treat (MITT) 
population (see Section 10.4.2). Subjects will be randomly assigned in a 1:1 ratio to receive 
miconazole oil or vehicle, for 14 days. The study drug will be administered as 5 drops per ear at 
~30 mg per drop instilled into the external ear canal of the ear(s) affected by otomycosis. 
Subjects with 
uncomplicated 
otomycosis a
Randomized in 1:1 ratio 
between miconazole oil 
for 14 days or vehicle oil 
for 14 days
Subject 
completes Test of 
Cure Visit (Day 
22) or Early 
Termination Visit 
and is eligible for 
open-label 
treatment b
Enrolled in optional
open-label treatment 
with miconazole oil for 
14 days
End of participation in 
study
Enrollment A
Subjects with 
healthy ears or 
with 
uncomplicated 
otomycosis c
Enrollment B
Randomization 
Period
Optional Open 
Label Extension
Enrolled in open-label 
treatment with 
miconazole oil for 14 
days


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3.1.1 
Randomization Period 
During the Randomization Period, 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 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 be randomized, and study drug will be weighed and 
dispensed to the subject along with a subject diary. 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 then be assessed. The 
subject will then leave the clinic and continue to administer the study drug and to complete the 
subject diary 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 return to the clinic on Day 8 for the On Treatment Visit, at which time a clinical 
evaluation of the signs and symptoms of otomycosis, a cleaning of the affected ear(s) (following 
the site’s normal procedures), a review of the subject diary, and an assessment of AEs and 
concomitant medications will be performed. Subjects will continue to administer the study drug 
and to complete the subject diary 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 and a fungal culture of the affected 
ear(s) will be performed; however, a fungal culture will not be required at this visit for subjects 
known to have a negative fungal culture at Screening/Baseline, as assessed after at least 14 days 
of incubation by the clinical laboratory performing the fungal culture. AEs and concomitant 
medications will also be assessed, and the subject will return all unused study drug along with 
the completed subject diary.  
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 a fungal culture of the affected 
ear(s) will be performed; however, a fungal culture will not be required at this visit for subjects 
known to have a negative fungal culture at Screening/Baseline, as assessed after at least 14 days 
of incubation by the clinical laboratory performing the fungal culture. AEs and concomitant 
medications will also be assessed. A urine pregnancy test will be performed in women of 
childbearing potential. 


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Efficacy assessments will include fungal culture of the affected ear(s), and 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 1 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. If only 1 ear has a positive fungal culture at Screening/Baseline, that ear will be 
used as the study ear for efficacy analyses. If both ears have a positive fungal culture at 
Screening/Baseline, the ear with the worse infection at Screening/Baseline, as assessed by the 
investigator by taking into account the clinical signs and symptoms of otomycosis, will be used 
as the study ear for efficacy analyses. If both ears have a positive fungal culture and 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. 
Safety assessments will include AEs. 
3.1.2 
Optional Open-label Extension 
Subjects who either complete the Randomization Period of the study (up through the Test of 
Cure Visit), or who are prematurely discontinued from study treatment during the 
Randomization Period due to worsening of signs and/or symptoms of otomycosis in the 
judgment of the investigator, will be offered the opportunity to participate in an optional open-
label extension, if they have a visual presence of fungal elements in at least one ear treated 
during the Randomization Period. Only the ear(s) that were treated in the Randomization Period 
will be potentially eligible for treatment during the Optional Open-label Extension. 
All subjects in the Optional Open-label Extension will receive miconazole oil for 14 days. No 
unblinding of the subject’s treatment in the Randomization Period will occur at this time. 
Before a subject enters the Optional Open-label Extension, all procedures for the Test of Cure 
Visit will be completed for that subject; however, a fungal culture will not be required at this 
visit for subjects known to have a negative fungal culture at Screening/Baseline, as assessed after 
at least 14 days of incubation by the clinical laboratory performing the fungal culture.  
At the first visit of the Optional Open-label Extension (Day OLE1, which will occur while the 
subject is already onsite for the Test of Cure or Early Termination Visit from the Randomization 
Period), study drug (miconazole oil) will be weighed and dispensed to the subject along with a 
subject diary. Subjects or their caregivers will administer the first dose of miconazole oil at the 
site. AEs and concomitant medications will then be assessed. Subjects will then continue to 
administer miconazole oil and to complete the subject diary twice per day for a total of 14 days, 
following the same instructions as provided at the Screening/Baseline Visit on Day 1. 
Subjects will return to the clinic on Day OLE15 for the End of Treatment Visit, at which time a 
clinical evaluation of the signs and symptoms of otomycosis will be performed, as well as an 
assessment of AEs and concomitant medications. A urine pregnancy test will be performed in 
women of childbearing potential. The subject will return all unused miconazole oil along with 
the completed subject diary. 


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The purpose of the Optional Open-label Extension is safety and to provide supportive evidence 
of efficacy. Efficacy assessments will include assessments of clinical signs and symptoms of 
otomycosis. Safety assessments will include AEs. 
3.1.3 
Timing of Analysis for Enrollment A 
Data for Enrollment A will be unblinded after all subjects planned for Enrollment A have 
completed both the Randomization Period and the Optional Open-label Extension, so that 
analyses from Enrollment A can be conducted even if Enrollment B is still ongoing (i.e., before 
the conclusion of Enrollment B). 
3.2 
Enrollment B 
Enrollment B may be initiated while Enrollment A is still actively enrolling subjects. An 
estimated 170 male or female subjects will receive study drug (miconazole oil) in Enrollment B, 
although this number may be higher or lower depending on the total number of subjects needed 
to achieve at least 300 subjects who are exposed to miconazole oil for 14 days in the study 
overall who are evaluable for safety.  
At Screening/Baseline (Day B1), potentially eligible subjects will provide informed consent, and 
subjects will undergo screening evaluations to include a physical examination 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 who meet 
all eligibility criteria will be entered into the study. Study drug will be weighed and dispensed to 
the subject along with a subject diary. The subject will then begin treatment with miconazole oil. 
In subjects who do not have otomycosis, treatment will be in the left ear if both ears are 
otherwise eligible; if only one ear is eligible, treatment will be in that ear. In subjects who have 
otomycosis (i.e., any signs and/or symptoms consistent with a clinical diagnosis of otomycosis in 
the judgment of the investigator), treatment will preferably be in the ear(s) with otomycosis, 
provided the ear(s) meet all eligibility criteria. If both ears are judged by the investigator to have 
otomycosis and both meet all eligibility criteria, both ears may be treated. The subject or 
caregiver will instill the first dose of miconazole oil at the site, under the supervision of the 
investigator or site personnel. AEs will then be assessed. The subject will then leave the clinic 
and continue to administer miconazole oil and to complete the subject diary twice per day, 
following the same instructions for miconazole oil administration as in Enrollment A. 
Subjects will return to the clinic on Day B15 for the End of Treatment Visit, at which time AEs 
and concomitant medications will be assessed. Subjects will return all unused miconazole oil 
along with the completed subject diary. A urine pregnancy test will be performed in women of 
childbearing potential. 
Safety assessments will include AEs. 
3.3 
Timing of Subject Recruitment Into Enrollment A and Enrollment B 
The study will start with Enrollment A, which will continue until the sponsor determines that a 
sufficient number of subjects (see Section 3.4) has been recruited to conduct the planned 


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analyses for Enrollment A, at which time the sponsor (or designee) will notify all study sites to 
terminate further enrollment into the Enrollment A portion of the study. 
Recruitment of subjects into Enrollment B will begin when the sponsor (or designee) notifies 
sites to begin recruiting subjects into Enrollment B, and will end when the sponsor (or designee) 
notifies study sites to pause or permanently terminate recruitment of subjects into Enrollment B. 
Enrollment B may occur over one or multiple time periods, each of which will begin and then 
pause (or permanently end) upon sponsor (or designee) notification to the study sites. The 
purpose of this mechanism is to allow concurrent enrollment of Enrollment A and Enrollment B 
at times (such as during the wintertime) when recruitment into Enrollment A is likely to be 
diminished due to a lower expected incidence of otomycosis, while also allowing the sponsor the 
flexibility to pause or permanently terminate recruitment into Enrollment B for reasons including 
(but not limited to) time periods during which a higher incidence of otomycosis is expected (at 
which times the sponsor may wish for the focus of the study to be on recruitment of subjects into 
Enrollment A), or evaluation by the sponsor of the number of subjects still needed for 
Enrollment B (see Section 3.4).  
At times when Enrollment A and Enrollment B are concurrently ongoing, if a subject is found to 
be eligible for both Enrollment A and Enrollment B, the subject should be enrolled into 
Enrollment A whenever possible. 
3.4 
Number of Subjects 
Approximately 390 total subjects are estimated to be enrolled into the study (~220 subjects 
estimated for Enrollment A and ~170 subjects estimated for Enrollment B) as described in 
Section 3.4.1 for Enrollment A and in Section 3.4.2 for Enrollment B. 
3.4.1 
Enrollment A 
An estimated 220 eligible subjects are planned to be enrolled in Enrollment A in order to achieve 
at least 128 evaluable subjects (i.e., included in the MITT population, defined as those who were 
randomized with a positive fungal culture at Screening/Baseline). The number of subjects who 
are enrolled may be higher or lower than 220 depending on the percentage of subjects eligible to 
be included in the MITT population; enrollment in Enrollment A will continue until the required 
numbers of subjects have been achieved. 
3.4.2 
Enrollment B 
An estimated 170 eligible subjects are planned to be enrolled in order to achieve at least 300 total 
subjects in the study (including both Enrollment A and Enrollment B) who are exposed to 
miconazole oil for 14 days who are evaluable for safety. This number has been estimated on the 
basis of the following assumptions: 
• A total of 220 subjects will be enrolled into the Randomization Period of Enrollment A, with 
110 subjects exposed to active treatment with miconazole oil (on the basis of the 1:1 
randomization for the Randomization Period), and 110 subjects exposed to the vehicle 
treatment: 


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• Of the 110 subjects exposed to active treatment (miconazole oil) in the Randomization 
Period, ~90% (100 subjects) will complete the full 14 days of treatment, with the 
remaining ~10% (10 subjects) completing less than the 14-day treatment course 
• Of the 110 subjects exposed to vehicle treatment in the Randomization Period, ~50% (55 
subjects) will opt to participate in the Optional Open-label Extension of Enrollment A, 
with the other ~50% (55 subjects) concluding participation in the study 
• Of the 55 subjects exposed to miconazole oil treatment in the Optional Open-label Extension, 
~90% (50 subjects) will complete the full 14 days of treatment, with the remaining ~10% (5 
subjects) completing less than the 14-day treatment course 
• On the basis of these assumptions, ~150 subjects will have been exposed to miconazole oil 
for the full 14-day treatment during Enrollment A (100 subjects during the Randomization 
Period and 50 subjects during the Optional Open-label Extension), and an additional ~150 
subjects exposed to miconazole oil for the full 14-day treatment will be needed to achieve the 
≥300 total subjects required to be exposed to miconazole oil for the full 14-day treatment 
• Assuming ~90% of subjects enrolled into Enrollment B complete the full 14 days of open-
label treatment with miconazole oil, ~170 subjects will be required to be enrolled in 
Enrollment B in order to achieve ~150 subjects who complete the full 14-day treatment with 
miconazole oil 
• Therefore, ~150 subjects from Enrollment A and ~150 subjects from Enrollment B are 
estimated to be needed for at least 300 total subjects in the study who are exposed to 
miconazole oil for a full 14 days. 
The actual number of subjects enrolled into Enrollment B may therefore be higher or lower than 
170 depending on the accuracy of the assumptions as stated above, including the number of 
subjects who have completed a full 14 days of treatment with miconazole oil in Enrollment A as 
well as in Enrollment B. Enrollment will continue into Enrollment B until the required number of 
subjects exposed to miconazole oil for 14 days and evaluable for safety has been achieved.  
3.5 
Investigators 
The study will be conducted at up to 20 investigative sites 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. 
3.6 
Study Duration 
3.6.1 
Enrollment A 
A diagram of the study duration for each subject participating in Enrollment A is presented in 
Figure 2. 


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During Enrollment A, the study duration for a subject who participates only in the 
Randomization Period of the study will be up to 31 days, which includes up to 1 day for 
screening (if screening procedures need to be initiated the day before treatment), 14 days for 
treatment, and 8 days of follow-up, including the visit window of up to 8 additional days after 
the scheduled day to complete the final Test of Cure Visit. 
The study duration for each subject who participates in both the Randomization Period and 
Optional Open-label Extension will be up to approximately 48 days, which includes up to 31 
days for the Randomization Period followed by up to 17 days for the Optional Open-label 
Extension (which includes a visit window of up to 3 additional days after the 14-day treatment to 
complete the final study visit). This study duration takes into account that the Day OLE1 
procedures will occur while the subject is already onsite for the Test of Cure or Early 
Termination Visit for the Randomization Period. 


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Figure 2: 
Diagram of Study Duration for Enrollment A 
 
3.6.2 
Enrollment B 
A diagram of the study duration for each subject participating in Enrollment B is presented in 
Figure 3. 
Randomization Period of Enrollment A
Optional Open-Label Extension of Enrollment A
Cumulative 
Days on 
Study
On-
Treatment 
Days
On-
Treatment 
Days
1
2
Day 1
3
Day 2
4
Day 3
5
Day 4
6
Day 5
7
Day 6
8
Day 7
9
First allowable day
Day 8
10
Day 9
11
Day 10
12
Last allowable day
Day 11
13
Day 12
14
Day 13
15
Day 14
16
First allowable day
17
18
19
Last allowable day
20
21
22
23
First allowable day
24
25
26
27
28
29
30
31
Last allowable day
Day OLE1
must occur
Day 1
32
Day 2
33
Day 3
34
Day 4
35
Day 5
36
Day 6
37
Day 7
38
Day 8
39
Day 9
40
Day 10
41
Day 11
42
Day 12
43
Day 13
44
Day 14
45
First allowable day
46
47
48
Last allowable day
First and Last Day when Each 
Study Visit May Occur
First and Last Day when Each 
Study Visit May Occur
End of Treatment 
(Day OLE15) 
Visit Window
On Treatment 
(Day 8) 
Visit Window
End of Treatment 
(Day 15) 
Visit Window
Test of Cure 
(Day 22) 
Visit Window
May occur over 2 days
Screening / 
Baseline (Day 1)


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In Enrollment B, the study duration for each subject will be up to 19 days, which includes up to 1 
day for screening (if screening procedures need to be initiated the day before treatment), 14 days 
of treatment, and a 1-day final study visit after the 14-day treatment (which has a visit window of 
up to 3 additional days). 
Figure 3: 
Diagram of Study Duration for Enrollment B 
 
4 
STUDY SUBJECTS 
4.1 
Enrollment A 
4.1.1 
Inclusion Criteria 
In order to be eligible for Enrollment A, 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 >0 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 at least two of the following signs or symptoms of 
otomycosis in each ear to be treated with study drug: pruritus, >1; debris, >1; or aural 
fullness, >0 
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 
Enrollment B
Cumulative 
Days on 
Study
On-
Treatment 
Days
1
2
Day 1
3
Day 2
4
Day 3
5
Day 4
6
Day 5
7
Day 6
8
Day 7
9
Day 8
10
Day 9
11
Day 10
12
Day 11
13
Day 12
14
Day 13
15
Day 14
16
First allowable day
17
18
19
Last allowable day
First and Last Day when Each 
Study Visit May Occur
Day B1 
Visit Window
May occur over 2 days
End of Treatment 
(Day B15) 
Visit Window


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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 Test of Cure 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 both ears meet all study eligibility criteria, the subject will be eligible 
for the study, both ears may be treated with study drug, 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. 
4.1.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will not be eligible for Enrollment A: 
1. Any other dermatoses or conditions of the ear that may interfere with the evaluation of 
otomycosis or with safety evaluations, including concomitant otic infections (including 
bacterial infection) other than otomycosis 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, in the ear(s) that will be treated with study drug, of any topical medicated treatments for 
otomycosis within 14 days of study entry: 


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• Topical corticosteroids prescribed specifically for the treatment of otomycosis are 
prohibited to be used within 14 days of study entry; however, use of topical 
corticosteroids for any other reason (e.g., for bacterial otitis externa and/or for control of 
symptoms in the ear such as itching and/or pain) will not require a 14-day washout 
• Alcohol and/or peroxide are prohibited when prescribed/used by a health care provider 
specifically for the treatment of otomycosis within 14 days of study entry; however, use 
of these substances for other purposes (e.g., as a drying agent) will not require a 14-day 
washout 
• Use of boric acid for any reason is prohibited within 14 days of study entry 
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. Otomycosis that has been unresponsive to previous antifungal treatment 
8. Known hypersensitivity to any of the components in the test formulation 
9. Participation in another investigative trial within 28 days of study entry 
10. Participation in the sponsor’s previous miconazole oil Study HD-MCZ-PHII-DRF062016 
unless the subject was enrolled into either the vehicle or the 7-day miconazole oil group of 
that study. 
4.2 
Enrollment B 
4.2.1 
Inclusion Criteria 
In order to be eligible for Enrollment B, subjects must meet all of the following criteria: 
1. Male or non-pregnant, non-lactating females 
2. Presence or absence of uncomplicated otomycosis of the external ear only, with otomycosis 
defined as the presence of any signs and/or symptoms consistent with a clinical diagnosis of 
otomycosis in the judgment of the investigator 
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 final study visit. 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, 


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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. In 
subjects who do not have otomycosis, treatment will be in the left ear if both ears are 
otherwise eligible. In subjects who have otomycosis, treatment will be in the ear(s) with 
otomycosis, provided the ear(s) meets all eligibility criteria. If both ears are judged by the 
investigator to have otomycosis and both meet all eligibility criteria, both ears may be 
treated.  
4.2.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will not be eligible for Enrollment B: 
1. Any other dermatoses or conditions of the ear that may interfere with safety evaluations, 
including concomitant otic infections (including bacterial infection) other than otomycosis 
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 systemic antifungal therapy or warfarin within 28 days of study entry 
5. Fever of ≥100°F at study entry 
6. Known hypersensitivity to any of the components in the test formulation 
7. Participation in another investigative trial within 28 days of study entry 
8. Participation in the sponsor’s previous miconazole oil Study HD-MCZ-PHII-DRF062016 
unless the subject was enrolled into either the vehicle or the 7-day miconazole oil group of 
that study 
9. Previous participation in Enrollment A of this study, unless the subject is known never to 
received active treatment (miconazole oil) during Enrollment A. 


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4.3 
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 
• For subjects participating in Enrollment A, a negative fungal culture at Screening/Baseline 
(as assessed after at least 14 days of incubation by the clinical laboratory performing the 
fungal cultures) 
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 
• 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 (Randomization Period) or the End of Treatment Visit 
(Optional Open-label Extension or Enrollment B) should be performed, and an effort should be 
made to collect all study drug. A fungal culture is not required for subjects who are prematurely 
discontinued from the study. 
For Enrollment A, due to the time required to obtain fungal culture results from 
Screening/Baseline, subjects will be enrolled into the study based on a clinical diagnosis of 
otomycosis (including the visible presence of fungal elements at Screening/Baseline), without a 
requirement for a positive fungal culture. Subjects who end up with a negative 
Screening/Baseline fungal culture are not required to be discontinued from the study, but these 
subjects will not be included in the primary efficacy analysis. Because the sponsor’s goal is to 
have at least 128 subjects in the MITT population (see Section 10.4.2), the total number of 
subjects enrolled into Enrollment A may be higher or lower than 220, depending on the 
percentage of subjects who are eligible to be included in the MITT population. 
Subject discontinuations will be documented clearly on the applicable electronic case report form 
(eCRF). Subjects who discontinue from the study will not be replaced, but additional subjects 
may be enrolled and randomized into Enrollment A if it appears that the estimated number of 
subjects for Enrollment A (approximately 220) is insufficient to meet the sponsor’s goal of 
having at least 128 subjects in the MITT population. After completion of Enrollment A, 
additional subjects (i.e., exceeding the 390 subjects total for the study) may be enrolled into 
Enrollment B if it appears that the estimated total number of study subjects is insufficient to 
achieve at least 300 subjects who have been exposed to miconazole oil for 14 days who are 
evaluable for safety.  


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4.4 
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. 
5 
CONCOMITANT THERAPIES 
All concomitant therapies must 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 
Enrollment A 
In addition to all concomitant therapies, all therapies within 3 months prior to Day 1 must also be 
recorded on the eCRF. 
5.1.1 
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. 


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5.1.2 
Prohibited Medications 
Other than the study drug, no other topical medications (including but not limited to antibiotics, 
alcohol, boric acid, peroxide, and/or corticosteroids) are allowed to be used in the ear(s) being 
treated with study drug. Other prohibited treatments include systemic antifungal therapy, 
warfarin, immunosuppressive or immune-stimulating drugs, and systemic steroids. A subject 
who discontinues study drug during the Randomization Period and who subsequently uses a 
topical corticosteroid (e.g., to treat an AE such as itching) in the ear(s) that were treated with 
study drug during the Randomization Period will be eligible for the Optional Open-label 
Extension if the topical corticosteroid is discontinued in the ear(s) that will be treated with study 
drug before the start of study drug in the Optional Open-label Extension, and as long as the 
subject meets all other eligibility criteria for the Optional Open-label Extension. 
5.2 
Enrollment B 
In addition to all concomitant therapies, all therapies within 28 days prior to Day B1 must also be 
recorded on the eCRF. 
5.2.1 
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 NSAIDs or acetaminophen are permitted. 
5.2.2 
Prohibited Medications 
Prohibited treatments include systemic antifungal therapy and warfarin. 
6 
STUDY SCHEDULE 
6.1 
Enrollment A 
6.1.1 
Study Flow Chart 
The study schedule for Enrollment A is presented in Table 3. 
 
 


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Table 3 
Study Schedule: Enrollment A 
Evaluations and Procedures: 
Randomization Period 
Optional OLE 
Screen/ 
Baselinea 
Day 1 
On  
Treat b 
Day 8 
End of 
Treat b 
Day 15 
Test of  
Cure c 
Day 22 d 
Start of 
Treat 
Day 
OLE1e 
End of 
Treat 
Day 
OLE15b 
Informed consent/assent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Medical/medication history 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
Otomycosis signs and symptoms 
X 
X 
X 
X 
 
X 
Urine pregnancy test f 
X 
 
 
X 
 
X 
Randomization 
X 
 
 
 
 
 
Dispensation of study drug 
X 
 
 
 
X 
 
Dispensation of subject diary 
X 
 
 
 
X 
 
Collection of subject diary 
 
X g 
X 
 
 
X 
Administration of study drug at site 
X 
 
 
 
X 
 
Weighing of study drug 
X 
X 
X 
 
X 
X 
Collection of study drug 
 
 
X 
 
 
X 
Fungal culture h 
X 
 
X 
X 
 
 
Ear cleaning 
X 
X 
 
 
 
 
AE evaluations 
X 
X 
X 
X 
X 
X 
Concomitant medications review 
X 
X 
X 
X 
X 
X 
a. Procedures for this visit may occur over a 2-day period, if necessary (with Day 1 defined as the first day on which 
study drug is administered). All procedures for this visit must occur before the first administration of study drug 
with the exceptions that AE evaluations and review of concomitant medications will also occur after the start of 
study drug on Day 1. 
b. This visit may occur up to 3 days later than the specified day. 
c. This visit may occur up to 1 day sooner or up to 8 days later than the specified day.  
d. In case of early termination, the assessments planned for the Test of Cure Visit should be performed with the 
exception of fungal culture, which is not required. 
e. This visit will occur on the same day as the final visit of the Randomization Period. 
f. Females of childbearing potential only. 
g. The subject diary will be returned to the subject after review by study staff for documentation of missed and/or 
extra study drug doses. 
h. Samples will be used for growth and identification of fungal organisms as well as susceptibility testing to 
miconazole. Fungal cultures are not required to be taken at Day 15 or at Day 22 for subjects known to have a 
negative fungal culture at Screening/Baseline (assessed after at least 14 days of incubation by the clinical 
laboratory performing the fungal cultures). 
OLE=Open-label Extension; Screen=Screening; Treat=Treatment 
6.1.2 
Study Visits for the Randomization Period 
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/or caregiver’s willingness and 
ability to meet the follow-up requirements of the study will be determined. 
The schedule of visits for Enrollment A is presented in Table 3. Details about study procedures 
and how they are to be performed are presented in Section 7. 


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6.1.2.1 
Screening / Baseline (Day 1) 
This visit may be performed over a period of 2 days if necessary for practical reasons (e.g., if 
study drug cannot reasonably be dispensed until the day after screening procedures are initiated). 
Screening procedures will occur prior to randomization and will include: 
• Informed consent and assent (as applicable) 
• Medical history 
• Prior and concomitant medications 
• 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: 
• Fungal culture 
• Ear cleaning 
• Randomization 
• Weighing of study drug, followed by dispensation of study drug to subject 
• Dispensation of subject diary 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 and to complete the 
subject diary twice daily and to bring their bottle of study drug and the diary to the site 
for their next visit 
6.1.2.2 
On Treatment (Day 8) 
This visit may occur up to 3 days later than the specified day.  
Subjects will be instructed not to administer any study drug on the day of this visit until after the 
visit has occurred, if the visit is scheduled for the morning. If the visit is scheduled for the 
afternoon, subjects will be instructed that the morning dose of the study drug can be administered 
prior to the visit. 
The following procedures and evaluations will occur during this visit: 
• Otomycosis signs and symptoms 


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• Ear cleaning 
• AE evaluation 
• Review of concomitant medications 
• Weighing of study drug and return of the bottle of study drug to the subject 
• Review of subject diary and return of the subject diary to the subject 
• Subjects will be instructed to continue administering study drug and to complete the 
subject diary twice daily up through Day 14, and to bring their bottle of study drug and 
the diary to the site for their next visit 
6.1.2.3 
End of Treatment (Day 15) 
This visit may occur up to 3 days later than the specified day.  
The following procedures and evaluations will occur during this visit: 
• Otomycosis signs and symptoms 
• Fungal culture (not required for subjects known to have a negative fungal culture at 
Screening/Baseline, as assessed after at least 14 days of incubation by the clinical 
laboratory performing the fungal culture) 
• AE evaluation 
• Review of concomitant medications 
• Collection and review of subject diary 
• Collection/weighing of study drug  
6.1.2.4 
Test of Cure (Day 22) 
This visit may occur up to 1 day sooner or up to 8 days later than the specified day. 
The following procedures and evaluations will occur during this visit: 
• Otomycosis signs and symptoms 
• Fungal culture (not required for subjects known to have a negative fungal culture at 
Screening/Baseline, as assessed after at least 14 days of incubation by the clinical 
laboratory performing the fungal culture) 
• AE evaluation 
• Review of concomitant medications 
• Urine pregnancy test (in female subjects of childbearing potential only) 
In case of early termination from the Randomization Period, the procedures planned for the Test 
of Cure Visit with the exception of fungal culture should be performed. 
Subjects who complete the Test of Cure Visit and who have a visual presence of fungal elements 
in at least one ear treated during the Randomization Period will be offered the opportunity to 
participate in the Optional Open-label Extension.  


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6.1.3 
Study Visits for the Optional Open-label Extension 
6.1.3.1 
Start of Treatment (Day OLE1) 
For subjects who opt to participate in the Optional Open-label Extension, this visit will occur on 
the same day as the final visit of the Randomization Period.  
The following procedures and evaluations will occur during this visit: 
• Weighing of study drug (miconazole oil), followed by dispensation to subject 
• Dispensation of subject diary to subject 
• Administration of the first dose of miconazole oil 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 miconazole oil 
• Subjects will be instructed to continue administering miconazole oil and to complete the 
subject diary twice daily for 14 days (i.e., up through Day OLE14) and to bring their 
bottle of miconazole oil and the diary to the site for their next visit 
6.1.3.2 
End of Treatment (Day OLE15) 
For subjects who opt to participate in the Optional Open-label Extension, this visit may occur up 
to 3 days later than the specified day. 
The following procedures and evaluations will occur during this visit: 
• Otomycosis signs and symptoms 
• AE evaluation 
• Review of concomitant medications 
• Collection and review of subject diary 
• Collection/weighing of miconazole oil 
• Urine pregnancy test (in female subjects of childbearing potential only) 
In case of early termination from the Optional Open-label Extension, the procedures planned for 
the Day OLE15 Visit should be performed if possible. 
6.2 
Enrollment B 
6.2.1 
Study Flow Chart 
The study schedule for Enrollment B is presented in Table 4. 


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Table 4: 
Study Schedule: Enrollment B 
Evaluations and Procedures: 
Screening/ Baselinea 
Day B1 
End of Treatment b,c 
Day B15 
Informed consent/assent 
X 
 
Inclusion/exclusion criteria 
X 
 
Medical/medication history 
X 
 
Physical examination 
X 
X  d 
Urine pregnancy test e 
X 
X 
Dispensation of study drug 
X 
 
Dispensation of subject diary 
X 
 
Collection of subject diary 
 
X 
Administration of study drug at site 
X 
 
Weighing of study drug 
X 
X 
Collection of study drug 
 
X 
AE evaluations 
X 
X 
Concomitant medications review 
X 
X 
a. Procedures for this visit may occur over a 2-day period, if necessary (with Day B1 defined as the first day on 
which study drug is administered). All procedures for this visit must occur before the first administration of study 
drug with the exceptions that AE evaluations and review of concomitant medications will also occur after the start 
of study drug on Day B1. 
b. This visit may occur up to 3 days later than the specified day. 
c. In case of early termination, the assessments planned for the End of Treatment Visit should be performed if 
possible. 
d. Physical examination of the treated ear(s) will be performed at the End of Treatment Visit; a more extensive 
physical examination is not required but may be performed if necessary in the judgment of the investigator (e.g., 
to support evaluation of an AE). 
e. Females of childbearing potential only. 
6.2.2 
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/or caregiver’s willingness and 
ability to meet the follow-up requirements of the study will be determined. 
The schedule of visits for Enrollment B is presented in Table 4. Details about study procedures 
and how they are to be performed are presented in Section 7. 
6.2.2.1 
Screening / Baseline (Day B1) 
This visit may be performed over a period of 2 days if necessary for practical reasons (e.g., if 
study drug cannot reasonably be dispensed until the day after screening procedures are initiated). 
Screening procedures will occur prior to dispensation of study drug (miconazole oil) and will 
include: 
• Informed consent and assent (as applicable) 


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• Medical history 
• Prior and concomitant medications 
• Physical examination 
• Urine pregnancy test (in female subjects of childbearing potential only) 
• Determination of subject eligibility for the study 
Subjects who are eligible for the study will undergo the following additional procedures: 
• Weighing of miconazole oil, followed by dispensation to subject 
• Dispensation of subject diary to subject 
• Administration of the first dose of miconazole oil 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 miconazole oil 
• Subjects will be instructed to continue administering miconazole oil and to complete the 
subject diary twice daily for 14 days (i.e., up through Day B14) and to bring their bottle 
of miconazole oil and the diary to the site for their next visit 
6.2.2.2 
End of Treatment (Day B15) 
This visit may occur up to 3 days later than the specified day.  
The following procedures and evaluations will occur during this visit: 
• AE evaluation 
• Review of concomitant medications 
• Collection and review of subject diary 
• Collection/weighing of miconazole oil 
• Urine pregnancy test (in female subjects of childbearing potential only) 
In case of early termination, the procedures planned for the End of Treatment Visit should be 
performed if possible. 
6.3 
Screen Failures 
Subjects in both portions of the study who sign informed consent and are then found not to meet 
all eligibility criteria will be considered screen failures. 
6.4 
Unscheduled Study Visits 
Additional visits may be scheduled in both portions of the study, 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 


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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 
Subjects who require further follow-up for an AE will be followed according to Section 8.4. 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. 
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 (Randomization 
Period of Enrollment A), or when the End of Treatment Visit is completed (Open-label 
Extension of Enrollment A or Enrollment B). Subjects who require further follow-up for an AE 
will be followed according to Section 8.4. 
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 screening/enrolling 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 the 
Randomization Period, or subjects who have not completed the End of Treatment Visit in the 
Optional Open-label Extension or in Enrollment B) in for a final study visit as soon as possible, 
and to arrange for study closeout at the site. 
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 


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specified by the inclusion and exclusion criteria or anticipate the need for any excluded 
concomitant medications. 
7.2 
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. For subjects participating in Enrollment B, a physical examination of the treated 
ear(s) will also be performed at the End of Treatment Visit; a more extensive physical 
examination is not required for these subjects at the End of Treatment Visit but may be 
performed if necessary in the judgment of the investigator (e.g., to support evaluation of an AE). 
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: 
“Over the last 24 hours, have you had itching in your ear?” 
“Over the last 24 hours, has your itching interfered 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?” 
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: 


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Score 
Category 
Description 
0 
None 
No itching 
1 
Mild 
Occasional itch, not interfering with daily activities 
2 
Moderate 
Fairly persistent itch, partially tolerated; sleep is not interrupted 
3 
Severe 
Intolerable, constant itch; 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. Scores will be according to the following scale: 
Score 
Category 
Description 
0 
None 
No debris 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 
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. 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. 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?” 


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“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: 
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 study drug, both ears will be cultured. 
The central laboratory will grow and identify fungal organisms from the sample provided by the 
investigator. The central laboratory will also test the susceptibility of the fungal isolates to 
miconazole. 
7.6 
Ear Cleaning 
At designated visits, the investigator or designee will clean the ear(s) that are being/have been 
treated with study drug, according to the site’s normal procedures. Ear(s) being treated will be 
cleaned at the designated visits even if they appear clear of debris. In cases in which the 
investigator would normally not clean the ear because it appears to be clear, this cleaning may be 
minimal. All ear cleaning will be documented in the eCRF. 
7.7 
Adverse Event Evaluations 
See Section 8. 
7.8 
Randomization 
See Section 9.2. 


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7.9 
Study Drug Administration 
See Section 9.1.1. 
7.10 Treatment Compliance 
Subjects or their caregivers (as appropriate) will complete a diary documenting each study drug 
administration. Additionally, each bottle of study drug will be weighed by the investigator or 
designee before dispensation to the subject and at each visit in which the used bottle is brought to 
the site. 
7.11 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. 
8 
ADVERSE EVENTS 
8.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject 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 (including a clinically 
significant abnormal laboratory finding), 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 
product. 
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. 


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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) 
• 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: 


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• 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. 
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.” 
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 will begin after the subject has signed informed consent and continue up 
through the Test of Cure Visit (Randomization Period) or up through the End of Treatment Visit 
(Optional Open-label Extension or Enrollment B). 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); 


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• 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 (Randomization Period) or up through the End of Treatment Visit (Optional Open-
label Extension or Enrollment B) 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. 
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 final study visit and which is not considered to be of “suspected” 
relationship to study drug does not need to be reported. 


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8.5 
Pregnancy 
Females of childbearing potential, as defined in Section 4.1.1 (Enrollment A) and Section 4.2.1 
(Enrollment B), must use an effective method of contraception from screening up through the 
final study 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. 
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 vehicle oil group, the vehicle oil will not contain miconazole and will instead 
contain a greater amount of refined peanut oil and mineral oil to account for the absence of the 
miconazole. 
Study drug will be supplied in bottles containing ~20 grams 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 study drug 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. 


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If both ears are being treated, the subject will then wait at least 5 minutes, then repeat this 
procedure for the second ear. 
During the Randomization Period, 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 in the Optional Open-label Extension and subjects in 
Enrollment B who have signs and/or symptoms of otomycosis may also be given these 
instructions. 
Subjects in both portions will be asked to avoid bathing or showering for at least 30 minutes after 
applying study drug. 
9.2 
Randomization 
For the Randomization Period, 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 miconazole oil vehicle. 
Randomization is not applicable to either the Optional Open-label Extension of Enrollment A or 
to Enrollment B. 
9.3 
Blinding/Unblinding 
The contents of the study drug (miconazole oil versus vehicle) will be blinded to both the 
investigator (and all study staff) and the subject during the Randomization Period of Enrollment 
A. 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 
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 oil vehicle will be manufactured, packaged and labeled by Hill 
Dermaceuticals, Inc. It will be packaged in dropper bottles, each of which will contain ~20 
grams of study drug. The dropper will dispense approximately 30 mg per drop. 
For the Randomization Period of Enrollment A, the study drug and vehicle will be packaged in 
primary bottle 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 


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subject loses a bottle (lost or damaged), the reserve bottle will be dispensed using a replacement 
process as defined in the randomization plan.  
For the Optional Open-label Extension of Enrollment A and for Enrollment B, the study drug 
will be packaged in a primary bottle that will be dispensed directly to the subject. The dropper 
bottles will be weighed with the cap on prior to dispensing. If the subject loses a bottle (lost or 
damaged), a reserve bottle will be dispensed from the study drug inventory packaged for open-
label use. 
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 grams) 
• 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. 
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.  


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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. 
10 STATISTICAL CONSIDERATIONS 
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. 
10.1 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 
“therapeutic cure”, defined as “mycological cure” plus “clinical cure” for the study ear, at the 
end of the Randomization Period for each subject. Mycological cure is defined as a negative 
mycological culture, and clinical cure is defined as the absence of all otomycosis signs and 
symptoms 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 
Secondary efficacy endpoints will include the following (each having been assessed at the end of 
the Randomization Period for each subject): 
• Percentage of subjects with mycological cure at the Test of Cure Visit. 
• Percentage of subjects with clinical cure at the Test of Cure Visit. 
10.1.3 
Tertiary Efficacy Endpoints 
Tertiary efficacy endpoints will include the following (each having been assessed at the end of 
the Randomization Period for each subject): 
• Percentage of subjects with “modified therapeutic cure” at the Test of Cure Visit, defined 
as mycological cure plus a score of 0 for the clinical sign of fungal elements plus a score 
of 0 or 1 for each of the clinical signs and symptoms of pruritus, debris, and aural 
fullness. 


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• Percentage of subjects with “therapeutic improvement” at the Test of Cure Visit, defined 
as mycological cure plus a score of 0 or 1 for each of the clinical signs and symptoms of 
fungal elements, pruritus, debris, and aural fullness. 
10.1.4 
Safety Endpoint 
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 “therapeutic cure”, defined as “mycological cure” plus “clinical cure” for the study ear. 
Mycological cure is defined as a negative mycological culture, and clinical cure is defined as the 
absence of all otomycosis signs and symptoms based on investigator assessment according to the 
scales for each individual sign or symptom. 
Analysis is based on the following hypothesis:  
H0: pT – pV = 0  
H1: pT - pV > 0.  
where H0 is the null hypothesis, H1 the alternative hypotheses, and pT and pV are percentage of 
subjects with success in the Treatment (miconazole oil) and Vehicle (vehicle oil) groups, 
respectively. Comparisons between groups for the difference in the percentage of subjects 
achieving the primary endpoint of therapeutic cure will be conducted using a chi-square test with 
a 2-sided significance level of 0.05. 
Comparisons will also be conducted similarly between the miconazole oil and vehicle oil groups 
for the secondary endpoints of clinical cure, and mycological cure. 
10.3 Sample Size 
For the Randomization Period, approximately 128 subjects (~64 in each group) are required to 
provide 80% power, using a chi-square test with a 2-sided significance level of 0.05, assuming a 
response rate for the primary efficacy endpoint of 25.0% in the miconazole oil group and 7.1% in 
the vehicle oil group.  
The sample size of 220 subjects for Enrollment A assumes that ~58% of subjects enrolled into 
Enrollment A will have a positive fungal culture at Screening/Baseline and will therefore be 
included in the MITT population. This number may be higher or lower depending on the 
percentage of subjects eligible to be included in the MITT population. 
The estimated sample size of 170 subjects for Enrollment B is not based on statistical 
considerations and is instead based on the achievement of at least 300 subjects who have been 
exposed to miconazole oil for 14 days who are evaluable for safety (see also Section 3.4.2). 


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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. 
10.4.2 
Modified Intent-to-treat Population 
The modified intent-to-treat (MITT) population will be a subset of the ITT population. The 
MITT population will include subjects in the ITT population with a positive fungal culture at 
Screening/Baseline. The MITT population will be the primary population to assess efficacy. 
10.4.3 
Per Protocol Population 
The per protocol (PP) population will be a subset of the MITT population and will include all 
subjects who complete the Test of Cure visit without any major protocol violations. The PP 
population will include subjects in the MITT population who did not meet 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) 
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. 
10.4.4 
Safety Population 
Two safety populations will be defined. 
The Randomization Period safety population will include all subjects who received at least one 
dose of study drug and had at least one post-Baseline safety assessment during the 
Randomization Period.  


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The Open Label safety population will include all subjects who received at least one dose of 
miconazole oil and had at least one post-Baseline safety assessment during the Optional Open-
label Extension or Enrollment B. 
Safety analyses for the Randomization Period will be performed using the Randomization Period 
safety population. Safety analyses for the Optional Open-label Extension and Enrollment B will 
be combined and presented using the Open Label safety population. 
10.5 Statistical Methods 
10.5.1 
Efficacy Analyses 
The primary population for efficacy analyses will be the MITT population (see Section 10.4). 
Efficacy analyses will also be performed on the ITT and the PP populations and will be 
considered supportive. 
The primary analysis will be conducted once Enrollment A is complete. 
The number and percent of subjects who demonstrate a positive outcome for the primary efficacy 
outcome as well as all secondary and tertiary efficacy outcomes will be presented. 
The primary endpoint, defined as the percentage of subjects at the Test of Cure Visit with 
“therapeutic cure”, will be compared between groups using a chi-square test with a 2-sided 
significance level of 0.05. 
The secondary endpoints will be analyzed analogously to the primary endpoint. 
In Enrollment A in cases of bilateral otomycosis, if only 1 ear has a positive fungal culture at 
Screening/Baseline, that ear will be used as the study ear for efficacy analyses. If both ears have 
a positive fungal culture at Screening/Baseline, the ear with the worse infection at 
Screening/Baseline, as assessed by the investigator by taking into account clinical signs and 
symptoms, will be used as the study ear for efficacy analyses. If both ears have a positive fungal 
culture at Screening/Baseline and 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 and also for clinical 
cure, modified therapeutic cure, and therapeutic improvement; each at Day 15 will be 
summarized using the ITT population for both the Randomization Period and the Optional Open-
label Extension. 
10.5.1.1 
Multiple Comparison/Multiplicity 
The overall Type I error will be controlled by requiring the primary efficacy endpoint to be 
statistically significant. Specifically, failure of the primary efficacy endpoint will invalidate the 
statistical significance of the secondary efficacy endpoints. 


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Evaluation of the secondary efficacy endpoints will use a gated sequential procedure in order to 
control for multiplicity. These tests will be performed for only the MITT population. The testing 
process will terminate whenever a statistical test for a step is not significant, i.e., any subsequent 
test will be considered not significant. The order of testing is: 
1. Percentage of subjects with mycological cure at the Test of Cure Visit. 
2. Percentage of subjects with clinical cure at the Test of Cure Visit. 
10.5.2 
Safety Analyses 
Safety summaries will be conducted using two safety populations (see Section 10.4.4). 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. 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. 
Summaries will be provided separately for the blinded and unblinded portions. Specifically, 
summaries will be provided by treatment group for the Randomization Period using the 
Randomization Period safety population, and for all open-label subjects using the Open Label 
safety population. 
All information pertaining to AEs noted during the study will be listed by study portion 
(Enrollment A or Enrollment B), study period (Randomization or Optional Open-label), as 
applicable, 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 
MITT, PP, and safety populations and will be supported with individual subject data listings. 
10.5.4 
Missing Data 
Missing data will be imputed as treatment failures for the primary and secondary efficacy 
analyses. 
Missing data otherwise will not be imputed. 


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10.5.5 
Sensitivity Analyses 
In order to explore the effects of missing data, sensitivity analyses will be performed on the 
primary endpoint. The first will be a tipping point analysis using the MITT population. The 
second sensitivity analysis will be analogous to the primary but will be performed on the ITT 
population. 
10.5.6 
Subgroup Analyses 
Descriptive summaries on the primary and secondary endpoints will be included for the 
following subgroups of gender, age, ethnicity, race, and fungal organism isolated at 
Screening/Baseline. 
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Institutional Review Board 
The protocol, informed consent documents, 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. 


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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 
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. 


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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 
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 
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. Data reconciliation will be performed between the EDC data and the 
external data reported by the central laboratory. Any discrepancies in the data will be queried 
first with the clinical site and second with the central laboratory. 


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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. 
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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12 REFERENCES 
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otomycosis. J Laryngol Otol. 1986 Aug;100(8):867-73. 
Kiakojuri K, Roushan MR, Sepidgar SA. Suction clearance and 2% topical miconazole versus 
the same combination with acidic drops in the treatment of otomycosis. Southeast Asian J Trop 
Med Public Health. 2007 Jul;38(4):749-53. 
Musaji N. Antifungal drug resistance: not all azoles are equal. Expert Rev Anti Infect Ther. 2010 
May;8(5):515-6. 
Navaneethan N, YaadhavaKrishnan RP. Type of Antifungals: Does it Matter in Empirical 
Treatment of Otomycosis? Indian J Otolaryngol Head Neck Surg. 2015 Mar;67(1):64-7. 
Paller AS, Nimmagadda S, Schachner L, Mallory SB, Kahn T, Willis I, Eichenfield LF. 
Fluocinolone acetonide 0.01% in peanut oil: therapy for childhood atopic dermatitis, even in 
patients who are peanut sensitive. J Am Acad Dermatol. 2003 Apr;48(4):569-77. 
Stern JC, Shah MK, Lucente FE. In vitro effectiveness of 13 agents in otomycosis and review of 
the literature. Laryngoscope. 1988 Nov;98(11):1173-7. 
Vandenbosch D, Bink A, Govaert G, Cammue BP, Nelis HJ, Thevissen K, Coenye T. 
Phytosphingosine-1-phosphate is a signaling molecule involved in miconazole resistance in 
sessile Candida albicans cells. Antimicrob Agents Chemother. 2012 May;56(5):2290-4. 
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 
4;28(2):202-11. 
Yunginger JW, Calobrisi SD. Investigation of the allergenicity of a refined peanut oil-containing 
topical dermatologic agent in persons who are sensitive to peanuts. Cutis. 2001 Aug;68(2):153-5. 


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13 SUMMARY OF PROTOCOL AMENDMENTS 
13.1 Amendment 1 Version 2 04 February 2020 
The purpose of this amendment was to remove the following secondary endpoints: 
• Percentage of subjects with mycological cure at the Test of Cure Visit 
• Percentage of subjects with clinical cure at the Test of Cure Visit. 
No detailed summary of changes was prepared for Version 2 because the prior version (Version 
1, 28 January 2020) was internal only. 
13.2 Amendment 2 Version 3 18 May 2020 
This amendment reflects updates and revisions to the protocol resulting from an End-of-Phase 2 
meeting with FDA and changes in sponsor strategy for the development of miconazole oil. An 
overview of major changes is as follows. 
• An optional open-label extension was added to the study to allow subjects the option to be 
treated with active drug (miconazole oil) if they have a visual presence of fungal elements in 
at least one ear following randomized treatment. 
• A second portion was added to the study (called Enrollment B), which will commence after 
completion of the first portion (called Enrollment A) in order to gather safety information for 
miconazole oil in additional subjects. Because the purpose of Enrollment B is safety, subjects 
in Enrollment B are not required to have a diagnosis of otomycosis. 
• Secondary and tertiary efficacy endpoints were added. 
Clarifications and minor changes to study conduct and statistical analyses were also made. 
A more complete summary of changes from the prior version is provided below. Insertions are 
bolded. Deletions are struck through. For sections that are new or have been completely revised, 
only a short description is provided. 
 
Location 
Change 
Rationale 
Header  
18 May 2020 / Version 304 Feb 2020 / Version 
2 
Update to new version and date 
Title page, Synopsis 
(Study Title) 
Randomized, Double-blind, Phase III Study of 
the Efficacy and Safety of Miconazole Oil 
versus Vehicle Oil in the Treatment of 
Otomycosis, Followed by an Open-label 
Safety Evaluation 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion to gather 
additional safety information in a 
greater number of subjects 
Title page  
18 May 2020 / Version 304 February 2020 / 
Version 2 
Previous versions: 
28 January 2020 / Version 1 (internal only) 
04 February 2020 / Version 2 
Update to new version and date 


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Rationale 
Protocol Approval page 
18 May 202004 February 2020 
Update to new date 
Study Acknowledgement 
page 
Version 3Version2 
Update to new version 
Synopsis (Study 
Center(s)) 
Up to 2015 study centers 
Allowance for additional study 
centers 
Synopsis (Number of 
Subjects Planned) 
Approximately 390220 (estimated); the actual 
number enrolled will be the numberthat needed 
to achieve at least 128 subjects eligible to be 
included in the modified intent-to-treat (MITT) 
population, defined as all subjects who were 
randomized, dispensed study drug, and with a 
clinical diagnosis of otomycosis confirmed by a 
positive fungal culture at Screening/Baseline, 
and to achieve at least 300 subjects exposed 
to miconazole oil for 14 days who are 
evaluable for safety. Thus, a higher or lower 
number than estimated may be enrolled, with 
enrollment continuing until depending on the 
required numberspercentage of subjects have 
been achievedeligible to be included in the 
MITT population. 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion; change 
to definition of MITT population in 
response to FDA comment at End-
of-Phase 2 meeting; clarification that 
enrollment will continue until the 
required numbers of subjects have 
been achieved 
Synopsis (Study Period) 
Study Period: 
The study duration for each subject will be up to 
approximately 30 days, which includes 14 days 
of treatment and 8 days of follow-up, plus a 
visit window of up to 8 additional days after the 
scheduled day for the follow-up (Test of Cure) 
visit. 
Rename section to Study Duration 
and move to later in the protocol 
(after Study Visits) for clarity of 
presentation 
Synopsis (Objectives), 
Section 2 (Study 
Objectives) 
• 
Confirm the efficacy of miconazole oil 
compared with vehicle over a 14-day 
treatment duration in subjectspatients with 
otomycosis 
• 
Assess the safety of miconazole oil over a 
14-day treatment duration in patients with 
otomycosis 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion to gather 
additional safety information in a 
greater number of subjects (some of 
whom will not have otomycosis); 
consistency of terminology 
throughout protocol 
Synopsis (Design and 
Methodology) 
This study will be conducted in 2 separate, 
sequential portions: 
1. Enrollment A, which will consist of 2 
treatment periods as follows and will be 
conducted in subjects with otomycosis: 
a. Ais a randomized, double-blind, parallel-
group treatment period. This treatment 
period will be referred to as the 
“Randomization Period” and will be 
followed by: 
b. An optional, open-label treatment period 
with miconazole oil. This treatment period 
will be referred to as the "Optional Open-
label Extension." 
2. Enrollment B, which will commence after 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion 


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Change 
Rationale 
completion of Enrollment A and will consist 
of open-label treatment with miconazole oil 
in subjects who will not be required to have 
signs and symptoms of otomycosis. 
Enrollment A 
The study will start with Enrollment A, in 
which anto be conducted at up to 15 study 
centers in the US. An estimated 220 male or 
female subjects with otomycosis will receive 
study drug, although this number may be higher 
or lower depending on the percentage of 
subjects eligible to be included in the MITT 
population. Subjects will be randomly assigned 
in a 1:1 ratio to receive miconazole oil or 
vehicle, for 14 days. The study drug will be 
[administered as 5 drops per ear at ~30 mg per 
drop instilled into the external ear canal of the 
ear(s) affected by otomycosis].  
Randomization Period 
During the Randomization Period, bothBoth 
the subject and the investigator and study staff 
will be blinded as to the contents of the study 
drug. 
Synopsis (Design and 
Methodology, 
Randomization Period), 
Section 3.1.1 
(Randomization Period) 
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 be randomized, 
and study drug will be weighed and 
dispensed to the subject along with a subject 
diary. The subject will then begin treatment… 
The subject will then leave the clinic and 
continue to administer the study drug and to 
complete the subject diary twice per day as 
instructed. 
Completeness in description of study 
procedures 
Synopsis (Design and 
Methodology, 
Randomization Period), 
Section 3.1.1 
(Randomization Period) 
Subjects will return to the clinic on Day 8 for 
the On Treatment Visit, at which time a clinical 
evaluation of the signs and symptoms of 
otomycosis, a cleaning of the affected ear(s) 
(following the site’s normal procedures), a 
review of the subject diary, and an assessment 
of AEs and concomitant medications will be 
performed. Subjects will continue to administer 
the study drug and to complete the subject 
diary twice per day, … 
Completeness in description of study 
procedures 
Synopsis (Design and 
Methodology, 
Randomization Period), 
Section 3.1.1 
(Randomization Period) 
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 and a fungal culture of the affected 
ear(s) will be performed; however, a fungal 
culture will not be required at this visit for 
subjects known to have a negative fungal 
culture at Screening/Baseline, as assessed 
after at least 14 days of incubation by the 
Elimination of unnecessary fungal 
culture in situations in which this 
culture will not contribute to the 
evaluation of efficacy; completeness 
in description of study procedures 
procedure 


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clinical laboratory performing the fungal 
culture. AEs and concomitant medications will 
also be assessed, and the subject will return all 
unused study drug along with the completed 
subject diary. 
Synopsis (Design and 
Methodology, 
Randomization Period), 
Section 3.1.1 
(Randomization Period) 
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 a fungal culture of the affected 
ear(s) will be performed; however, a fungal 
culture will not be required at this visit for 
subjects known to have a negative fungal 
culture at Screening/Baseline, as assessed 
after at least 14 days of incubation by the 
clinical laboratory performing the fungal 
culture. AEs and concomitant medications will 
also be assessed. A urine pregnancy test will be 
performed in women of childbearing potential. 
Elimination of unnecessary fungal 
culture in situations in which this 
culture will not contribute to the 
evaluation of efficacy 
Synopsis (Design and 
Methodology, Optional 
Open-label Extension) 
Optional Open-label Extension 
Subjects who either complete the 
Randomization Period of the study (up 
through the Test of Cure Visit), or who are 
prematurely discontinued from study 
treatment during the Randomization Period 
due to worsening… 
…The subject will return all unused 
miconazole oil along with the completed 
subject diary. 
Addition of entire section to reflect 
addition to the study of an optional 
open-label extension  
Synopsis (Design and 
Methodology, 
Enrollment B) 
Enrollment B 
Enrollment B will begin at or after the 
conclusion of Enrollment A. … 
… A urine pregnancy test will be performed 
in women of childbearing potential. 
Addition of entire section to reflect 
addition to the study of Enrollment 
B portion of study 
Synopsis (Study Visits) 
Enrollment A 
Randomization Period 
• 
Day 1: Screening/Baseline (1 visit); 
• 
Day 8: On Treatment (1 visit); 
• 
Day 15: End of Treatment (1 visit); 
• 
Day 22: Test of Cure (1 visit) 
Optional Open-label Extension: 
• 
Day OLE1 (which will occur while 
the subject is already onsite for the 
Test of Cure or Early Termination 
Visit for the Randomization Period); 
• 
Day OLE15 (1 visit) 
Enrollment B 
• 
Day B1: Screening/Baseline (1 visit); 
• 
Day B15: End of Treatment (1 visit) 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion; clarity of 
presentation 
Synopsis (Study 
Study DurationStudy Period: 
Rename section to Study Duration 


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Rationale 
Duration) 
Enrollment A 
During Enrollment A, theThe study duration 
for each subject who participates only in the 
Randomization Period will be up to 
approximately 3130 days, which includes up to 
1 day for screening (if screening procedures 
need to be initiated the day before 
treatment), 14 days of treatment, and 8 days of 
follow-up, plus a visit window of up to 8 
additional days after the scheduled day for the 
follow-up (Test of Cure) Visitvisit. 
The study duration for each subject who 
participates in both the Randomization 
Period and the Optional Open-label 
Extension will be up to approximately 48 
days, which includes up to 31 days for the 
Randomization Period followed by up to 17 
days for the Optional Open-label Extension 
(which includes a visit window of up to 3 
additional days after the 14-day treatment to 
complete the final study visit). This study 
duration takes into account that the Day 
OLE1 procedures will occur while the 
subject is already onsite for the Test of Cure 
or Early Termination Visit for the 
Randomization Period. 
Enrollment B 
In Enrollment B, the study duration for each 
subject will be up to 19 days, which includes 
up to 1 day for screening (if screening 
procedures need to be initiated the day 
before treatment), 14 days of treatment, and 
a 1-day final study visit after the 14-day 
treatment (which has a visit window of up to 
3 additional days). 
and move to after the Study Visits 
section of Synopsis for clarity of 
presentation; allowance for 1 
additional day at screening for 
investigator flexibility in initiating 
screening procedures; addition to the 
study of an optional open-label 
extension and an Enrollment B 
portion 
Synopsis (Key Inclusion 
Criteria) 
Enrollment A 
Male or non-pregnant, non-lactating females 
with a clinical diagnosis of uncomplicated 
otomycosis of the external ear only, with an 
intact tympanic membrane in the ear(s) to be 
treated with study drug, who are in general 
good health… 
Enrollment B 
Male or non-pregnant, non-lactating females 
with an intact tympanic membrane in the 
ear(s) to be treated with study drug, who are 
in general good health… 
Addition of entire subsection to 
reflect the addition to the study of an 
Enrollment B portion with different 
eligibility criteria; clarification as to 
ear(s) for which intact tympanic 
membrane is required 
Synopsis (Key Exclusion 
Criteria) 
Enrollment A 
Subjects with any other dermatoses or 
conditions of the ear that may interfere with the 
evaluation of otomycosis or with safety 
evaluations, including concomitant otic 
Clarity; addition of entire subsection 
to reflect the addition to the study of 
an Enrollment B portion with 
different eligibility criteria; 
clarification of exclusion criterion 


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infections…recurrent otomycosis that has… 
Enrollment B 
Subjects with any other dermatoses or 
conditions of the ear that may interfere with 
safety evaluations, including concomitant otic 
infections... 
about otomycosis that has been 
unresponsive to previous antifungal 
treatment 
Synopsis (Reference 
Product…) 
Reference Product, Dose, and Mode of 
Administration (Enrollment A Only): 
Clarification that this section is now 
only applicable to Enrollment A 
Synopsis (Endpoints) 
Secondary Efficacy Endpoints 
• 
Percentage of subjects with mycological 
cure… 
Tertiary Efficacy Endpoints 
• 
Percentage of subjects with “modified 
therapeutic cure” at the Test of Cure 
Visit, defined as… 
Addition of secondary and tertiary 
efficacy endpoints  
Synopsis (Statistical 
Analyses) 
Descriptive statistics will also be presented for 
the percentages of subjects by treatment group 
with success at each secondary and tertiary 
endpoint, and for each sign or symptom…  
Addition of secondary and tertiary 
efficacy endpoints 
Synopsis (Statistical 
Analyses) 
In Enrollment A in cases of bilateral 
otomycosis, the ear with… 
Clarification that this statement is 
now only applicable to Enrollment A 
Synopsis (Statistical 
Analyses) 
For the primary efficacy endpoint, percentages 
of subjects with therapeutic cure at the Test of 
Cure Visit will be compared using a chi-square 
test with a 2-sided significance level of 0.05. 
Comparisons will be conducted in a similar 
manner between the miconazole oil and 
vehicle oil groups for the secondary 
endpoints of clinical cure and mycological 
cure. Missing data will be imputed as 
treatment failures for the primary and 
secondary efficacy analyses; missing data 
otherwise will not be imputed. 
Addition of secondary and tertiary 
efficacy endpoints; addition for 
completeness of statement about the 
handling of missing data 
Synopsis (Statistical 
Analyses) 
The primary population for all efficacy analyses 
will be the MITT population, defined as all 
subjects who were randomized with a positive 
fungal culture at Screening/Baseline. 
Addition of an optional open-label 
extension for which the ITT 
population will be used for efficacy 
analyses 
Synopsis (Statistical 
Analyses) 
TwoThe primary population for all safety 
populations will be used for safety analyses. 
The first will be the Randomization Period 
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 during the Randomization Period; 
this population will be used for safety data 
for the Randomization Period. The second 
will be the Open Label safety population, 
defined as all subjects who received at least 
one dose of miconazole oil and had at least 
one post-Baseline safety assessment during 
the Optional Open-label Period; this 
Change to presentation of safety 
information because of the addition 
of an optional open-label extension 
and an open-label Enrollment B 
portion of the study 


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Rationale 
population will be used for safety data for the 
Optional Open-label Extension and 
Enrollment B. 
Synopsis (Statistical 
Analyses) 
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. … All reported serious AEs 
(SAEs)SAEswill 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. 
 
Change to presentation of safety 
information because of the addition 
of an optional open-label extension 
and an open-label Enrollment B 
portion of the study; corrections to 
use of abbreviations 
Synopsis (Sample Size) 
For the Randomization Period of Enrollment 
A, approximatelyApproximately 128 subjects 
(~64 in each group) are required to provide 80% 
power,… 
The sample size of 220 subjects for Enrollment 
Athis study assumes that ~58% of subjects 
enrolled into Enrollment Athe study will have a 
positive fungal culture at Screening/Baseline 
Clarification that this statement is 
now only applicable to the 
Randomization Period of Enrollment 
A 
Synopsis (Sample Size) 
The overall study sample size of ~390 
subjects is the total number of study subjects 
estimated to achieve at least 300 subjects 
exposed to miconazole oil for 14 days who are 
evaluable for safety. A higher or lower 
number of total subjects may be enrolled in 
order to achieve the required total numbers 
of subjects for each of Enrollment A and 
Enrollment B. 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion 
List of Abbreviations 
LOCF Last observation carried forward 
Change to method for handling 
missing data in response to FDA 
comment at End-of-Phase 2 meeting  
Section 1.2 (Study 
Purpose) 
During the Randomization Period of the 
Enrollment A portion of the study, aA 14-day 
regimen of twice-daily administration of 2% 
miconazole oil will be compared with the same 
treatment regimen using the product vehicle. 
During the Optional Open-label Extension of 
the Enrollment A portion and the Enrollment 
B portion of the study, a 14-day regimen of 
twice-daily administration of 2% miconazole 
oil will be administered in an open-label 
fashion in order to gather safety information 
in additional subjects. 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion 
Section 3 (Study Design) 
This study will be conducted in 2 separate, 
sequential portions (see also Figure 1 for a 
schematic diagram of the study design): 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion  


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1. Enrollment A, which will consist of 2 
treatment periods as follows and will be 
conducted in subjects with otomycosis: 
a. Ais a randomized, double-blind, parallel-
group treatment period. This treatment 
period will be referred to as the 
“Randomization Period” and will be 
followed by: 
b. An optional, open-label treatment period 
with miconazole oil. This treatment period 
will be referred to as the "Optional Open-
label Extension." 
2. Enrollment B, which will commence after 
completion of Enrollment A and will consist 
of open-label treatment with miconazole oil 
in subjects who will not be required to have 
signs and symptoms of otomycosis. 
Section 3 (Study Design) 
Figure 1 Diagram of Study Design… 
Addition of figure and footnotes for 
clarity about study design 
incorporating the addition to the 
study of an optional open-label 
extension and Enrollment B portion  
Section 3 (Study Design) 
3.1 Enrollment A 
The study will start with Enrollment A, in 
which anto be conducted at up to 15 study 
centers in the US. An estimated 220 male or 
female subjects with otomycosis will receive 
study drug, although this number may be higher 
or lower depending on the percentage of 
subjects eligible to be included in the modifed 
intent to treat (MITT) population (see Section 
10.4.2). Subjects will be randomly assigned in a 
1:1 ratio to receive miconazole oil or vehicle, 
for 14 days. The study drug will be 
[administered as 5 drops per ear at ~30 mg per 
drop instilled into the external ear canal of the 
ear(s) affected by otomycosis].  
3.1.1 Randomization Period 
During the Randomization Period, bothBoth 
the subject and the investigator and study staff 
will be blinded as to the contents of the study 
drug. 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion 
Section 3 (Study Design) 
3.1.2 Optional Open-label Extension 
Subjects who either complete the 
Randomization Period of the study (up 
through the Test of Cure Visit), or who are 
prematurely discontinued from study 
treatment during the Randomization Period 
due to worsening… 
…The purpose of the Optional Open-label 
Extension is safety and to provide supportive 
evidence of efficacy. Efficacy assessments will 
Addition of entire section to reflect 
addition to the study of an optional 
open-label extension  


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include assessments of clinical signs and 
symptoms of otomycosis. Safety assessments 
will include AEs. 
Section 3 (Study Design) 
3.2 Enrollment B 
Enrollment B will begin at or after the 
conclusion of Enrollment A. … 
…Safety assessments will include AEs. 
Addition of entire section to reflect 
addition to the study of Enrollment 
B portion of study 
Section 3.3 (Number of 
Subjects) 
3.33.1 Number of Subjects 
Approximately 390 total subjects are 
estimated to be enrolled into the study (~220 
subjects estimated for Enrollment A and 
~170 subjects estimated for Enrollment B) as 
described in Section 3.3.1 for Enrollment A 
and in Section 3.3.2 for Enrollment B. 
3.3.1 Enrollment A 
An estimated 220 eligible subjects are planned 
to be enrolled in Enrollment A in order to 
achieve at least 128 evaluable subjects (i.e., 
included in the MITT population, defined as 
those who were randomized, dispensed study 
drug, and with a clinical diagnosis of 
otomycosis confirmed by a positive fungal 
culture at Screening/Baseline). The number of 
subjects who are enrolled may be higher or 
lower than 220 depending on the percentage of 
subjects eligible to be included in the MITT 
population; enrollment in Enrollment A will 
continue until the required numbers of 
subjects have been achieved. 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion; change 
to definition of MITT population in 
response to FDA comment at End-
of-Phase 2 meeting; clarification that 
enrollment in Enrollment A will 
continue until the required numbers 
of subjects have been achieved 
Section 3.3 (Number of 
Subjects) 
3.3.2 Enrollment B 
An estimated 170 eligible subjects are 
planned to be enrolled in order to achieve at 
least 300 total subjects in the study… 
… Enrollment will continue into Enrollment 
B until the required number of subjects 
exposed to miconazole oil for 14 days and 
evaluable for safety has been achieved. 
Addition of entire section to reflect 
addition to the study of Enrollment 
B portion of study 
Section 3.4 
(Investigators) 
3.43.2 Investigators 
The study will be conducted at up to 2015 
investigative sites located in the US. 
Allowance for additional 
investigative sites 
Section 3.5 (Study 
Duration) 
3.53.3 Study Duration 
3.5.1 Enrollment A 
A diagram of the study duration for each 
subject participating in Enrollment A is 
presented in Figure 2. 
During Enrollment A, theThe study duration 
for each subject who participates only in the 
Randomization Period of the study will be up 
to approximately 3130 days, which includes up 
to 1 day for screening (if screening 
procedures need to be initiated the day 
Allowance for 1 additional day at 
screening for investigator flexibility 
in initiating screening procedures; 
addition to the study of an optional 
open-label extension 


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before treatment), 14 days for treatment, and 
8 days of follow-up, (including the visit 
window of up to 8 additional days after the 
scheduled day to complete the final Test of 
Cure Visitvisit). 
The study duration for each subject who 
participates in both the Randomization 
Period and Optional Open-label Extension 
will be up to approximately 48 days, which 
includes up to 31 days for the Randomization 
Period followed by up to 17 days for the 
Optional Open-label Extension (which 
includes a visit window of up to 3 additional 
days after the 14-day treatment to complete 
the final study visit). This study duration 
takes into account that the Day OLE1 
procedures will occur while the subject is 
already onsite for the Test of Cure or Early 
Termination Visit for the Randomization 
Period. 
Section 3.5 (Study 
Duration) 
Figure 2: Diagram of Study Duration for 
Enrollment A… 
Addition of figure to clarify study 
duration after addition to the study 
of an optional open-label extension 
Section 3.5 (Study 
Duration) 
3.5.2 Enrollment B 
A diagram of the study duration for each 
subject participating in Enrollment B is 
presented in Figure 3. 
In Enrollment B, the study duration for each 
subject will be up to 19 days, which includes 
up to 1 day for screening (if screening 
procedures need to be initiated the day 
before treatment), 14 days of treatment, and 
a 1-day final study visit after the 14-day 
treatment (which has a visit window of up to 
3 additional days). 
Addition to the study of an 
Enrollment B portion; allowance for 
1 additional day at screening for 
investigator flexibility in initiating 
screening procedures 
Section 3.5 (Study 
Duration) 
Figure 3: Diagram of Study Duration for 
Enrollment B… 
Addition of figure to clarify study 
duration after addition to the study 
of an Enrollment B portion 
Section 4 (Study 
Subjects) 
4.1 Enrollment A 
4.1.14.1 Inclusion Criteria 
In order to be eligible for Enrollment Athe 
study, subjects… 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion 
Section 4 (Study 
Subjects) 
4.1.24.2 Exclusion Criteria 
Subjects meeting any of the following criteria 
will not be eligible for Enrollment Athe study: 
1. Any other dermatoses or conditions of the ear 
that may interfere with the evaluation of 
otomycosis or with safety evaluations, 
including concomitant otic infections (including 
bacterial infection) other than otomycosis that 
require antimicrobial treatment, disease that has 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion; 
clarification of exclusion criteria #1 
and #7; addition of exclusion 
criterion #10 


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spread beyond the external ear(s), or pre-
existing skin atrophy of the affected ear(s) that 
will be treated with study drug… 
7. OtomycosisRecurrent otomycosis that has 
been unresponsive to previous antifungal 
treatment… 
10. Participation in the sponsor’s previous 
miconazole oil Study HD-MCZ-PHII-
DRF062016 unless the subject was enrolled 
into either the vehicle or the 7-day 
miconazole oil group of that study. 
Section 4 (Study 
Subjects) 
4.2 Enrollment B 
4.2.1 Inclusion Criteria 
In order to be eligible for Enrollment B… 
… 
4.2.2 Exclusion Criteria 
Subjects meeting any of the following 
criteria… 
…9. Previous participation in Enrollment A 
of this study, unless the subject is known 
never to received active treatment 
(miconazole oil) during Enrollment A. 
Addition of entire section to reflect 
addition to the study of Enrollment 
B portion of study 
Previous Section 4.3 
(Subject Completion) 
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. 
Deletion of redundant section 
(presented also in Section 6.7) 
Section 4.3 (Subject 
Discontinuation) 
4.34.4 Subject Discontinuation 
A subject MAY be withdrawn from the study… 
• 
Failure to follow required study procedures 
• 
For subjects participating in Enrollment 
A, a negative fungal culture at 
Screening/Baseline (as assessed after at 
least 14 days of incubation by the clinical 
laboratory performing the fungal 
cultures) 
…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 
(Randomization Period) or the End of 
Treatment Visit (Optional Open-label 
Extension or Enrollment B) should be 
performed, and an effort should be made to 
collect all study drug. A fungal culture is not 
required for subjects who are prematurely 
discontinued from the study. 
For Enrollment A, dueDue to the time 
required to obtain fungal culture results from 
Screening/Baseline, subjects will be enrolled 
Provision for subjects with a 
negative fungal culture to be 
discontinued from the study; 
addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion; 
elimination of unnecessary fungal 
culture in situations in which this 
culture will not contribute to the 
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into the study based on a clinical diagnosis of 
otomycosis (including the visible presence of 
fungal elements at Screening/Baseline), without 
a requirement for a positive fungal culture. 
Subjects who end up with a negative 
Screening/Baseline fungal culture arewill not 
required to be discontinued from the study, but 
these subjects will not be included in the 
primary efficacy analysis. Because the 
sponsor’s goal is to have at least 128 subjects in 
the MITT population (see Section 10.4.2), the 
total number of subjects enrolled into 
Enrollment Athe study may be higher or lower 
than 220, depending on the percentage of 
subjects who are eligible to be included in the 
MITT population. 
Section 4.3 (Subject 
Discontinuation) 
Subject discontinuations will be documented 
clearly on the applicable electronic case report 
form (eCRF). Subjects who discontinue from 
the study will not be replaced, but additional 
subjects may be enrolled and randomized into 
Enrollment A if it appears that the estimated 
number of subjects for Enrollment A 
(approximately 220) is insufficient to meet the 
sponsor’s goal of having at least 128 subjects in 
the MITT population. After completion of 
Enrollment A, additional subjects (i.e., 
exceeding the 390 subjects total for the study) 
may be enrolled into Enrollment B if it 
appears that the estimated total number of 
study subjects is insufficient to achieve at 
least 300 subjects who have been exposed to 
miconazole oil for 14 days who are evaluable 
for safety. 
Addition to the study of an optional 
open-label extension and an open-
label Enrollment B portion 
Section 4.4 (Subjects 
Lost to Follow-up) 
4.44.5 Subjects Lost to Follow-up 
Renumbering of section due to 
revisions above 
Section 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. 
5.1 Enrollment A 
In addition to all concomitant therapies, all 
therapies within 3 months prior to Day 1 
must also be recorded on the eCRF. 
5.1.15.1 Permitted Medications 
Therapies… 
5.1.25.2 Prohibited Medications 
Other than… 
Reorganization of information 
because of addition to the study of 
an Enrollment B portion 
Section 5 (Concomitant 
Therapies) 
5.2 Enrollment B 
In addition to all concomitant therapies… 
…Prohibited treatments include systemic 
antifungal therapy and warfarin. 
Addition of entire section because of 
addition to the study of an 
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Section 6 (Study 
Schedule) 
6.1 Enrollment AStudy Flow Chart 
6.1.1 Study Flow Chart 
The study schedule for Enrollment A is 
presented in Table 3. 
Table 3: Study Schedule: Enrollment A 
Addition to the study of an 
Enrollment B portion 
Section 6 (Study 
Schedule) 
See revised Table 3 below and footnotes 
Allowance for 1 additional day at 
screening for investigator flexibility 
in initiating screening procedures; 
addition to the study of an optional 
open-label extension and an 
Enrollment B portion; clarification 
for completeness about return of the 
subject diary to the subject after 
review on Day 8 of Enrollment A; 
elimination of unnecessary fungal 
culture in situations in which this 
culture will not contribute to the 
evaluation of efficacy 
Section 6 (Study 
Schedule) 
6.1.26.2 Study Visits for the Randomization 
Period 
…The schedule of visits for Enrollment A is 
presented in Table 3. 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion 
Section 6 (Study 
Schedule) 
6.1.2.16.2.1 Screening / Baseline (Day 1) 
This visit may be performed over a period of 
2 days if necessary for practical reasons (e.g., 
if study drug cannot reasonably be dispensed 
until the day after screening procedures are 
initiated). 
Renumbering of section; allowance 
for 1 additional day at screening for 
investigator flexibility in initiating 
screening procedures; addition of 
visit day (Day 1) for clarity of 
presentation 
Section 6.1.2.1 
(Screening/Baseline 
(Day 1)) 
• 
Subjects will be instructed to continue 
administering study drug and to complete 
the subject diary twice daily and to bring 
their bottle of study drug and the diary to 
the site for their next visit 
Mention of subject diary for 
completeness 
Section 6 (Study 
Schedule) 
6.1.2.26.2.2 On Treatment (Day 8) 
Renumbering of section; addition of 
visit day (Day 8) for clarity 
Section 6.1.2.2 (On 
Treatment (Day 8)) 
• 
Review of subject diary and return of the 
subject diary to the subject 
• 
Subjects will be instructed to continue 
administering study drug and to complete 
the subject diary twice daily up through 
Day 14, and to bring their bottle of study 
drug and the diary to the site for their next 
visit 
Mention of subject diary and its 
return to the subject for 
completeness 
Section 6 (Study 
Schedule) 
6.1.2.36.3 End of Treatment (Day 15) 
Renumbering of section; addition of 
visit day (Day 15) for clarity 
Section 6.1.2.3 (End of 
Treatment (Day 15)), 
Section 6.1.2.4 (Test of 
Cure (Day 22)) 
• 
Fungal culture (not required for subjects 
known to have a negative fungal culture 
at Screening/Baseline, as assessed after at 
least 14 days of incubation by the clinical 
laboratory performing the fungal 
Elimination of unnecessary fungal 
culture in a situation in which this 
culture will not contribute to the 
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culture) 
Section 6 (Study 
Schedule) 
6.1.2.46.4 Test of Cure (Day 22) 
Renumbering of section; addition of 
visit day (Day 22) for clarity 
Section 6.1.2.4 (Test of 
Cure (Day 22)) 
In case of early termination from the 
Randomization Period, the procedures planned 
for the Test of Cure Visit with the exception of 
fungal culture should be performed if possible. 
Subjects who complete the Test of Cure Visit 
and who have a visual presence of fungal 
elements in at least one ear treated during 
the Randomization Period will be offered the 
opportunity to participate in the Optional 
Open-label Extension. 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion; elimination of 
unnecessary fungal culture in a 
situation in which this culture will 
not contribute to the evaluation of 
efficacy 
Section 6 (Study 
Schedule) 
6.1.3 Study Visits for the Optional Open-
label Extension 
Addition of entire section to reflect 
addition to the study of optional 
open-label extension 
Section 6 (Study 
Schedule) 
6.2 Enrollment B 
… 
Addition of entire section to reflect 
addition to the study of Enrollment 
B portion 
Section 6 (Study 
Schedule) 
6.3 Screen Failures 
Subjects in both portions of the study who 
sign informed consent and are then found not 
to meet all eligibility criteria will be 
considered screen failures. 
Addition of entire section to indicate 
how patients who sign informed 
consent but then do not meet all 
eligibility criteria will be handled 
Section 6 (Study 
Schedule) 
6.46.5 Unscheduled Study Visits 
Additional visits may be scheduled in both 
portions of the study, as necessary, to ensure… 
Renumbering of section; addition to 
the study of an open-label 
Enrollment B portion 
Section 6 (Study 
Schedule) 
6.56.6 Post-study Follow-up 
Subjects who require further follow-up for 
an AE will be followed according to Section 
8.4. If a subject requires… 
Renumbering of section; 
reorganization of information 
Section 6 (Study 
Schedule) 
6.66.7 Missed Visits 
Renumbering of section 
Section 6 (Study 
Schedule) 
6.76.8 Subject Completion 
The subject has completed the study when the 
Test of Cure Visit is completed 
(Randomization Period of Enrollment A), or 
when the End of Treatment Visit is 
completed (Open-label Extension of 
Enrollment A or Enrollment B). Subjects who 
require further follow-up for an AE will be 
followed according to Section 8.46.6. 
Renumbering of section; addition to 
the study of an optional open-label 
extension and an Enrollment B 
portion; reorganization of 
information 
Section 6 (Study 
Schedule) 
6.86.9 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 
Renumbering of section; addition to 
the study of an optional open-label 
extension and an Enrollment B 
portion 


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applicable. The sponsor or designee will instruct 
the investigator to stop 
screening/enrollingrandomizing 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 
the Randomization Period, or subjects who 
have not completed the End of Treatment 
Visit in the Optional Open-label Extension or 
in Enrollment B) in for a final study visit) in 
for a Test of Cure Visit as soon as possible, and 
to arrange for study closeout at the site. 
Section 7.2 (Physical 
Examination) 
At Screening/Baseline, the investigator or 
designee will perform a complete 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. For subjects 
participating in Enrollment B, a physical 
examination of the treated ear(s) will also be 
performed at the End of Treatment Visit; a 
more extensive physical examination is not 
required for these subjects at the End of 
Treatment Visit but may be performed if 
necessary in the judgment of the investigator 
(e.g., to support evaluation of an AE). 
Clarification of extent of physical 
examination; addition to the study of 
an Enrollment B portion 
Section 8.1 (Definition of 
an Adverse Event) 
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…  
…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. 
Addition of 2 paragraphs to clarify 
how adverse events that could be 
considered signs and symptoms of 
otomycosis should be reported 
Section 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 willshould begin 
after the subject has signed informed consent 
and continue up through the Test of Cure Visit 
(Randomization Period) or up through the 
End of Treatment Visit (Optional Open-label 
Extension or Enrollment B). 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion 
Section 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 (Randomization Period) or up 
through the End of Treatment Visit 
(Optional Open-label Extension or 
Enrollment B) will be reported… 
Addition to the study of an optional 
open-label extension and an 
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… Any SAE occurring after the final study 
visitTest of Cure Visit and which is not 
considered to be of “suspected” relationship to 
study drug does not need to be reported. 
Section 8.5 (Pregnancy) 
Females of childbearing potential, as defined in 
Section 4.1.1 (Enrollment A) and Section 
4.2.1 (Enrollment B)Section 4.1, must use an 
effective method of contraception from 
screening up through the final study visitTest 
of Cure Visit. 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion 
Section 9.1.1 
(Administration) 
The subject or caregiver will gently pull the ear 
lobe backward and upward and apply 5 drops of 
study drugmiconazole oil 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 study 
drugmiconazole oil to coat the ear canal. 
Clarification to accommodate 
vehicle comparator 
Section 9.1.1 
(Administration) 
During the Randomization Period, 
whileWhile 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 in the Optional 
Open-label Extension and subjects in 
Enrollment B who have signs and/or 
symptoms of otomycosis may also be given 
these instructions. 
Subjects in both portions will be asked to 
avoid bathing or shower for at least 30 minutes 
after applying study drug. 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion 
Section 9.2 
(Randomization) 
For the Randomization Period, 
subjectsSubjects 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 
miconazole oil vehicle. Randomization is not 
applicable to either the Optional Open-label 
Extension of Enrollment A or to Enrollment 
B. 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion 
Section 9.3 
(Blinding/Unblinding) 
The contents of the study drug (miconazole oil 
versus vehicle) will be blinded to both the 
investigator (and all study staff) and the subject 
during the Randomization Period of 
Enrollment A. 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion 
Section 9.4.1 (Packaging 
and Labeling) 
For the Randomization Period of Enrollment 
A, theThe study drug and vehicle will be 
packaged in primary bottle 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 
Addition to the study of an optional 
open-label extension and an 
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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. 
For the Optional Open-label Extension of 
Enrollment A and for Enrollment B, the 
study drug will be packaged in a primary 
bottle that will be dispensed directly to the 
subject. The dropper bottles will be weighed 
with the cap on prior to dispensing. If the 
subject loses a bottle (lost or damaged), a 
reserve bottle will be dispensed from the 
study drug inventory packaged for open-
label use. 
Each drug kit dispensed will be documented on 
the drug accountability log.  
Labels on the drug kit will contain the following 
information: 
Section 10 (Statistical 
Considerations) 
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. 
10.1 Study Endpoints… 
Reorganization of information (text 
moved from the previous Section 
10.5 Statistical Methods to the 
beginning of Section 10) 
Section 10.1.1 (Primary 
Efficacy Endpoint) 
The primary efficacy endpoint will be the 
percentage of subjects at the Test of Cure Visit 
with “therapeutic cure”, defined as 
“mycological cure”a negative mycological 
culture plus “clinical cure” for the study ear, at 
the end of the Randomization Period for each 
subject. Mycological cure is defined as a 
negative mycological culture, and 
clinicalClinical cure is defined as the absence of 
all otomycosis signs and symptoms based on 
investigator assessment according to the scales 
for each individual sign or symptom. 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion; consistency of 
presentation throughout protocol 
Section 10.1.2 
(Secondary Efficacy 
10.1.2 Secondary Efficacy Endpoints 
Secondary endpoints will include… 
Addition of entire section due to 
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Endpoints) 
secondary endpoints 
Section 10.1.3 (Tertiary 
Efficacy Endpoints) 
10.1.3 Tertiary Efficacy Endpoints 
Tertiary endpoints will include… 
Addition of entire section due to 
addition to protocol of new tertiary 
endpoints 
Section 10.1.4 (Safety 
Endpoint) 
10.1.410.1.2 Safety Endpoint 
Renumbering of section 
Section 10.2 
(Hypotheses) 
The primary efficacy endpoint of the study is 
percentage of subjects at the Test of Cure Visit 
with “therapeutic cure”, defined as 
“mycological cure”a negative mycological 
culture plus “clinical cure” for the study ear. 
Mycological cure is defined as a negative 
mycological culture, and clinicalClinical cure 
is defined as the absence of all otomycosis signs 
and symptoms based on investigator assessment 
according to the scales for each individual sign 
or symptom. 
Consistency of presentation 
throughout protocol 
Section 10.2 
(Hypotheses) 
Comparisons will also be conducted similarly 
between the miconazole oil and vehicle oil 
groups for the secondary endpoints of clinical 
cure, and mycological cure. 
Addition to protocol of secondary 
endpoints 
Section 10.3 (Sample 
Size) 
For the Randomization Period, 
approximatelyApproximately 128 subjects 
(~64 in each group) are required to provide 80% 
power… 
The sample size of 220 subjects for Enrollment 
Athis study assumes that ~58% of subjects 
enrolled into Enrollment Athe study will have a 
positive fungal culture at Screening/Baseline… 
The estimated sample size of 170 subjects for 
Enrollment B is not based on statistical 
considerations and is instead based on the 
achievement of at least 300 subjects who have 
been exposed to miconazole oil for 14 days 
who are evaluable for safety (see also Section 
3.3.2). 
Addition to the study of an optional 
open-label extension and an 
Enrollment B portion 
Section 10.4.2 (Modified 
Intent-to-treat 
Population) 
The MITT population will include subjects in 
the ITT populationwho were randomized, 
dispensed study drug, and with a clinical 
diagnosis of otomycosis confirmed by a positive 
fungal culture at Screening/Baseline. 
Modification to definition of MITT 
population in response to FDA 
comment at End-of-Phase 2 meeting 
10.4.4 Safety Population 
Two safety populations will be defined. 
The Randomization Period 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 
during the Randomization Period. 
The Open Label safety population will 
include all subjects who received at least one 
dose of miconazole oil and had at least one 
post-Baseline safety assessment during the 
Modification to presentation of 
safety information due to addition to 
the study of an optional open-label 
extension and an Enrollment B 
portion 


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Optional Open-label Extension or 
Enrollment B. 
SafetyAll safety analyses for the 
Randomization Period will be performed using 
the Randomization Period safety population. 
Safety analyses for the Optional Open-label 
Extension and Enrollment B will be 
combined and presented using the Open 
Label safety population. 
Section 10.5 (Statistical 
Methods) 
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. 
Reorganization of information (text 
moved to the beginning of Section 
10) 
Section 10.5.1 (Efficacy 
Analyses) 
The primary population for all efficacy analyses 
will be the MITT population (see Section 10.4). 
Efficacy analyses will also be performed on the 
ITT andfor the PP populationspopulation and 
will be considered supportive. 
Modification to populations used for 
efficacy analyses in response to 
FDA comment at End-of-Phase 2 
meeting; addition of an optional 
open-label extension for which the 
ITT population will be used for 
efficacy analyses 
Section 10.5.1 (Efficacy 
Analyses) 
The primary analysis will be conducted once 
Enrollment A is complete. 
Specification of when analysis will 
be conducted given the addition to 
the study of an optional open-label 
extension and an Enrollment B 
portion 
Section 10.5.1 (Efficacy 
Analyses) 
The number and percent of subjects who 
demonstrate a positive outcome for the primary 
efficacy outcome as well as all secondary and 
tertiary efficacy outcomes will be presented. 
… 
The secondary endpoints will be analyzed 
analogously to the primary endpoint. 
Addition to protocol of secondary 
and tertiary endpoints 
Section 10.5.1 (Efficacy 
Analyses) 
In Enrollment A in cases of bilateral 
otomycosis… 
Addition to the study of an 
Enrollment B portion 
Section 10.5.1 (Efficacy 
Analyses) 
Descriptive statistics will be provided for 
otomycosis signs and symptoms and also for 
clinical cure, modified therapeutic cure, and 
therapeutic improvement; each at Day 15 
will be summarized using the ITT population 
Modification to populations used for 
efficacy analyses in response to 
FDA comment at End-of-Phase 2 
meeting; addition of an optional 
open-label extension for which the 


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for both the Randomization Period and the 
Optional Open-label Extension. 
ITT population will be used for 
efficacy analyses 
Section 10.5.1.1 
(Multiple 
Comparison/Multiplicity) 
Section 10.5.1.1 Multiple 
Comparison/Multiplicity 
The overall Type I error will be controlled… 
Addition of entire section due to 
addition to protocol of secondary 
endpoints 
Section 10.5.2 (Safety 
Analyses) 
Safety summaries will be conducted using 
twothe safety populationspopulation (see 
Section 10.4.4). 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 
summarizedby treatment group. … 
Summaries will be provided separately for 
the blinded and unblinded portions. 
Specifically, summaries will be provided by 
treatment group for the Randomization 
Period using the Randomization Period 
safety population, and for all open-label 
subjects using the Open Label safety 
population. 
All information pertaining to AEs noted during 
the study will be listed by study portion 
(Enrollment A or Enrollment B), study 
period (Randomization or Optional Open-
label), as applicable, 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. 
Modification to presentation of 
safety information due to addition to 
the study of an optional open-label 
extension and an Enrollment B 
portion 
Section 10.5.4 (Missing 
Data) 
Missing data will be imputed as treatment 
failures for the primary and secondary 
efficacy analysesaccording to the last 
observation carried forward (LOCF) method. 
Sensitivity analyses including a tipping point 
analysis will also be conducted. 
Missing data otherwise will not be imputed. 
Change to method for handling 
missing data in response to FDA 
comment at End-of-Phase 2 
meeting; addition to the protocol of 
secondary efficacy endpoints; 
reorganization of information 
regarding sensitivity analyses into a 
new section 
Section 10.5.5 
(Sensitivity Analyses) 
10.5.5 Sensitivity Analyses 
In order to explore the effects of missing 
data, sensitivity analyses… 
Addition of entire section for 
reorganization of information; 
modification to sensitivity analyses 
in response to FDA comment at 
End-of-Phase 2 meeting 
Section 10.5.6 (Subgroup 
Analyses) 
10.5.6 Subgroup Analyses 
Descriptive summaries on the primary and 
secondary endpoints will be included for the 
following subgroups of gender, age, ethnicity, 
Addition of entire section to describe 
subgroup analyses for this Phase 3 
study 


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race, and fungal organism isolated at 
Screening/Baseline. 
Section 11.6 (Case 
Report Form 
Requirements) 
SourcePaper source documents will be created 
and retained at the clinical site. 
Flexibility with regard to format of 
source documents 
Section 13 (Summary of 
Protocol Amendments) 
13 SUMMARY OF PROTOCOL 
AMENDMENTS 
… 
Addition of entire section to include 
a summary of protocol amendments 
 
 


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Revised Table 3 Study Schedule: Enrollment A 
Evaluations and Procedures: 
Randomization Period 
Optional OLE 
Screening
Screen/ 
Baselinea 
Day 1 
On  
Treatment
aTreat b 
Day 8 
End of 
Treat ab 
Day 15 
Test of  
Cure bc 
Day 
22 cd 
Start of 
Treat 
Day 
OLE1e 
End of 
Treat 
Day 
OLE15b 
Informed consent/assent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Medical/medication history 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
Otomycosis signs and symptoms 
X 
X 
X 
X 
 
X 
Urine pregnancy test df 
X 
 
 
X 
 
X 
Randomization 
X 
 
 
 
 
 
Dispensation of study drug 
X 
 
 
 
X 
 
Dispensation of subject diary 
X 
 
 
 
X 
 
Collection of subject diary 
 
X g 
X 
 
 
X 
Administration of study drug at site 
X 
 
 
 
X 
 
Weighing of study drug 
X 
X 
X 
 
X 
X 
Collection of study drug 
 
 
X 
 
 
X 
Fungal culture eh 
X 
 
X 
X 
 
 
Ear cleaning 
X 
X 
 
 
 
 
AE evaluations 
X 
X 
X 
X 
X 
X 
Concomitant medications review 
X 
X 
X 
X 
X 
X 
a. Procedures for this visit may occur over a 2-day period, if necessary (with Day 1 defined as the first day 
on which study drug is administered). All procedures for this visit must occur before the first 
administration of study drug with the exceptions that AE evaluations and review of concomitant 
medications will also occur after the start of study drug on Day 1. 
ab. This visit may occur up to 3 days later than the specified day. 
bc. This visit may occur up to 1 day sooner or up to 8 days later than the specified day.  
cd. In case of early termination, the assessments planned for the Test of Cure Visit should be performed with the 
exception of fungal culture, which is not required. 
e. This visit will occur on the same day as the final visit of the Randomization Period. 
df. Females of childbearing potential only. 
g. The subject diary will be returned to the subject after review by study staff for documentation of missed 
and/or extra study drug doses. 
eh. Samples will be used for growth and identification of fungal organisms as well as susceptibility testing to 
miconazole. Fungal cultures are not required to be taken at Day 15 or at Day 22 for subjects known to have 
a negative fungal culture at Screening/Baseline (assessed after at least 14 days of incubation by the 
clinical laboratory performing the fungal cultures). 
OLE=Open-label Extension; Screen=Screening; Treat=Treatment 
13.3 Amendment 3 Version 4 14 September 2020 
This amendment revises the timing of the study so that Enrollment B may be conducted over 
multiple time periods, including times when Enrollment A and Enrollment B may be 
concurrently ongoing. This amendment also clarifies prohibited topical medications prior to and 
during Enrollment A. 


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14 Sep 2020 / Version 4 
Page 85 of 88 
A more complete summary of changes from the prior version is provided below. Insertions are 
bolded. Deletions are struck through. For sections that are new or have been completely revised, 
only a short description is provided. 
 
Location 
Change 
Rationale 
Header  
14 Sep 2020 / Version 418 May 2020 / Version 
3 
Update to new version and date 
Title page  
14 Sep 2020 / Version 418 May 2020 / Version 
3 
Previous versions: 
28 January 2020 / Version 1 (internal only) 
04 February 2020 / Version 2 
18 May 2020 / Version 3 
Update to new version and date 
Protocol Approval page 
14 September 202018 May 2020 
Update to new date 
Study Acknowledgement 
page 
Version 4Version 3 
Update to new version 
Synopsis (Design and 
Methodology), Section 3 
(Study Design) 
This study will be conducted in 2 separate, 
sequential portions… 
1. Enrollment A, which will… 
…2. Enrollment B, which will commence after 
completion of Enrollment A and will consist of 
open-label treatment with miconazole oil in 
subjects who will not be required to have signs 
and symptoms of otomycosis. 
Change in timing of Enrollment B 
relative to Enrollment A 
Synopsis (Design and 
Methodology) 
Subjects will return to the clinic on Day OLE15 
for the End of Treatment Visit, at which time a 
clinical evaluation of the signs and symptoms of 
otomycosis will be performed, as well as an 
assessment of AEs and concomitant 
medications. A urine pregnancy test will be 
performed in women of childbearing potential. 
The subject will return all unused miconazole 
oil along with the completed subject diary.  
Data for Enrollment A will be unblinded 
after all subjects planned for Enrollment A 
have completed both the Randomization 
Period and the Optional Open-label 
Extension, so that analyses from Enrollment 
A can be conducted even if Enrollment B is 
still ongoing (i.e., before the conclusion of 
Enrollment B). 
Change in timing of Enrollment B 
relative to Enrollment A 
Synopsis (Design and 
Methodology), Section 
3.2 (Enrollment B) 
Enrollment B 
Enrollment B may be initiated while 
Enrollment A is still actively enrolling 
subjects.Enrollment B will begin at or after the 
conclusion of Enrollment A. Data for 
Enrollment A will be unblinded after all 
subjects participating in Enrollment A have 
completed both the Randomization Period and 
the Optional Open-label Extension, so that 
Change in timing of Enrollment B 
relative to Enrollment A 


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Protocol MZ-0120-ESP3-052 
 
 
14 Sep 2020 / Version 4 
Page 86 of 88 
Location 
Change 
Rationale 
analyses from Enrollment A can be conducted 
before and/or during the conduct of Enrollment 
B. An estimated 170 male or female subjects 
will receive study drug (miconazole oil) in 
Enrollment B, although this number may be 
higher or lower… 
Synopsis (Design and 
Methodology) 
Subjects will return to the clinic on Day B15 for 
the End of Treatment Visit, at which time AEs 
and concomitant medications will be assessed. 
Subjects will return all unused miconazole oil 
along with the completed subject diary. A urine 
pregnancy test will be performed in women of 
childbearing potential. 
Timing of Subject Recruitment Into 
Enrollment A and Enrollment B 
The study will start with Enrollment A, 
which will continue until the sponsor 
determines that a sufficient number of 
subjects (see Sample Size below) has been 
recruited to conduct the planned analyses for 
Enrollment A, at which time the sponsor (or 
designee) will notify all study sites to 
terminate further enrollment into the 
Enrollment A portion of the study. … 
…At times when Enrollment A and 
Enrollment B are concurrently ongoing, if a 
subject is found to be eligible for both 
Enrollment A and Enrollment B, the subject 
should be enrolled into Enrollment A 
whenever possible. 
Addition of several paragraphs 
regarding the change in timing of 
Enrollment B relative to 
Enrollment A 
Synopsis (Key Exclusion 
Criteria, Enrollment A) 
Subjects with any other dermatoses or 
conditions of the ear that may interfere with the 
evaluation of otomycosis or with safety 
evaluations, 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, in the ear(s) that will be treated with 
study drug, of any topical medicated treatments 
for otomycosis within 14 days of study entry; 
use of any systemic antifungal therapy 
Clarification that topical medicated 
treatments for otomycosis within 14 
days of study entry are only 
exclusionary if used in the ear(s) that 
will be treated with study drug 
Synopsis (Sample Size) 
For the Randomization Period of Enrollment A, 
approximately 128 subjects (~64 in each group) 
are required to provide 80% power, using a 
Correction of clerical error 


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14 Sep 2020 / Version 4 
Page 87 of 88 
Location 
Change 
Rationale 
using a chi-square test… 
Figure 1 
See revised Figure 1 
Figure updated to reflect change in 
timing of Enrollment B relative to 
Enrollment A 
Figure 1 (footnotes) 
a. Subjects must meet all eligibility criteria in 
Section 4.1 to be randomized in Enrollment A. 
b. Subject must have a visual presence of fungal 
elements to be enrolled in the Optional Open-
label Extension. 
c. Enrollment B can only commence after all 
subjects participating in Enrollment A have 
completed both the Randomization Period and 
Optional Open-label Extension. 
c.d. Subject must meet all eligibility criteria in 
Section 4.2 to receive treatment with 
miconazole oil in Enrollment B. 
Consistency with the updated Figure 
1 reflecting the change in timing of 
Enrollment B relative to 
Enrollment A 
Section 3.1.3 (Timing of 
Analysis for Enrollment 
A) 
See Section 3.1.3 
Entire section added to reflect 
change in timing of Enrollment B 
relative to Enrollment A 
Section 3.3 (Timing of 
Subject Recruitment Into 
Enrollment A and 
Enrollment B) 
See Section 3.3 
Entire section added to reflect 
change in timing of Enrollment B 
relative to Enrollment A 
Sections 3.4 (Number of 
Subjects), 3.5 
(Investigators), and 3.6 
(Study Duration) 
Renumbering of these sections to accommodate 
the addition of Section 3.3 
Addition of Section 3.3 
Section 4.1.2 (Exclusion 
Criteria) 
4. Use, in the ear(s) that will be treated with 
study drug, of any topical medicated treatments 
for otomycosis within 14 days of study entry: 
Clarification that topical medicated 
treatments for otomycosis within 14 
days of study entry are only 
exclusionary if used in the ear(s) that 
will be treated with study drug  
Section 4.1.2 (Exclusion 
Criterion #4) 
• 
Topical corticosteroids prescribed 
specifically for the treatment of 
otomycosis are prohibited to be used 
within 14 days of study entry; however, 
use of topical corticosteroids for any 
other reason (e.g., for bacterial otitis 
externa and/or for control of symptoms 
in the ear such as itching and/or pain) 
will not require a 14-day washout 
• 
Alcohol and/or peroxide are prohibited 
when prescribed/used by a health care 
provider specifically for the treatment of 
otomycosis within 14 days of study entry; 
however, use of these substances for 
other purposes (e.g., as a drying agent) 
will not require a 14-day washout 
• 
Use of boric acid for any reason is 
prohibited within 14 days of study entry 
Addition of several paragraphs to 
clarify commonly-used topical 
treatments that are exclusionary 
within 14 days of study entry for the 
ear(s) that will be treated with study 
drug 
Section 5.1.2 (Prohibited 
Other than the study drug, no other topical 
Clarification that topical medications 


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14 Sep 2020 / Version 4 
Page 88 of 88 
Location 
Change 
Rationale 
Medications) 
medications (including but not limited to 
antibiotics, alcohol, boric acid, peroxide, 
and/or corticosteroids) are allowed to be used 
in the ear(s) being treated with study 
drugears. Other prohibited treatments include 
systemic antifungal therapy, warfarin, 
immunosuppressive or immune-stimulating 
drugs, and systemic steroids. A subject who 
discontinues study drug during the 
Randomization Period and who subsequently 
uses a topical corticosteroid (e.g., to treat an 
AE such as itching) in the ear(s) that were 
treated with study drug during the 
Randomization Period will be eligible for the 
Optional Open-label Extension if the topical 
corticosteroid is discontinued in the ear(s) 
that will be treated with study drug before 
the start of study drug in the Optional Open-
label Extension, and as long as the subject 
meets all other eligibility criteria for the 
Optional Open-label Extension. 
are prohibited only in the ear(s) 
being treated with study drug; 
clarification regarding use of topical 
corticosteroid to treat an AE in 
relation to subject eligibility for the 
Optional Open-label Extension 
Section 13.3 
(Amendment 3 Version 4 
14 September 2020) 
See Section 13.3 
Addition of entire section to describe 
Amendment 3