Efficacy and Safety Study of Miconazole Oil Versus Vehicle on Fungal Infection of the Ear Canal (Otomycosis)

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.

• miconazole 2% oil (Drug), also known as active treatment: Drug treatment of otomycosis for 14 days
• vehicle oil (Drug), also known as placebo treatment: Placebo treatment of otomycosis for 14 days

Primary outcomes

• Percentage of Subjects With Therapeutic Cure [21 days from first day of drug application]: "therapeutic cure" is "mycological cure" plus "clinical cure, in the Modified intent to treat (MITT) only: patients with + fungal culture at baseline. Fungal culture results verified as (+) or (-) after enrollment. Intent to treat (ITT) population were all subjects enrolled and randomized. Active group: ITT=89 (100%), MITT=67 (75.3%); Placebo Group: ITT=90 (100%), MITT=64 (71.1%). Mycological cure is a negative mycological culture (culture is either positive or negative). Score=0 is best. Clinical cure is absence of all otomycosis signs and symptoms (s/s) of Pruritus, Debris, and Aural fullness, graded as (scores) 0=none, 1=mild, 2=moderate, 3=severe; and Presence of fungal elements, score 0=No fungal elements, 1=fungal elements present on visual inspection. Score=0 is best. Efficacy analysis was performed only on MITT (modified intent-to-treat) population, consisting of only those patients that had positive fungal culture at Baseline.

Secondary outcomes

• Percentage of Subjects With Mycological Cure [21 days from first day of drug application]: Mycological cure is a negative mycological culture for the study ear at test of cure visit, in Modified intent to treat (MITT) only: patients with + fungal culture at baseline. Subjects that had negative fungal culture at Baseline were not included in MITT. Fungal culture results verified as (+) or (-) after enrollment. Grading is based on positive or negative mycological (fungal) culture. Negative culture is required. Efficacy analysis was performed only on MITT (modified intent-to-treat) population, consisting of only those patients that had positive fungal culture at Baseline. Intent to treat (ITT) population were all subjects enrolled and randomized. Active group: ITT=89 (100%), MITT=67 (75.3%); Placebo Group: ITT=90 (100%), MITT=64 (71.1%).
• Percentage of Subjects With Clinical Cure [21 days from first day of drug application]: Absence of all otomycosis signs and symptoms according to the scales for each individual sign/symptom. Score=0 is best. Clinical cure is absence of all otomycosis signs and symptoms of Pruritus, Debris, and Aural fullness, graded as (scores) 0=none, 1=mild, 2=moderate, 3=severe; and Presence of fungal elements, score 0=No fungal elements, 1=fungal elements present on visual inspection. Score=0 is best. Efficacy analysis was performed only on MITT (modified intent-to-treat) population, consisting of only those patients that had positive fungal culture at Baseline. Subjects that had negative fungal culture at Baseline were not included in MITT. Fungal culture results verified as (+) or (-) after enrollment. ITT (intent to treat) population were all subjects enrolled and randomized. Active group: ITT=89 (100%), MITT=67 (75.3%); Placebo Group: ITT=90 (100%), MITT=64 (71.1%).

Sex: All, ages: 7 Years to any, accepts healthy volunteers

Inclusion Criteria:

Randomized blinded initial phase of study:

* Male or non-pregnant, non-lactating females with a clinical diagnosis of uncomplicated otomycosis of the external ear only,
* Intact tympanic membrane in the ear(s) to be treated with study drug,
* In general good health as determined by medical examination and medical history,
* Free of clinically significant disease, including diabetes mellitus, that is not well-controlled or that could interfere with the study.

Open-label second phase of study:

* Male or non-pregnant, non-lactating females with an intact tympanic membrane in the ear(s) to be treated with study drug,
* In general good health as determined by medical examination and medical history,
* Free of clinically significant disease, including diabetes mellitus, that is not well-controlled or that could interfere with the study.

Exclusion Criteria::

* Presence of dermatoses or conditions of the ear that may interfere with evaluation of otomycosis or with safety evaluations, including concomitant otic infections 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;
* History of prior surgery directly affecting and compromising the external auditory canal and/or tympanic membrane, except for prior tympanostomy tube(s) that have already been removed and completely healed;
* Use of any topical medicated treatments for otomycosis within 14 days of study entry;
* Use of any systemic antifungal therapy within 28 days of study entry, warfarin within 28 days of study entry, immunosuppressive or immune-stimulating drugs within 28 days of study entry, or systemic steroids within 3 months of study entry;
* Fever of ≥100°F at study entry;
* Otomycosis that has been unresponsive to previous antifungal treatment;
* Known hypersensitivity to any of the components in the test formulation;
* Participation in another investigative trial within 28 days of study entry

Participant flow

Outcome results

• Percentage of Subjects With Therapeutic Cure (Primary), Count of participants, Participants: Active Treatment Arm 14; Placebo Treatment Arm 11
• Percentage of Subjects With Mycological Cure (Secondary), Count of participants, Participants: Active Treatment Arm 24; Placebo Treatment Arm 15
• Percentage of Subjects With Clinical Cure (Secondary), Count of participants, Participants: Active Treatment Arm 22; Placebo Treatment Arm 14

Adverse events

Time frame: Adverse events (AEs) are collected at the start and during use of study drug, Day 1 to Day 14 of study drug application. Collection of adverse events start the day the patient first applied the study drug and end the day of the patient's last study visit, Day 21. Adverse events were monitored through study completion.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The limited number of patients with otomycosis at any one time, and the lack of standardized FDA-approved clinical studies on otomycosis have proven to be challenging and difficult to assign predetermined analysis endpoints. This is in line with the challenges described in the FDA Accelerating Rare disease Cures Program, such as challenges faced when using well-established trial designs, and complexities in endpoint selection when there is limited information or understanding of the disease.

• Study Protocol and Statistical Analysis Plan (PDF, 2020-09-14)

• Arnaldo Rivera, MD, Principal investigator, University of Missouri-Columbia
• Quyen T Nguyen, MD, Principal investigator, UCSD
• Kenneth Hodge, MD, Principal investigator, Advanced ENT and Allergy
• Patrick Dennis, MD, Principal investigator, DelRicht Research
• Sammy Vaught, MD, Principal investigator, Lake ENT & FPS
• Timothy Fitzgibbon, MD, Principal investigator, OnSite Clinical Solutions
• John Ansley, MD, Principal investigator, Carolina ENT
• Randall Ow, MD, Principal investigator, DaVinci Research LLC
• Oscar DeValle, MD, Principal investigator, West Houston Clinical Research Service
• Linda Woo, MD, Principal investigator, Head and Neck Surgery Specialists
• Brent Benscoter, MD, Principal investigator, Sacramento ENT / DaVinci Research
• Jeffrey Adelglass, MD, Principal investigator, Research Your Health
• Gary Brandt, MD, Principal investigator, Delricht