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

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

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.

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.

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