Otoprotection With SPI-1005 for Prevention of Temporary Auditory Threshold Shift

Phase 2 Study of the Safety and Efficacy of an Oral Formulation of SPI-1005 for Prevention of Temporary Auditory Threshold Shift

Exposure to loud sounds can cause hearing loss. The purpose of this research study is to evaluate potential prevention of temporary changes in hearing that may occur after listening to music through an iPod or personal music player. We will measure temporary changes in hearing in subjects who listen to music and take either the study drug, SPI-1005, or a placebo for 4 days. SPI-1005 is a proprietary preparation of ebselen that allows it to be taken by mouth. Ebselen contains the mineral selenium and behaves like Glutathione Peroxidase, an enzyme that helps to rid the body of damaging chemicals caused by loud sounds.

The objective of this study was to determine the safety and efficacy of SPI-1005 in the prevention of sensorineural hearing loss or temporary auditory threshold shift (TTS) using pure tone audiometry. Subjects with normal to slight hearing loss were screened on clinic visit day 1 (CV1) and after satisfying specific otologic inclusion and exclusion criteria, were enrolled and randomized to either SPI-1000 (placebo) or one of three doses of ebselen (SPI-1005): 200, 400 or 600 mg. Subjects began taking placebo or SPI-1005 by mouth for four days beginning two days prior to CV2. On CV2 subjects had their blood drawn for peak/trough analysis of ebselen and metabolites and their baseline hearing thresholds determined by audiometry. Subjects were then exposed to 100 decibels (dBA) of sound delivered from a calibrated iPod® via insert earphones for 4 continuous hours. Subjects had their hearing serially tested at 4 additional times post-noise exposure on the same day to determine their threshold shift. Subjects returned to clinic 24 hours later on CV3 and 7 days later on CV4 for additional safety and efficacy assessments including repeat audiometry. Efficacy was determined by comparing the threshold shift in an SPI-1005 treated group vs placebo.

Exposure to SPI-1005 (ebselen and the major and minor metabolites) was quantified from plasma by LC-MS/MS. The plasma values from the peak/trough sampling were taken before and after the 5th oral dose on Clinic Visit 2 (CV2) when subjects were expected to be at steady-state. Plasma selenium levels were quantified by ICP-MS prior to dosing at CV1, at CV2 during peak/trough sampling for ebselen and metabolites, and at CV4 or 5 days after the last scheduled dose.

The multi-dose safety of SPI-1005 was determined by repeated History & Physical examinations, serology (Chemistry Panel-20), hematology (CBC with differential), and radiology (chest x-rays). Safety was determined by comparing the changes in laboratory values in SPI-1005 groups vs placebo.

Inclusion Criteria:

• Healthy subjects at the time of enrollment.
• Each subject will give informed consent to participate in this study and agrees to the treatment protocol.
• Each subject will be interviewed regarding hearing and health to reveal any history of hearing loss, tinnitus, known ear pathology, use of any potentially ototoxic medications (i.e. diuretics, minocycline).
• Non-occupational sound exposure (e.g., concerts, firearms, fireworks, power tools) will be avoided during the 24-hour period preceding baseline testing and throughout the duration of the study.
• Subjects will have vital signs (i.e., heart rate, blood pressure, respirations, temperature) within normal limits upon medical examination.
• Subjects must have normal audiologic assessment at baseline consisting of:
• Baseline audiometric evaluation confirms that subjects have symmetric hearing with air conduction thresholds no worse than 25 decibels of Hearing Loss (dBHL) at frequencies between 0.25 to 8 kilo Hertz (kHz) bilaterally.
• No significant threshold asymmetry (i.e. greater than 15 dB) between the ears at any tested frequency.
• No significant air-bone gaps (i.e. greater than 10 dB)
• Type A tympanograms bilaterally, defined as a range of -140 to +40 dekaPascals (daPa) based on the 90% range for adults (Margolis and Hunter 2000)

Exclusion Criteria:

• • Subjects with abnormal hearing levels > 25 dBHL at any tested frequency (250, 500, 1000, 2000, 3000, 4000, 6000 and 8000 Hz) for either ear.
• Exposure to any duration of non-occupational high-level sound (e.g., concerts, firearms, fireworks, power tools) during the 24 hour period preceding baseline audiometric testing as revealed in the subject questionnaire or during the medical examination.
• Pathology of the external ear discovered upon otoscopic examination.
• Pathology of the middle ear revealed by otoscopic examination, abnormal tympanometry, or reported history of middle ear problems.
• Pathology of the inner ear or auditory nerve as revealed by reported history.
• Subject complaints of aural pain, pressure, fullness, or drainage.
• Subjects testing positive for pregnancy will be excluded from the study.
• Subjects with other medical/health issues that would preclude voluntary participation in a drug study may be excluded at the discretion of the Principal Investigator.
• Subjects that have previously received any known potentially ototoxic medication. This includes, but is not limited to, high dose salicylates (>2 g/day), platinum-based chemotherapeutics and aminoglycoside antibiotics, such as streptomycin, gentamicin,tobramycin, amikacin, neomycin, and netilmycin.
• Subjects that are currently using of any potentially ototoxic medications (i.e. diuretics or minocycline).
• Subjects that have received any investigational treatment (drug or device) in the six months prior to this study.
• Subjects exhibiting or self-reporting shortness of breath, wheezing, coughing, or hemoptysis