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.

Study Overview

• Status: Completed
• Conditions: Temporary Auditory Threshold Shift
• Intervention / Treatment: Drug: SPI-1005 Low dose; Drug: SPI-1005 Middle dose; Drug: SPI-1005 High dose; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 27 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SPI-1005 Low dose; 200mg SPI-1005, capsule, bid, po, x4d	Drug: SPI-1005 Low dose; Oral capsules, 200 mg ebselen, twice daily, 4 days; Other Names: 200 mg Ebselen
Active Comparator: SPI-1005 Middle Dose; 400mg SPI-1005, capsule, bid, po, x4d	Drug: SPI-1005 Middle dose; Oral capsules, 400 mg ebselen, twice daily, 4 days; Other Names: 400 mg Ebselen
Active Comparator: SPI-1005 High Dose; 600mg SPI-1005, capsule, bid, po, x4d	Drug: SPI-1005 High dose; Oral capsules, 600 mg ebselen, twice daily, 4 days; Other Names: 600mgEbselen
Placebo Comparator: Placebo; 0mg SPI-1005, capsule, bid, po, x4d	Drug: Placebo; Oral capsules, 0 mg ebselen, twice daily, 4 days; Other Names: 0 mg Ebselen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Temporary Threshold Shift at 4 kHz--Intent To Treat (ITT) Population	The primary efficacy analysis was change in air conduction threshold at 4 kHz collected in the ITT Population on the day of sound exposure. Baseline hearing thresholds were collected on Clinic Visit 2 prior to sound exposure and used in calculating the primary efficacy endpoints. Hearing thresholds after sound exposure were collected and compared to baseline threshold to calculate change from baseline. Threshold changes from baseline were determined for each ear, frequency, and post sound time point, then analyzed by Mixed-effects Model Repeated Measures (MMRM) methods using triply repeated measurements for each subject. The MMRM had fixed effects for treatment, ear, frequency, and time, all 2-way interactions and the 3-way interaction treatment by-frequency-by-time plus a random effect for subject nested within treatment.	15 minutes post Controlled Sound Challenge
Change in Temporary Threshold Shift at 4 kHz--Per Protocol (PP) Population	The primary efficacy analysis was change in air conduction threshold at 4 kHz collected in the PP Population on the day of sound exposure. Baseline hearing thresholds were collected on Clinic Visit 2 prior to sound exposure and used in calculating the primary efficacy endpoints. Hearing thresholds after sound exposure were collected and compared to baseline threshold to calculate change from baseline. Threshold changes from baseline were determined for each ear, frequency, and post sound time point, then analyzed by Mixed-effects Model Repeated Measures (MMRM) methods using triply repeated measurements for each subject. The MMRM had fixed effects for treatment, ear, frequency, and time, all 2-way interactions and the 3-way interaction treatment by-frequency-by-time plus a random effect for subject nested within treatment.	15 minutes post Controlled Sound Challenge

Collaborators and Investigators

• Sponsor: Sound Pharmaceuticals, Incorporated
• Collaborators: University of Florida
• Investigators: Principal Investigator: Colleen Le Prell, PhD, University of Florida; Study Director: Jonathan Kil, MD, Sound Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Kil J, Pierce C, Tran H, Gu R, Lynch ED. Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase. Hear Res. 2007 Apr;226(1-2):44-51. doi: 10.1016/j.heares.2006.08.006. Epub 2006 Oct 6.
• Pourbakht A, Yamasoba T. Ebselen attenuates cochlear damage caused by acoustic trauma. Hear Res. 2003 Jul;181(1-2):100-8. doi: 10.1016/s0378-5955(03)00178-3.
• Lynch ED, Gu R, Pierce C, Kil J. Ebselen-mediated protection from single and repeated noise exposure in rat. Laryngoscope. 2004 Feb;114(2):333-7. doi: 10.1097/00005537-200402000-00029.
• Lynch ED, Gu R, Pierce C, Kil J. Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. Hear Res. 2005 Mar;201(1-2):81-9. doi: 10.1016/j.heares.2004.08.002.
• Yamasoba T, Pourbakht A, Sakamoto T, Suzuki M. Ebselen prevents noise-induced excitotoxicity and temporary threshold shift. Neurosci Lett. 2005 Jun 3;380(3):234-8. doi: 10.1016/j.neulet.2005.01.047. Epub 2005 Feb 1.
• Lynch ED, Kil J. Compounds for the prevention and treatment of noise-induced hearing loss. Drug Discov Today. 2005 Oct 1;10(19):1291-8. doi: 10.1016/S1359-6446(05)03561-0.
• Lynch E, Kil J. Development of Ebselen, a Glutathione Peroxidase Mimic, for the Prevention and Treatment of Noise-Induced Hearing Loss. Semin Hear 2009; 30(1): 047-055
• Le Prell CG, Yang Q, Harris JG. Modification of digital music files for use in human temporary threshold shift studies. J Acoust Soc Am. 2011 Oct;130(4):EL142-6. doi: 10.1121/1.3630017.
• Le Prell CG, Dell S, Hensley B, Hall JW 3rd, Campbell KC, Antonelli PJ, Green GE, Miller JM, Guire K. Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects. Ear Hear. 2012 Nov-Dec;33(6):e44-58. doi: 10.1097/AUD.0b013e31825f9d89.
• Kil J, Lobarinas E, Spankovich C, Griffiths SK, Antonelli PJ, Lynch ED, Le Prell CG. Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2017 Sep 2;390(10098):969-979. doi: 10.1016/S0140-6736(17)31791-9. Epub 2017 Jul 14.
• Spankovich C, Le Prell CG. Associations between dietary quality, noise, and hearing: data from the National Health and Nutrition Examination Survey, 1999-2002. Int J Audiol. 2014 Nov;53(11):796-809. doi: 10.3109/14992027.2014.921340. Epub 2014 Jun 30.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: September 29, 2011
• First Submitted That Met QC Criteria: September 30, 2011
• First Posted (Estimated): October 3, 2011

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Hearing Loss; Deafness; SPI-1005; Ebselen; Temporary Auditory Threshold Shift
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Hearing Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hearing Loss; Deafness; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gastrointestinal Agents; Neuroprotective Agents; Protective Agents; Anti-Ulcer Agents; Antioxidants; ebselen
• Other Study ID Numbers: SPI-1005-202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO