Study to Evaluate SPI-1005 in Adults With Meniere's Disease

Randomized, double-blind, placebo-controlled safety, pharmacokinetic, pharmacodynamic study of oral SPI-1005 in adults with Meniere's disease. All subjects will undergo baseline audiometric testing and have their severity of sensorineural hearing loss, tinnitus and vertigo determined before the start of a 21-day course of treatment with SPI-1005 or placebo. During treatment with SPI-1005, and 7 days and 28 days following the cessation of SPI-1005, subjects will have their hearing loss, tinnitus and vertigo assessed. Additional testing including electrocochleography will be performed at baseline, at the end of SPI-1005 treatment, and 28 days after the SPI-1005 treatment has stopped. Six outpatient visits will be performed over a 7-week period.

• SPI-1005 (Drug), also known as ebselen: Ebselen is a small molecule mimic and inducer of glutathione peroxidase (GPx). GPx reduces reactive oxygen species by the binding of free radicals to its selenium moiety. Ebselen has strong anti-inflammatory characteristics.

Primary outcomes

• Incidence of of Treatment-Emergent Adverse Events [7 weeks]: Safety and tolerability of SPI-1005 using histories, physical exams, and clinical measures.

Secondary outcomes

• Plasma Ebselen Levels of SPI-1005 After 21 Days of Dosing [21 days]: Trough values
• Plasma Selenium Levels [7 weeks]: Plasma selenium levels at 28 days post-treatment
• Impact on Sensorineural Hearing Loss [7 weeks]: Number of participants demonstrating improvement in Sensorineural Hearing Loss measured using pure tone audiometry. Improvement was defined as a decrease from baseline value by 10 dB or more at one or more low-frequency thresholds (0.25, 0.5, or 1.0 kHz) in at least one ear.
• Impact on Speech Discrimination [7 weeks]: Number of participants demonstrating improvement in Speech Discrimination measured using the Words in Noise test. Improvement was defined as an increase from baseline value by 10% or more in the total score (0-35, where a higher score is a better outcome) in at least one ear.
• Impact on Tinnitus [7 weeks]: Number of participants demonstrating improvement in the Tinnitus Functional Index (TFI). Improvement was defined as a decrease from baseline value by 10 points or more in the total score (0-100, where a higher score is a worse outcome).
• Impact on Vertigo [7 weeks]: Number of participants demonstrating improvement in the Vertigo Symptom Scale - Short Form (VSS). Improvement was defined as a decrease from baseline value by 6 points or more in the total score (0-60, where a higher score is a worse outcome).

Sex: All, ages: 19 Years to 70 Years

Inclusion Criteria:

* Diagnosis of probable or definite Meniere's Disease by AAO-HNS 1995 criteria within 12 months of study enrollment;
* Voluntarily consent to participate in the study;
* Females of childbearing potential should be using and committed to continue using one of the following acceptable birth control methods:

  * Sexual abstinence (inactivity) for 14 days prior to screening through study completion; or
  * IUD in place for at least 3 months prior to study through study completion; or
  * Barrier method (condom or diaphragm) with spermicide for at least 14 days prior to screening through study completion; or
  * Stable hormonal contraceptive for at least 3 months prior to study through study completion; or
  * Surgical sterilization (vasectomy) of partner at least 6 months prior to study.
* Females of non-childbearing potential should be surgically sterile (bilateral tubal ligation with surgery at least 6 months prior to study, hysterectomy, or bilateral oophorectomy at least 2 months prior to study) or be at least 3 years since last menses.

Exclusion Criteria:

* Current use or within 90 days prior to study of ototoxic medications such as aminoglycoside antibiotics (gentamicin, tobramycin, amikacin, streptomycin); platinum-containing chemotherapies (cisplatin, carboplatin, oxaliplatin); or loop diuretic (furosemide);
* History of idiopathic sensorineural hearing loss, otosclerosis, or vestibular schwannoma;
* History of middle ear or inner ear surgery;
* Current conductive hearing loss or middle ear effusion;
* Significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, or psychiatric disease;
* History of hypersensitivity or idiosyncratic reaction to compounds related to ebselen;
* Current use or within 30 days prior to study of drugs or substances known to be strong inhibitors or inducers of cytochrome P450 enzymes;
* Participation in another investigational drug or device study within 90 days prior to study enrollment;
* Female patients who are pregnant or breastfeeding.

Participant flow

Outcome results

• Incidence of of Treatment-Emergent Adverse Events (Primary), Count of participants, Participants: Placebo 4; Low Dose 2; Mid Dose 5; High Dose 5
• Plasma Ebselen Levels of SPI-1005 After 21 Days of Dosing (Secondary), Geometric mean, ng/mL: Placebo ; Low Dose 16.766 +/- 1.4675; Mid Dose 67.232 +/- 1.4578; High Dose 77.209 +/- 1.5030
• Plasma Selenium Levels (Secondary), Mean, ng/mL: Placebo 139.5556 +/- 23.17925; Low Dose 171.7778 +/- 32.11611; Mid Dose 187.3333 +/- 45.73292; High Dose 201.7500 +/- 37.96145
• Impact on Sensorineural Hearing Loss (Secondary), Count of participants, Participants: Placebo 3; Low Dose 6; Mid Dose 6; High Dose 4
• Impact on Speech Discrimination (Secondary), Count of participants, Participants: Placebo 4; Low Dose 3; Mid Dose 6; High Dose 3
• Impact on Tinnitus (Secondary), Count of participants, Participants: Placebo 5; Low Dose 6; Mid Dose 5; High Dose 3
• Impact on Vertigo (Secondary), Count of participants, Participants: Placebo 7; Low Dose 5; Mid Dose 4; High Dose 3

Adverse events

Time frame: 7 weeks

Other adverse events by term

• 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. PMID 17030476
• 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):47-55.
• Kil J, Harruff EE, Longenecker RJ. Development of ebselen for the treatment of sensorineural hearing loss and tinnitus. Hear Res. 2022 Jan;413:108209. doi: 10.1016/j.heares.2021.108209. Epub 2021 Feb 19. PMID 33678494
• Results publication: Garland M, Hryckowian AJ, Tholen M, Bender KO, Van Treuren WW, Loscher S, Sonnenburg JL, Bogyo M. The Clinical Drug Ebselen Attenuates Inflammation and Promotes Microbiome Recovery in Mice after Antibiotic Treatment for CDI. Cell Rep Med. 2020 Apr 21;1(1):100005. doi: 10.1016/j.xcrm.2020.100005. PMID 32483557

• Study Protocol (PDF, 2016-11-14)
• Statistical Analysis Plan (PDF, 2017-09-07)

• Jonathan Kil, MD, Study chair, Sound Pharmaceuticals