SPI-1005 for Prevention and Treatment of Tobramycin Induced Ototoxicity

Study Overview
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Brief Summary
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The primary objective of this study is to determine the safety and efficacy of SPI-1005 treatment in CF patients with active pulmonary exacerbation that are receiving an IV course of tobramycin, determined by comparing hearing assessments, spirometry, Pharmacokinetic (PK), Physical Exam, Adverse Events (AEs) and Labs baseline to post-treatment. The secondary objectives of this study are to determine Pharmacogenomics and Pharmacodynamics of SPI-1005.

Detailed Description
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Randomized, double-blind, placebo-controlled study to evaluate the safety, and efficacy of SPI-1005 in Cystic Fibrosis patients with Acute Pulmonary Exacerbation receiving intravenous tobramycin at risk for ototoxicity. All patients will undergo baseline testing and have their severity of lung function, sensorineural hearing loss, tinnitus and vertigo determined before the start of SPI-1005 treatment. SPI-1005 treatment will start within first two days of IV tobramycin treatment and be administered concomitantly. At the end of the 21-day course of SPI-1005 and 28 days following the cessation of SPI-1005, patients will have their hearing loss, tinnitus and vertigo reassessed. Assessments may also include additional audiometric and pulmonary testing, and additional follow-up testing.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of SPI-1005 in Cystic Fibrosis (CF) Patients With Acute Pulmonary Exacerbation (APE) Receiving IV Tobramycin at Risk for Ototoxicity

Conditions
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Ototoxicity

Intervention / Treatment
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* Drug: Placebo
* Drug: SPI-1005 Ebselen 200mg Capsule x1
* Drug: SPI-1005 Ebselen 200mg Capsule x2
* Drug: SPI-1005 Ebselen 200mg Capsule x3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cystic fibrosis patients about to receive IV tobramycin for acute pulmonary exacerbation. 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. Ability to perform all behavioral tests as indicated. Exclusion Criteria: Current use or within 60 days prior to study enrollment the following IV ototoxic medications: 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, hepatic, renal, hematologic, endocrine, immunologic, or psychiatric disease. History of hypersensitivity or idiosyncratic reaction to compounds related to ebselen. Participation in another investigational drug or device study within 30 days prior to study enrollment. Female patients who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SPI-1000 Capsule 0mg Ebselen Placebo<br>0mg Ebselen SPI-1000 bid po x 21d | Drug: Placebo<br>* 0 mg SPI-1005 bid po x 21d<br>* Other names: SPI-1000;|
| Experimental: SPI-1005 Ebselen 200mg Capsule x1<br>200mg SPI-1005 bid po x 21d Low Dose Arm | Drug: SPI-1005 Ebselen 200mg Capsule x1<br>* 200 mg SPI-1005 bid po x21d<br>* Other names: SPI-1005 Low Dose;|
| Experimental: SPI-1005 Ebselen 200mg Capsule x2<br>400mg SPI-1005 bid po x 21d Mid Dose Arm | Drug: SPI-1005 Ebselen 200mg Capsule x2<br>* 400 mg SPI-1005 bid po x 21d<br>* Other names: SPI-1005 Mid Dose;|
| Experimental: SPI-1005 Ebselen 200mg Capsule x3<br>600mg SPI-1005 bid po x 21d High Dose Arm | Drug: SPI-1005 Ebselen 200mg Capsule x3<br>* 600 mg SPI-1005 bid po x 21d<br>* Other names: SPI-1005 High Dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with sensorineural hearing loss as a measure of safety and efficacy of SPI-1005 | Determination of sensorineural hearing loss using pure-tone audiometry | 7 weeks | 
| Distortion Product Otoacoustic Emissions | Changes in hearing thresholds using pure-tone audiometry with extended high frequency testing | 7 weeks | 
| Speech discrimination | Change in Words in noise test (WINT) score | 7 weeks | 
| Tinnitus severity | Changes in Tinnitus Functional Index (TFI) score | 7 weeks | 
| Vertigo severity | vertigo symptom scale | 7 weeks | 
| Changes in lung function | Evaluation of lung function using FEV1 | 7 weeks | 
| Trough Level of SPI-1005 at 200, 400, and 600 mg Ebselen po bid x 21d | Plasma ebselen and major metabolite quantified in plasma by LC-MS/MS | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacogenomics | Pharmacogenomics analysis will explore SPI-1005 as an inducer of gene expression for Nrf2, glutathione peroxidase-1, hemeoxygenase-1, and thioredoxin class of redox proteins. | 5 weeks | 
| Pharmacodynamics of Nrf2 | Explore SPI-1005 on the level of Nrf2 by PCR | 5 weeks | 
| Pharmacodynamics of Glutathione, cysteine and cystine | Explore SPI-1005 on the level of Glutathione, cysteine and cystine measured in µM. | 5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ebselen, Tinnitus, Hearing Loss, Vertigo, Cystic Fibrosis, Pulmonary Exacerbation, Tobramycin, Safety, Pharmacokinetics, Pharmacodynamics, Aminoglycoside, SPI-1005, Efficacy, Pharmacogenomics, Ototoxicity