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SPI-1005 for Prevention and Treatment of Tobramycin Induced Ototoxicity

Primary Purpose

Ototoxicity

Status

Enrolling by invitation

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Placebo

SPI-1005 Ebselen 200mg Capsule x1

SPI-1005 Ebselen 200mg Capsule x2

SPI-1005 Ebselen 200mg Capsule x3

About this trial

This is an interventional treatment trial for Ototoxicity focused on measuring Ebselen, Tinnitus, Hearing Loss, Vertigo, Cystic Fibrosis, Pulmonary Exacerbation, Tobramycin, Safety, Pharmacokinetics, Pharmacodynamics, Aminoglycoside, SPI-1005, Efficacy, Pharmacogenomics, Ototoxicity

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Medical University of South Carolina

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Experimental

Arm Label

SPI-1000 Capsule 0mg Ebselen Placebo

SPI-1005 Ebselen 200mg Capsule x1

SPI-1005 Ebselen 200mg Capsule x2

SPI-1005 Ebselen 200mg Capsule x3

Arm Description

0mg Ebselen SPI-1000 bid po x 21d

200mg SPI-1005 bid po x 21d Low Dose Arm

400mg SPI-1005 bid po x 21d Mid Dose Arm

600mg SPI-1005 bid po x 21d High Dose Arm

Outcomes

Primary Outcome Measures

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

Distortion Product Otoacoustic Emissions

Changes in hearing thresholds using pure-tone audiometry with extended high frequency testing

Speech discrimination

Change in Words in noise test (WINT) score

Tinnitus severity

Changes in Tinnitus Functional Index (TFI) score

Vertigo severity

vertigo symptom scale

Changes in lung function

Evaluation of lung function using FEV1

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

Secondary Outcome Measures

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.

Pharmacodynamics of Nrf2

Explore SPI-1005 on the level of Nrf2 by PCR

Pharmacodynamics of Glutathione, cysteine and cystine

Explore SPI-1005 on the level of Glutathione, cysteine and cystine measured in µM.

Full Information

NCT ID

NCT02819856

First Posted

June 16, 2016

Last Updated

December 7, 2022

Sponsor

Sound Pharmaceuticals, Incorporated

Collaborators

Medical University of South Carolina, Cystic Fibrosis Foundation

1. Study Identification

Unique Protocol Identification Number

NCT02819856

Brief Title

SPI-1005 for Prevention and Treatment of Tobramycin Induced Ototoxicity

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Enrolling by invitation

Study Start Date

July 21, 2017 (Actual)

Primary Completion Date

April 2023 (Anticipated)

Study Completion Date

April 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sound Pharmaceuticals, Incorporated

Collaborators

Medical University of South Carolina, Cystic Fibrosis Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ototoxicity

Keywords

Ebselen, Tinnitus, Hearing Loss, Vertigo, Cystic Fibrosis, Pulmonary Exacerbation, Tobramycin, Safety, Pharmacokinetics, Pharmacodynamics, Aminoglycoside, SPI-1005, Efficacy, Pharmacogenomics, Ototoxicity

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

SPI-1000 Capsule 0mg Ebselen Placebo

Arm Type

Placebo Comparator

Arm Description

0mg Ebselen SPI-1000 bid po x 21d

Arm Title

SPI-1005 Ebselen 200mg Capsule x1

Arm Type

Experimental

Arm Description

200mg SPI-1005 bid po x 21d Low Dose Arm

Arm Title

SPI-1005 Ebselen 200mg Capsule x2

Arm Type

Experimental

Arm Description

400mg SPI-1005 bid po x 21d Mid Dose Arm

Arm Title

SPI-1005 Ebselen 200mg Capsule x3

Arm Type

Experimental

Arm Description

600mg SPI-1005 bid po x 21d High Dose Arm

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

SPI-1000

Intervention Description

0 mg SPI-1005 bid po x 21d

Intervention Type

Drug

Intervention Name(s)

SPI-1005 Ebselen 200mg Capsule x1

Other Intervention Name(s)

SPI-1005 Low Dose

Intervention Description

200 mg SPI-1005 bid po x21d

Intervention Type

Drug

Intervention Name(s)

SPI-1005 Ebselen 200mg Capsule x2

Other Intervention Name(s)

SPI-1005 Mid Dose

Intervention Description

400 mg SPI-1005 bid po x 21d

Intervention Type

Drug

Intervention Name(s)

SPI-1005 Ebselen 200mg Capsule x3

Other Intervention Name(s)

SPI-1005 High Dose

Intervention Description

600 mg SPI-1005 bid po x 21d

Primary Outcome Measure Information:

Title

Number of participants with sensorineural hearing loss as a measure of safety and efficacy of SPI-1005

Description

Determination of sensorineural hearing loss using pure-tone audiometry

Time Frame

7 weeks

Title

Distortion Product Otoacoustic Emissions

Description

Changes in hearing thresholds using pure-tone audiometry with extended high frequency testing

Time Frame

7 weeks

Title

Speech discrimination

Description

Change in Words in noise test (WINT) score

Time Frame

7 weeks

Title

Tinnitus severity

Description

Changes in Tinnitus Functional Index (TFI) score

Time Frame

7 weeks

Title

Vertigo severity

Description

vertigo symptom scale

Time Frame

7 weeks

Title

Changes in lung function

Description

Evaluation of lung function using FEV1

Time Frame

7 weeks

Title

Trough Level of SPI-1005 at 200, 400, and 600 mg Ebselen po bid x 21d

Description

Plasma ebselen and major metabolite quantified in plasma by LC-MS/MS

Time Frame

7 weeks

Secondary Outcome Measure Information:

Title

Pharmacogenomics

Description

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.

Time Frame

5 weeks

Title

Pharmacodynamics of Nrf2

Description

Explore SPI-1005 on the level of Nrf2 by PCR

Time Frame

5 weeks

Title

Pharmacodynamics of Glutathione, cysteine and cystine

Description

Explore SPI-1005 on the level of Glutathione, cysteine and cystine measured in µM.

Time Frame

5 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jonathan Kil, MD

Organizational Affiliation

SOUND PHARMACEUTICALS, INC.

Official's Role

Study Chair

Facility Information:

Facility Name

Medical University of South Carolina

City

Charleston

State/Province

South Carolina

ZIP/Postal Code

29425

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

10095194

Citation

Takumida M, Popa R, Anniko M. Free radicals in the guinea pig inner ear following gentamicin exposure. ORL J Otorhinolaryngol Relat Spec. 1999 Mar-Apr;61(2):63-70. doi: 10.1159/000027643.

Results Reference

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PubMed Identifier

17030476

Citation

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.

Results Reference

background

PubMed Identifier

19729669

Citation

Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC; Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009 Nov 1;180(9):802-8. doi: 10.1164/rccm.200812-1845PP. Epub 2009 Sep 3.

Results Reference

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PubMed Identifier

32147183

Citation

Gu R, Longenecker RJ, Homan J, Kil J. Ebselen attenuates tobramycin-induced ototoxicity in mice. J Cyst Fibros. 2021 Mar;20(2):271-277. doi: 10.1016/j.jcf.2020.02.014. Epub 2020 Mar 5.

Results Reference

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PubMed Identifier

33341407

Citation

Harruff EE, Kil J, Ortiz MGT, Dorgan D, Jain R, Poth EA, Fifer RC, Kim YJM, Shoup AG, Flume PA. Ototoxicity in cystic fibrosis patients receiving intravenous tobramycin for acute pulmonary exacerbation: Ototoxicity following tobramycin treatment. J Cyst Fibros. 2021 Mar;20(2):288-294. doi: 10.1016/j.jcf.2020.11.020. Epub 2020 Dec 16.

Results Reference

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SPI-1005 for Prevention and Treatment of Tobramycin Induced Ototoxicity

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