SPI-1005 for Prevention and Treatment of Tobramycin Induced Ototoxicity

Ototoxicity Clinical Trial

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02819856
• Other study ID #: SPI-3005-501
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: July 21, 2017
• Est. completion date: April 2023

Study information

• Verified date: December 2022
• Source: Sound Pharmaceuticals, Incorporated
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 80
• Est. completion date: April 2023
• Est. primary completion date: April 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Ototoxicity

Intervention

Drug:
• Placebo
0 mg SPI-1005 bid po x 21d
• SPI-1005 Ebselen 200mg Capsule x1
200 mg SPI-1005 bid po x21d
• SPI-1005 Ebselen 200mg Capsule x2
400 mg SPI-1005 bid po x 21d
• SPI-1005 Ebselen 200mg Capsule x3
600 mg SPI-1005 bid po x 21d

Locations

Country	Name	City	State
United States	Medical University of South Carolina	Charleston	South Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Sound Pharmaceuticals, Incorporated	Cystic Fibrosis Foundation, Medical University of South Carolina

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Distortion Product Otoacoustic Emissions	Changes in hearing thresholds using pure-tone audiometry with extended high frequency testing	7 weeks
Primary	Speech discrimination	Change in Words in noise test (WINT) score	7 weeks
Primary	Tinnitus severity	Changes in Tinnitus Functional Index (TFI) score	7 weeks
Primary	Vertigo severity	vertigo symptom scale	7 weeks
Primary	Changes in lung function	Evaluation of lung function using FEV1	7 weeks
Primary	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	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
Secondary	Pharmacodynamics of Nrf2	Explore SPI-1005 on the level of Nrf2 by PCR	5 weeks
Secondary	Pharmacodynamics of Glutathione, cysteine and cystine	Explore SPI-1005 on the level of Glutathione, cysteine and cystine measured in µM.	5 weeks