SPI-1005 for Prevention and Treatment of Tobramycin Induced Ototoxicity

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Ototoxicity
• Intervention / Treatment: Drug: Placebo; Drug: SPI-1005 Ebselen 200mg Capsule x1; Drug: SPI-1005 Ebselen 200mg Capsule x2; Drug: SPI-1005 Ebselen 200mg Capsule x3

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.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sound Pharmaceuticals, Incorporated
• Collaborators: Medical University of South Carolina; Cystic Fibrosis Foundation
• Investigators: Study Chair: Jonathan Kil, MD, Sound Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2017
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: June 16, 2016
• First Submitted That Met QC Criteria: June 27, 2016
• First Posted (Estimate): June 30, 2016

Study Record Updates

• Last Update Posted (Estimate): December 9, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Safety; Efficacy; Pharmacokinetics; Cystic Fibrosis; Pulmonary Exacerbation; Vertigo; Hearing Loss; Pharmacodynamics; Pharmacogenomics; Tinnitus; Ototoxicity; SPI-1005; Ebselen; Tobramycin; Aminoglycoside
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Wounds and Injuries; Otorhinolaryngologic Diseases; Ear Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Ototoxicity; 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-3005-501

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No