SPI-1005 for Prevention and Treatment of Tobramycin Induced Ototoxicity

• ClinicalTrials.gov Identifier: NCT02819856
• Recruitment Status: Enrolling by invitation
• First Posted: June 30, 2016
• Last Update Posted: December 9, 2022
• Sponsor: Sound Pharmaceuticals, Incorporated
• Collaborators: Medical University of South Carolina; Cystic Fibrosis Foundation
• Information provided by (Responsible Party): Sound Pharmaceuticals, Incorporated

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.

Condition or disease	Intervention/treatment	Phase
Ototoxicity	Drug: Placebo; Drug: SPI-1005 Ebselen 200mg Capsule x1; Drug: SPI-1005 Ebselen 200mg Capsule x2; Drug: SPI-1005 Ebselen 200mg Capsule x3	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: July 21, 2017
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: SPI-1005 High Dose

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Pharmacogenomics [ Time Frame: 5 weeks ]
   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.
2. Pharmacodynamics of Nrf2 [ Time Frame: 5 weeks ]
   Explore SPI-1005 on the level of Nrf2 by PCR
3. Pharmacodynamics of Glutathione, cysteine and cystine [ Time Frame: 5 weeks ]
   Explore SPI-1005 on the level of Glutathione, cysteine and cystine measured in µM.

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

Sponsors and Collaborators

Sound Pharmaceuticals, Incorporated

Medical University of South Carolina

Cystic Fibrosis Foundation

Investigators

• Study Chair: Jonathan Kil, MD; SOUND PHARMACEUTICALS, INC.

More Information

Publications:

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.

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.

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.

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.

• Responsible Party: Sound Pharmaceuticals, Incorporated
• ClinicalTrials.gov Identifier: NCT02819856
• Other Study ID Numbers: SPI-3005-501
• First Posted: June 30, 2016
• Last Update Posted: December 9, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sound Pharmaceuticals, Incorporated:

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

Additional relevant MeSH terms:

Ototoxicity; Ear Diseases; Otorhinolaryngologic Diseases; Pathologic Processes; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries; Ebselen; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Anti-Ulcer Agents; Gastrointestinal Agents; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Neuroprotective Agents