Clinical trial NCT02819856: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ototoxicity
Keywords: Ebselen
Tinnitus
Hearing Loss
Vertigo
Cystic Fibrosis
Pulmonary Exacerbation
Tobramycin
Safety
Pharmacokinetics
Pharmacodynamics
Aminoglycoside
SPI-1005
Efficacy
Pharmacogenomics
Ototoxicity
Lead sponsor: Sound Pharmaceuticals, Incorporated
Sponsor class: INDUSTRY
Collaborators: name: Medical University of South Carolina
name: Cystic Fibrosis Foundation
First posted: 2016-06-30
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of participants with sensorineural hearing loss as a measure of safety and efficacy of SPI-1005
timeFrame: 7 weeks
measure: Distortion Product Otoacoustic Emissions
timeFrame: 7 weeks
measure: Speech discrimination
timeFrame: 7 weeks
measure: Tinnitus severity
timeFrame: 7 weeks
measure: Vertigo severity
timeFrame: 7 weeks
measure: Changes in lung function
timeFrame: 7 weeks
measure: Trough Level of SPI-1005 at 200, 400, and 600 mg Ebselen po bid x 21d
timeFrame: 7 weeks
Secondary outcomes:
measure: Pharmacogenomics
timeFrame: 5 weeks
measure: Pharmacodynamics of Nrf2
timeFrame: 5 weeks
measure: Pharmacodynamics of Glutathione, cysteine and cystine
timeFrame: 5 weeks
Other outcomes:
Locations:
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: SOUND PHARMACEUTICALS, INC.
name: Jonathan Kil, MD
role: STUDY_CHAIR
References:
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.
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.
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.
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.
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.