Prevention of Ototoxicity in NTM Patients Treated With IV Amikacin

NCT05730283 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: SOUNDS TrialU01DC020175
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 5

Brief Summary

The goal of this clinical trial is to test the effectiveness of the study drug, ORC-13361, in preventing hearing loss in patients with NTM infection who are undergoing treatment with IV amikacin therapy. The main question this study aims to answer is:

• Is ORC-13661 effective for preventing or lessening hearing loss induced by amikacin treatment?
• Is ORC-13661 effective for preventing or lessening other measures of hearing impairment? Participants will be asked to take a study drug while they are being treated with IV amikacin. Participants will take study drug for 90 days or until the end of their amikacin treatment, whichever comes first. During this time, researchers will gather clinical data on the participants' health. Researchers will compare three groups - two groups taking different doses of the study drug and one group taking a placebo drug - to see if dose of drug has any effect on preventing hearing loss. A placebo is a look-alike substance that contains no active drug.

Conditions

Ototoxicity, Drug-Induced

Keywords

NTM; nontuberculous mycobacteria; ototoxicity; hearing loss

Outcome Measures

Primary Outcomes (1)

• Mitigation or Prevention of Ototoxicity

  Outcome is measured by changes from baseline using the American Speech-Language-Hearing Association (ASHA) shift criterion in patients with NTM disease undergoing treatment with IV amikacin therapy

  Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.

Secondary Outcomes (3)

• Mitigation or Prevention of hearing impairment with regards to speech perceptions

  Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.

• Mitigation or Prevention of hearing impairment with regards to perceived auditory and balance effects

  Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.

• Mitigation or Prevention of hearing impairment with regards to speech, spatial and quality of hearing

  Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.

Study Arms (3)

High Dose ORC-13661

EXPERIMENTAL

This arm is a daily treatment regimen of study drug (ORC-13661) with a loading dose of 150mg followed by a daily dose of 30mg. Treatment regimen will run concurrently with treatment with IV amikacin. Study drug treatment will continue until treatment with IV amikacin ends or 90 days, whichever is earlier.

Drug: ORC-13661

Low Dose ORC-13661

EXPERIMENTAL

This arm is a daily treatment regimen of study drug (ORC-13661) with a loading dose of 60mg capsules followed by a daily dose of 12mg capsules. Treatment regimen will run concurrently with treatment with IV amikacin. Study drug treatment will continue until treatment with IV amikacin ends or 90 days, whichever is earlier.

Drug: ORC-13661

Placebo

PLACEBO COMPARATOR

This arm is a daily treatment regimen of a placebo with a loading dose and a daily dose of placebo capsules to match the treatment arms. Placebo regimen will run concurrently with treatment with IV amikacin. Placebo regimen will continue until treatment with IV amikacin ends or 90 days, whichever is earlier.

Drug: Placebo

Interventions

ORC-13661 DRUG

High-dose intervention (30mg daily)

High Dose ORC-13661

Placebo DRUG

Placebo intervention

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Providing informed consent, documented by signing and dating the currently valid informed consent form.
• Considered by the Investigator to have unimpaired consent capacity, without reliance on a legally authorized representative.
• Stated willingness and ability to comply with study procedures and availability for the duration of the study.
• Aged \> 18 and \< 80.
• NTM infection meeting current Pulmonary NTM guidelines from the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) for systemic (IV) aminoglycoside therapy.
• Anticipated duration of IV amikacin treatment of at least 30 days at time of study entry.
• Statement of ability to take oral medication and adhere to the daily dosing regimen.
• For females of reproductive potential: If they are of childbearing potential, they must agree in writing to practice an effective double barrier method of contraception from the signing of the informed consent form until 1 month following discontinuation of study drug treatment or agree to practice true abstinence, when this is consistent with the preferred and usual lifestyle of the subject.
• For males of reproductive potential: Agree to practice effective barrier contraception from the signing of the informed consent form until 3 months (one spermatogenesis cycle) following the last dose of study drug or agree to practice true abstinence.

You may not qualify if:

• Received a systemic aminoglycoside antibiotic within 6 months prior to planned first dose of amikacin.
• ECG at Screening or prior to randomization (mean of triplicate values) with QT interval corrected using Fridericia's formula (QTcF interval) ≥ 450 msec.
• ECG at Screening or prior to randomization with abnormalities that, in the Investigator's judgment, might predispose patient to clinically significant arrhythmia.
• Patients taking strong CYP3A4 inducers such as rifampin and rifabutin in the 7 days prior to randomization or have the need for ongoing treatment with concomitant oral or intravenous therapy with strong CYP3A4 inducers during the study. If an additional antibiotic is needed, then azithromycin will be used.
• Patients taking strong CYP3A4 inhibitors such as clarithromycin in the 7 days prior to randomization or the need for ongoing treatment with concomitant oral or intravenous therapy with strong CYP3A4 inhibitors during the study. If an additional antibiotic is needed, then azithromycin will be used.
• Patients taking clofazimine or bedaquiline AND who also have congestive heart failure, significant ventricular arrhythmia, uncorrected hypokalemia, or ECG (single at Screening, mean of triplicate prior to randomization) showing QRS \> 120 msec or heart rate \< 50 bpm.
• Patients with amikacin exposure within the 6 months prior to randomization.
• Patients with known amikacin resistance (MIC \>64)
• Progressive liver disease (Child-Pugh B or C) which would affect or invalidate interpretation of change from the baseline liver function tests over the course of the study.
• Signs of disturbed integrity of the tympanic membrane, determined by otoscopy or tympanometry, including chronic perforation or middle ear or ear canal inflammation or effusion.
• History of congenital hearing loss, otological surgery (excluding myringotomy tubes or simple tympanoplasty healed and currently intact), sudden hearing loss, or Meniere's disease.
• Bilateral profound hearing loss (\>90 Decibels \[dB\] HL) at all test frequencies.
• Conductive hearing loss evidenced by average air-bone-gaps \>15 dB HL for 0.25-4.0 kilohertz (kHz)
• History of active malignancy, either untreated or under active treatment.
• History of risk factors for Torsades des Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).

Sponsors & Collaborators

• National Center for Advancing Translational Sciences (NCATS): collaborator
• Oricula Therapeutics: collaborator
• University of Washington: collaborator
• National Jewish Health: collaborator
• Mayo Clinic: collaborator
• Medical University of South Carolina: collaborator
• National Institute on Deafness and Other Communication Disorders (NIDCD): collaborator
• Kevin Winthrop: lead
• The University of Texas Health Science Center at Tyler: collaborator

Study Sites (5)

National Jewish Health

Denver, Colorado, 80206, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

RECRUITING

Oregon Health & Science University

Portland, Oregon, 97239, United States

RECRUITING

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

RECRUITING

University of Texas Health Science Center

Tyler, Texas, 75708, United States

RECRUITING

Related Publications (15)

• Chowdhury S, Owens KN, Herr RJ, Jiang Q, Chen X, Johnson G, Groppi VE, Raible DW, Rubel EW, Simon JA. Phenotypic Optimization of Urea-Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss. J Med Chem. 2018 Jan 11;61(1):84-97. doi: 10.1021/acs.jmedchem.7b00932. Epub 2017 Oct 27.

  PMID: 28992413 BACKGROUND

• Garinis A, Gleser M, Johns A, Larsen E, Vachhani J. Prospective cohort study of ototoxicity in persons with cystic fibrosis following a single course of intravenous tobramycin. J Cyst Fibros. 2021 Mar;20(2):278-283. doi: 10.1016/j.jcf.2020.07.001. Epub 2020 Jul 24.

  PMID: 32713806 BACKGROUND

• Gleser MA, Zettner EM. Negative hearing effects of a single course of IV aminoglycoside therapy in cystic fibrosis patients. Int J Audiol. 2018 Dec;57(12):917-924. doi: 10.1080/14992027.2018.1514537. Epub 2018 Nov 1.

  PMID: 30382794 BACKGROUND

• Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis. 2011 Mar 1;52(5):565-71. doi: 10.1093/cid/ciq237.

  PMID: 21292659 BACKGROUND

• Kitcher SR, Kirkwood NK, Camci ED, Wu P, Gibson RM, Redila VA, Simon JA, Rubel EW, Raible DW, Richardson GP, Kros CJ. ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity. JCI Insight. 2019 Aug 8;4(15):e126764. doi: 10.1172/jci.insight.126764. eCollection 2019 Aug 8.

  PMID: 31391343 BACKGROUND

• Potgieter JM, Swanepoel W, Smits C. Evaluating a smartphone digits-in-noise test as part of the audiometric test battery. S Afr J Commun Disord. 2018 May 21;65(1):e1-e6. doi: 10.4102/sajcd.v65i1.574.

  PMID: 29781704 BACKGROUND

• Smits C, Theo Goverts S, Festen JM. The digits-in-noise test: assessing auditory speech recognition abilities in noise. J Acoust Soc Am. 2013 Mar;133(3):1693-706. doi: 10.1121/1.4789933.

  PMID: 23464039 BACKGROUND

• Zettner EM, Gleser MA. Progressive Hearing Loss among Patients with Cystic Fibrosis and Parenteral Aminoglycoside Treatment. Otolaryngol Head Neck Surg. 2018 Nov;159(5):887-894. doi: 10.1177/0194599818782444. Epub 2018 Jun 19.

  PMID: 29914288 BACKGROUND

• Carhart R, Jerger, J. Preferred method for clinical determination of pure-tone thresholds. J Speech Hear Disord. 1959; 24: 330-345.

  BACKGROUND

• Kemp DT. Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am. 1978 Nov;64(5):1386-91. doi: 10.1121/1.382104.

  PMID: 744838 BACKGROUND

• Chisholm J, Lacey C, Zalewski C, Christensen J, Wafa T, Kim J, Beri A, Fennelly K, Olivier K, Brewer C. Factors Influencing the Prevalence of Amikacin Ototoxicity. Poster presented at the National Center for Rehabilitative Research (NCRAR) Biennial Conference, Ototoxicity and Noise Damage: Translating Preclinical Findings to Audiological Management. 2019 September 25-27; Portland, Oregon.

  BACKGROUND

• Lacey C, Chisholm J, Zalewski C, Christensen J, Wafa T, Kim HJ, Beri A, Olivier K, Fennelly K, Brewer C. Amikacin Ototoxicity: Risk Factors and Sensitivity of Grading Scales. Poster presented at The NIH Summer Poster Day. 2019 August 8; Bethesda, Maryland.

  BACKGROUND

• Prasad K, Borre ED, Dillard LK, Ayer A, Der C, Bainbridge KE, McMahon CM, Tucci DL, Wilson BS, Schmidler GDS, Saunders J. Priorities for hearing loss prevention and estimates of global cause-specific burdens of hearing loss: a systematic rapid review. Lancet Glob Health. 2024 Feb;12(2):e217-e225. doi: 10.1016/S2214-109X(23)00514-4.

  PMID: 38245112 BACKGROUND

• Bellairs JA, Redila VA, Wu P, Tong L, Webster A, Simon JA, Rubel EW, Raible DW. An in vivo Biomarker to Characterize Ototoxic Compounds and Novel Protective Therapeutics. Front Mol Neurosci. 2022 Jul 18;15:944846. doi: 10.3389/fnmol.2022.944846. eCollection 2022.

  PMID: 35923755 BACKGROUND

• Owens KN, Santos F, Roberts B, Linbo T, Coffin AB, Knisely AJ, Simon JA, Rubel EW, Raible DW. Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death. PLoS Genet. 2008 Feb 29;4(2):e1000020. doi: 10.1371/journal.pgen.1000020.

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MeSH Terms

Conditions

Ototoxicity; Hearing Loss

Interventions

ORC-13661

Condition Hierarchy (Ancestors)

Ear Diseases; Otorhinolaryngologic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries; Hearing Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms

Study Officials

• Kevin L Winthrop, MD, MPH

  Oregon Health and Science University

  PRINCIPAL INVESTIGATOR

• Edwin Rubel, PhD

  Oricula Therapeutics

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Daniel Bouchat

CONTACT

503-494-2568; johdanie@ohsu.edu

Alyssa Schroeder

CONTACT

503-494-2136; schroeder@ohsu.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: If not specifically designated by protocol to be unblinded, all study patients, Sponsor, other entities and individuals will be blinded to study drug assignments. Site pharmacy personnel, one or more statisticians, patient dose monitor, and designated central project management personnel will be unblinded. Data Safety Monitoring Board (DSMB) members may choose to unblind themselves.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 7, 2023
• First Posted: February 15, 2023
• Study Start: June 2, 2025
• Primary Completion (Estimated): February 29, 2028
• Study Completion (Estimated): February 29, 2028
• Last Updated: March 9, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)