Prevence ototoxicity u pacientů s NTM léčených IV amikacinem
Fáze 2 studie účinnosti a bezpečnosti ORC-13661 pro prevenci ztráty sluchu vyvolané léky u pacientů, kteří dostávají intravenózně amikacin k léčbě netuberkulózního mykobakteriálního onemocnění
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.
Přehled studie
Postavení
Podmínky
Intervence / Léčba
Detailní popis
Nontuberculous mycobacteria (NTM) are environmental bacteria that can cause chronic, debilitating pulmonary disease, primarily affecting those over age 60. In more severe cases of NTM infection, patients are given a therapy with parenteral aminoglycoside antibiotics (AGs), to achieve control or cure. Amikacin is the most commonly used aminoglycoside for treatment in this setting, however it is limited by in its use by its tendency to cause ototoxicity including hearing loss and/or vestibular dysfunction. Ototoxicity refers to substances (i.e. medications) which are damaging to the inner ear sensory cells and may result in functional hearing loss and other negative effects.
This main goal of this study is to test the effectiveness of the study drug, ORC-13661, a small molecule compound being developed as an adjunct therapy to be administered during AG use in order to prevent associated ototoxicity. This study is a randomized, double-blind, placebo-controlled, multicenter, dose-ranging clinical trial to compare the effects and safety of ORC-13661 in preventing or mitigating hearing in patients taking amikacin.
105 participants will be enrolled across 5 enrolling sites over the course of the study. Participants will be randomized in equal numbers between three different study arms: high-dose ORC-13661, low-dose ORC-13661, and placebo. Participants will take study drug for 90 days from the start of their amikacin treatment or until their amikacin treatment ends, whichever comes first.
The primary outcome of this study is prevention or mitigation of amikacin-induced ototoxicity. Secondary outcomes include changes in speech perception, auditory and balance effects, and quality of hearing.
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 2
Kontakty a umístění
Studijní kontakt
- Jméno: Daniel Bouchat
- Telefonní číslo: 503-494-2568
- E-mail: johdanie@ohsu.edu
Studijní záloha kontaktů
- Jméno: Violet Tiffee
- Telefonní číslo: 503-494-1433
- E-mail: tiffee@ohsu.edu
Studijní místa
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California
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San Francisco, California, Spojené státy, 94143
- Nábor
- University of California, San Francisco
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Dílčí vyšetřovatel:
- Shoshana Zha, MD, PhD
-
Vrchní vyšetřovatel:
- Catherine DeVoe, MD
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Kontakt:
- Amira Flores Banuelos
- Telefonní číslo: 415-502-0276
- E-mail: amira.floresbanuelos@ucsf.edu
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Colorado
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Denver, Colorado, Spojené státy, 80206
- Nábor
- National Jewish Health
-
Vrchní vyšetřovatel:
- Charles L Daley, MD
-
Kontakt:
- Shane Hopkins, RN
- Telefonní číslo: 303-270-2622
- E-mail: hopkinss@NJHealth.org
-
Kontakt:
- Cindy Wainscoat, RN
- E-mail: WainscoatC@NJHealth.org
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Maryland
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Baltimore, Maryland, Spojené státy, 21224
- Nábor
- Johns Hopkins University
-
Kontakt:
- Pooja Akoijam
- Telefonní číslo: 410-955-1201
- E-mail: pakoija1@jh.edu
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Vrchní vyšetřovatel:
- Elisa Ignatius, MD, MSc
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Kontakt:
- Deya Chatterji
- Telefonní číslo: 410-955-1201
- E-mail: dchatte5@jh.edu
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Minnesota
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Rochester, Minnesota, Spojené státy, 55905
- Staženo
- Mayo Clinic
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New York
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Manhasset, New York, Spojené státy, 11030
- Nábor
- Northwell Health
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Vrchní vyšetřovatel:
- Lisa Hayes, MD
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Dílčí vyšetřovatel:
- Marcia Epstein, MD
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Kontakt:
- Andrew Diaz
- Telefonní číslo: 516-562-3361
- E-mail: ADiaz34@northwell.edu
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Kontakt:
- Jessica Rao
- Telefonní číslo: 516-562-3363
- E-mail: JRao@Northwell.edu
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Oregon
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Portland, Oregon, Spojené státy, 97239
- Nábor
- Oregon Health & Science University
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Vrchní vyšetřovatel:
- Kevin Winthrop, MD, MPH
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Kontakt:
- Daniel Bouchat
- Telefonní číslo: 503-494-2568
- E-mail: johdanie@ohsu.edu
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Kontakt:
- Violet Tiffee
- Telefonní číslo: 503-494-1433
- E-mail: tiffee@ohsu.edu
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South Carolina
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Charleston, South Carolina, Spojené státy, 29425
- Nábor
- Medical University of South Carolina
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Vrchní vyšetřovatel:
- Patrick Flume, MD
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Kontakt:
- Cameron Mathison
- Telefonní číslo: 843-792-7156
- E-mail: mathisoc@musc.edu
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Kontakt:
- Anna Lares
- E-mail: laresa@musc.edu
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Texas
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Tyler, Texas, Spojené státy, 75708
- Nábor
- University of Texas Health Science Center
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Kontakt:
- Kimberly Greenlee
- Telefonní číslo: 903-877-5986
- E-mail: Kimberly.Greenlee@uthct.edu
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Vrchní vyšetřovatel:
- Devanshi Mehta, MD
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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).
- Venous access not adequate for performance of study procedures.
- Presence of any circumstance, condition, ECG or laboratory finding that, based on investigator judgment, would interfere with study procedures or assessments or present to the patient an unreasonable risk from participation in this study.
- Current or anticipated use of excluded concomitant medications as specified in Section 6.5.
- Pregnant or lactating.
- Female of childbearing potential who does not have a negative serum pregnancy test and does not agree in writing to using a double barrier method of contraception.
- Female relying on menopausal status for contraception who does not have Follicle-Stimulating Hormone (FSH) level consistent with that condition and who does not agree in writing to using a double barrier method of contraception.
- Currently under correctional supervision (imprisoned, on probation or parole).
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Prevence
- Přidělení: Randomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Čtyřnásobek
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
|---|---|
|
Experimentální: High Dose ORC-13661
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. |
High-dose intervention (30mg daily) Low-dose intervention (12mg daily) |
|
Experimentální: Low Dose ORC-13661
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. |
High-dose intervention (30mg daily) Low-dose intervention (12mg daily) |
|
Komparátor placeba: Placebo
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. |
Placebo intervention |
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Mitigation or Prevention of Ototoxicity
Časové okno: Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.
|
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.
|
Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Mitigation or Prevention of hearing impairment with regards to speech perceptions
Časové okno: Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.
|
Outcome is measured by changes to patient's speech perceptions using the High Frequency Digits-in-Noise (HF-DIN) test |
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
Časové okno: Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.
|
Outcome is measured by changes to patient's tinnitus using the Modified-Tinnitus Ototoxicity Monitoring Interview (TOMI) |
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
Časové okno: Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.
|
Outcome is measured by changes to patient's Speech, Spatial and Quality of Hearing Scale (SSQ12) |
Baseline to 28 (±5) days after study treatment discontinuation or 28 days after 90 days of study treatment, whichever comes first.
|
Spolupracovníci a vyšetřovatelé
Sponzor
Spolupracovníci
Vyšetřovatelé
- Vrchní vyšetřovatel: Kevin L Winthrop, MD, MPH, Oregon Health and Science University
- Vrchní vyšetřovatel: Edwin Rubel, PhD, Oricula Therapeutics
Publikace a užitečné odkazy
Obecné publikace
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Carhart R, Jerger, J. Preferred method for clinical determination of pure-tone thresholds. J Speech Hear Disord. 1959; 24: 330-345.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
- Neurologické projevy
- Nemoci nervového systému
- Rány a zranění
- Patologické procesy
- Chemicky indukované poruchy
- Otorinolaryngologická onemocnění
- Poruchy vnímání
- Nemoci uší
- Vedlejší účinky a nežádoucí účinky související s léky
- Radiační zranění
- Poruchy sluchu
- Patologické stavy, příznaky a symptomy
- Příznaky a symptomy
- Ototoxicita
- Ztráta sluchu
- ORC-13661
Další identifikační čísla studie
- SOUNDS Trial
- U01DC020175 (Grant/smlouva NIH USA)
Plán pro data jednotlivých účastníků (IPD)
Plánujete sdílet data jednotlivých účastníků (IPD)?
Informace o lécích a zařízeních, studijní dokumenty
Studuje lékový produkt regulovaný americkým FDA
Studuje produkt zařízení regulovaný americkým úřadem FDA
produkt vyrobený a vyvážený z USA
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