Prevention of Ototoxicity in NTM Patients Treated With IV Amikacin

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 2 Study of the Efficacy and Safety of ORC-13661 for the Prevention of Drug-Induced Hearing Loss in Patients Receiving Intravenous Amikacin for Treatment of Non-Tuberculous Mycobacterium Disease

Conditions
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Ototoxicity, Drug-Induced

Intervention / Treatment
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* Drug: ORC-13661
* Drug: ORC-13661
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose ORC-13661<br>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<br>* High-dose intervention (30mg daily)<br>|
| Experimental: Low Dose ORC-13661<br>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<br>* Low-dose intervention (12mg daily)<br>|
| Placebo Comparator: Placebo<br>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<br>* Placebo intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitigation or Prevention of hearing impairment with regards to speech perceptions | 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 | 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 | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NTM, nontuberculous mycobacteria, ototoxicity, hearing loss