Preventing hearing loss in patients with NTM treated with amikacin

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

This study is testing whether a new drug called ORC-13661 can help prevent hearing loss in patients with nontuberculous mycobacterial infections who are being treated with amikacin.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 105 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: Oregon Health and Science University (Academic / other)
• Locations: 7 sites (San Francisco, California and 6 other locations)
• Trial ID: NCT05730283 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effectiveness of ORC-13661 in preventing hearing loss in patients with nontuberculous mycobacterial (NTM) infections undergoing treatment with IV amikacin. Participants will be randomly assigned to receive either a high dose, low dose of ORC-13661, or a placebo for 90 days or until their amikacin treatment ends. The study will assess the drug's ability to mitigate ototoxicity and other measures of hearing impairment. A total of 105 participants will be enrolled across five sites, and the trial will follow a double-blind, placebo-controlled design.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 to 80 with a confirmed NTM infection requiring systemic aminoglycoside therapy.

Not a fit: Patients who are not undergoing treatment with IV amikacin or those with contraindications to the study drug will not benefit from this study.

Why it matters

Potential benefit: If successful, this study could significantly reduce the incidence of hearing loss in patients receiving amikacin therapy for NTM infections.

How similar studies have performed: While the approach of using adjunct therapies to mitigate ototoxicity is not novel, the specific application of ORC-13661 in this context is being tested for the first time.

Eligibility criteria

Inclusion Criteria:

1. Providing informed consent, documented by signing and dating the currently valid informed consent form.
2. Considered by the Investigator to have unimpaired consent capacity, without reliance on a legally authorized representative.
3. Stated willingness and ability to comply with study procedures and availability for the duration of the study.
4. Aged \> 18 and \< 80.
5. 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.
6. Anticipated duration of IV amikacin treatment of at least 30 days at time of study entry.
7. Statement of ability to take oral medication and adhere to the daily dosing regimen.
8. 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.
9. 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:

1. Received a systemic aminoglycoside antibiotic within 6 months prior to planned first dose of amikacin.
2. ECG at Screening or prior to randomization (mean of triplicate values) with QT interval corrected using Fridericia's formula (QTcF interval) ≥ 450 msec.
3. ECG at Screening or prior to randomization with abnormalities that, in the Investigator's judgment, might predispose patient to clinically significant arrhythmia.
4. 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.
5. 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.
6. 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.
7. Patients with amikacin exposure within the 6 months prior to randomization.
8. Patients with known amikacin resistance (MIC \>64)
9. 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.
10. 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.
11. History of congenital hearing loss, otological surgery (excluding myringotomy tubes or simple tympanoplasty healed and currently intact), sudden hearing loss, or Meniere's disease.
12. Bilateral profound hearing loss (\>90 Decibels \[dB\] HL) at all test frequencies.
13. Conductive hearing loss evidenced by average air-bone-gaps \>15 dB HL for 0.25-4.0 kilohertz (kHz)
14. History of active malignancy, either untreated or under active treatment.
15. History of risk factors for Torsades des Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
16. Venous access not adequate for performance of study procedures.
17. 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.
18. Current or anticipated use of excluded concomitant medications as specified in Section 6.5.
19. Pregnant or lactating.
20. 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.
21. 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.
22. Currently under correctional supervision (imprisoned, on probation or parole).

Where this trial is running

San Francisco, California and 6 other locations

• University of California, San Francisco — San Francisco, California, United States (Recruiting)
• National Jewish Health — Denver, Colorado, United States (Recruiting)
• Johns Hopkins University — Baltimore, Maryland, United States (Not_yet_recruiting)
• Mayo Clinic — Rochester, Minnesota, United States (Recruiting)
• Oregon Health & Science University — Portland, Oregon, United States (Recruiting)
• Medical University of South Carolina — Charleston, South Carolina, United States (Recruiting)
• University of Texas Health Science Center — Tyler, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Kevin L Winthrop, MD, MPH — Oregon Health and Science University
• Study coordinator: Daniel Bouchat

Conditions Ototoxicity, Drug-Induced; NTM; nontuberculous mycobacteria; ototoxicity; hearing loss