First-In-Human Study of Apramycin

This is a first-in-human study to assess the safety, tolerability and pharmacokinetics of escalating single doses of apramycin. This trial will be conducted as a single ascending dose trial in up to 5 sequential dose cohorts (group-comparison). Each cohort will consist of 8 healthy subjects, 6 will receive apramycin and 2 placebo.


Eligibility Criteria:
Inclusion Criteria:

* Healthy male and female subjects of non-childbearing potential, 18-45 years of age (both inclusive), body mass index 18.0 - 29.9 kg/m2 (inclusive) and body weight from 50 to 100 kg (inclusive).
* Glomerular filtration rate (GFR) ≥ 90 mL/min /1.73 m2.
* Subjects with systemic hearing, with air conduction thresholds no worse than 20 decibels (dB) hearing loss for the frequencies 0.5-1-2-4-6-8 kilohertz (kHz) bilaterally and, no threshold asymmetry ≥ 20 dB at any frequency, normal (reproducibility 70% or better) transient evoked otoacoustic emissions (TEOAE).
* From the signing of the informed consent until the last follow-up visit, subjects must be willing to avoid exposure to loud noise and Subjects must be willing to avoid excessive physical exercise within 48 h prior to dosing.
* Normal blood pressure and pulse rate, ECG recording without clinically significant abnormalities.
* Thyroid-stimulating hormone, free triiodothyronine and free thyroxine within the reference ranges.
* Having had no febrile or infectious illness for at least 7 days prior to the first administration of the Investigational medicinal product (IMP) of the study.
* Normal microscopic findings in the ears, normal tympanic membrane mobility and stapedial reflex present.

Exclusion Criteria:

* Vegetarian or vegan.
* Demonstrating excess in xanthine consumption.
* More than low-risk alcohol consumption (men: ≥24 g of pure alcohol regularly per day; women: ≥12 g of pure alcohol regularly per day).
* Any history of alcohol or drug abuse or a positive urine drug screen test. Positive alcohol breath test.
* Consumption of xanthine-containing food or beverages within 48 h before dosing.
* Smokers smoking more than 10 cigarettes or equivalent per day.
* Exposure to loud noise within 3 days prior to drug administration.
* Taking any medication on a regular basis, with the exception of solitary doses of up to 1000 mg paracetamol.
* Use of any investigational drug product within 30 days or 5 half-lives before screening.
* Use of aminoglycosides or other antibiotics within 3 months prior to screening.
* Use of neuromuscular blocking agents within 1 week or 5 half-lives prior to screening.
* Use of potentially nephrotoxic medication 2 weeks prior to the drug administration.
* Any history of drug hypersensitivity, asthma, urticaria or other severe allergic diathesis as well as hay fever with ongoing symptoms.
* Any history of hypersensitivity to aminoglycosides.
* Any history or signs of acute, chronic or recurrent metabolic, renal, hepatic, pulmonary, gastrointestinal, neurological, neuromuscular disorders, endocrinological, immunological, psychiatric or cardiovascular disease, myopathies, and bleeding tendency.
* Problems with hearing and/or balance.
* Previous injury or surgery to the middle or inner ears, family history of hearing loss before the age of 60.
* Genetic predisposition to aminoglycoside-driven ototoxicity.
* Laboratory values outside the reference range that are of clinical relevance.
* Positive test for HIV antibodies, hepatitis B-virus surface antigen, or anti-hepatitis C-virus antibodies.
* Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days before signing an informed consent to this trial.
* Judged by the investigator to have occupational noise exposure of high risk during the trial.
* Positive test for SARS-CoV-2.