First-In-Human Study of Apramycin

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Apramycin Administered Intravenously in Healthy Adults.

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Apramycin injection
* Drug: Placebo injection


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apramycin injection in escalating doses<br>Apramycin, solution for infusion. | Drug: Apramycin injection<br>* 30-min infusion<br>|
| Placebo Comparator: Placebo<br>Physiological saline, solution for infusion. | Drug: Placebo injection<br>* 30-min infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Type and incidence of treatment-emergent adverse events (TEAEs) until 2 weeks after dosing. |  | until 2 weeks after dosing | 
| Type and incidence of TEAEs related to auditory and vestibular function tests. |  | until 3 months after dosing | 
| Number of subjects with clinically significant vital sign measurement blood pressure. | Frequency is defined as number of subjects with clinically significant observations. | until 2 weeks after dosing | 
| Number of subjects with clinically significant vital sign measurement pulse rate. | Frequency is defined as number of subjects with clinically significant observations. | until 2 weeks after dosing | 
| Number of subjects with clinically significant observation in physical examination. | Frequency is defined as number of subjects with clinically significant observations. | until 2 weeks after dosing | 
| Number of subjects with clinically significant changes in clinical laboratory parameters. | Frequency is defined as number of subjects with clinically significant observations. | until 2 weeks after dosing | 
| Number of subjects with clinically significant changes in ECG parameters. | ECG parameters include heart rate and PQ, QT, RS. Frequency is defined as number of subjects with clinically significant observations. | until 2 weeks after dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-Bacterial Agents