| Eligibility |
Inclusion Criteria:
1. Subject reads and signs the Informed Consent Form (ICF) and agree to have bronchoscopy
with bronchoalveolar lavage under sedation or light anesthesia and comply with study
procedures.
2. Healthy male or non-pregnant, non-lactating female subjects 18 to 45 years of age
(both inclusive) at the time of dosing.
*Note 1: Determined by medical history (MH), medication use, physical examination
(PE), and vital signs, clinical laboratory tests and 12-lead ECG within reference
ranges at Screening and Day-2. (See Sections 8.1 and 8.2; and Appendix B, Table 2,
Table 3 and Table 4 and the study-specific MOP.)
Exceptions to BP, HR and laboratory test values being with normal ranges are:
- Abnormal HR and BP on first measurement may be repeated twice more with the
subject resting between measurements for at least 5 min according to Section
8.1.6.
- Subjects with baseline HR >/= 45 to 50 bpm may be accepted if otherwise healthy
adults with known history of asymptomatic bradycardia.
- Subjects with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be accepted
if otherwise healthy.
- A laboratory value that is Grade 1 will be allowed if not considered to be
clinically significant by the investigator, with the exception of ALT, AST, AP,
BUN, urine protein, serum creatinine or estimated glomerular filtration rate
(eGFR) <70 mL/min /1.73 m^2 by the Chronic Kidney Disease Epidemiology
collaboration (CKD-EPI) equation.
3. Female subjects of childbearing potential should use highly effective methods of
contraception from the time of screening to 30 days after dosing.
- Note 1: A female is considered of childbearing potential unless post-menopausal
(defined as history of >/=1 year of spontaneous amenorrhea and a FSH level >40
IU/L), or permanently surgically sterilized.
- Note 2: Highly effective contraceptive methods include: (a) surgical
sterilization methods, such as tubal ligation, bilateral oophorectomy,
salpingectomy, hysterectomy, or successful tubal obliteration (e.g., Essure(R))
with documented radiological confirmation test at least 90 days after the
procedure, or (b) long-acting reversible contraception, such as
progestin-releasing subdermal implants, copper intrauterine devices (IUDs),
levonorgestrel-releasing IUDs.
- Note 3: A subject who is not sexually active and abstains from sexual intercourse
can be enrolled and abstinence documented.
4. Males, including vasectomized men, having sexual intercourse with women of
childbearing potential must agree to consistent use of condoms from IMP administration
through at least 30 days after dosing, and must also agree to not donate sperm during
this same time period.
*Note: A subject who is not sexually active and abstains from sexual intercourse can
be enrolled and abstinence documented.
5. BMI 18.0 to 32.0 kg/m^2 (inclusive) and body weight not less than 50 kg.
6. Subjects with normal hearing, i.e., symmetric hearing with air conduction thresholds
no worse than 20 dB hearing loss for the frequencies 0.5-1-2-4-6-8 kHz bilaterally.
7. Normal (reproducibility 70% or better) of distortion product otoacoustic emissions
(DPOAEs).
*Note: Absence of DPOAEs at no more than two consecutive or non-consecutive DPOAEs in
each ear is acceptable.
8. Normal otoscopic findings in the ears, normal tympanic membrane mobility and stapedial
reflex present.
9. From the signing of the informed consent until the last follow-up visit, subjects must
be willing to avoid exposure to loud music or noise.
*Note: Noise avoidance to include continuous usage of earpieces at high volume,
attending loud concerts or dance events, or using firearms or attending fireworks.
10. Normal lung function with Forced Expiratory Volume in the first second (FEV1)
predicted >/= 80% and FEV1/Forced Vital Capacity (FVC) > 70%.
11. Subjects must be willing to avoid excessive physical exercise within 48 h prior to
dosing until discharge from the CTU on Day 3, and 24 h before each follow-up visit
(Day 14 +/- 3 days and Day 30 +/- 4 days).
12. No history of acute febrile or infectious illness for at least 7 days prior to the
administration of the IMP.
13. No history of lower respiratory tract infection within 4 weeks prior to screening.
14. Have adequate venous access for infusion and blood draws.
Exclusion Criteria:
All must be answered NO for the subject to be eligible for study participation:
1. Lactating females.
Medical and surgical history:
2. Any history of hypersensitivity to aminoglycosides.
3. Any history of drug hypersensitivity, asthma, urticaria or other severe allergic
diathesis.
4. Any history of seasonal allergies with ongoing symptoms for more than a week prior to
dosing requiring glucocorticoids and/or frequent use of antihistamines for treatment.
5. Any history of a chronic condition that may increase risk to subject or interfere with
endpoint assessment, or any unstable chronic disease.
- Note 1: Unstable chronic disease is defined by need for frequent medical
interventions that lead to a change in medications and/or required
hospitalization, surgery or an invasive procedure or emergency department/urgent
care visit.
- Note 2: Any chronic disease, that has been diagnosed within 90 days of screening
is excluded.
6. History of any psychiatric medical condition that has required hospitalization in the
last 5 years or subject is considered psychologically unstable by the investigator.
7. History of acute or chronic problems with hearing and/or balance in the last 24
months.
-Note: These include but not limited to use of hearing aid, head injury leading to
otologic damage, tumor of the head or neck, autoimmune disease of the inner ear,
tinnitus, vestibular disease, auditory neurinoma, endolymphatic hydrops and/or
Meniere's disease, perilymphatic fistula, otitis media, labyrinthitis, sudden hearing
loss, known retrocochlear hearing impairment, conductive hearing loss exceeding 10 dB
at any frequency, ear canal and/or middle ear disease including inflammation or
effusion, pathological tympanometry.
8. Past injury or surgery to the middle or inner ears.
-Note: Myringotomy or tympanic tube insertion in childhood with complete healing and
normal hearing test are excluded.
9. Family history of hearing loss before the age of 60.
10. Subjects who have had previous intolerance or contraindications to medications applied
for sedation or anesthesia during bronchoscopy.
-Note: These include benzodiazepines or topical anesthetic agents (lidocaine or
xylocaine) including reversal agents such as flumazenil.
Laboratory examinations:
11. Positive serum pregnancy test for women at screening or urine pregnancy test at
check-in.
12. Positive test for HIV antibodies, hepatitis B-virus surface antigen (HBsAg), or
anti-hepatitis C-virus antibodies (anti-HCV).
Prior medication:
13. Use of any prescription or non-prescription medication prior to the dose of IMP
-Note: Exceptions are hormonal contraceptives, which are permitted throughout the
study, and solitary doses of up to 1,000 mg paracetamol.
14. Use of any investigational drug product within 30 days or 5 half-lives (whichever is
longer) before dosing.
15. Planned participation in a clinical research study that requires treatment with a
study drug or blood draws or other invasive assessments during the study period
(screening until final visit).
Lifestyle restrictions:
16. More than low-risk alcohol consumption (men: >/= 24 g of pure alcohol regularly per
day; women: >/=12g of pure alcohol regularly per day) for the previous 3 months.
17. Any history of alcohol or drug abuse or positive alcohol breathalyzer test.
18. Suspicion of illicit drug use / abuse or positive urine drug screen test.
19. History of >/=10 pack-years smoking, or history of any nicotine use in the 6 months
before check-in (Day -2) or positive urine cotinine screen at check-in.
- Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing
tobacco, nicotine patch.
- Note 2: A positive urine cotinine at screening is allowed if negative at check-in
(Day -2).
20. Caffeinated beverages/foods are prohibited within 48 hours before dosing to Day 3 of
the trial. During the follow up period, consumption is restricted to not more than 3
cups or equivalent per day.
21. Judged by the investigator to have occupational noise exposure of high risk during the
trial (e.g., construction site workers, military workers, etc.).
22. Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days
before signing informed consent or planned donation prior to completion of this trial.
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